Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[N:7]([CH2:15][C:16]([OH:18])=[O:17])[C:6]2=[O:19].C(Cl)CCl.[Cl:24][C:25]1[CH:26]=[N+:27]([O-:50])[CH:28]=[C:29]([Cl:49])[C:30]=1[CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:24][C:25]1[CH:26]=[N+:27]([O-:50])[CH:28]=[C:29]([Cl:49])[C:30]=1[CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)[O:17][C:16](=[O:18])[CH2:15][N:7]1[C:6](=[O:19])[C:5]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:14]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1cc2c(cc1OC)C(=O)N(CC(=O)O)C2=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Reaction time: 4 h
Yield: 41 %

Procedure:
To a suspension of 2-(5,6-dimethoxy-1,3-dioxoisoindolin-2-yl)acetic acid (151 mg, 0.571 mmol) in DCM (25 ml), DMAP (69.8 mg, 0.571 mmol), EDC (274 mg, 1.428 mmol) and (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (200 mg, 0.476 mmol) were added in one portion at room temperature, and the resulting mixture was stirred for 4 hours. The solution was diluted with DCM (40 ml) and washed with a saturated solution of NaHCO3 (40 ml), with 1N HCl (30 ml) and finally with brine (30 ml). The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. The crude was purified by crystallization from ethyl acetate (40 ml) to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5,6-dimethoxy-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide as a white solid (130 mg, 0.195 mmol, 40.9% yield). MS/ESI+ 667.16 [MH]+; [αD]=−42.80, c=0.25, DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.43 (s, 2H), 7.43 (s, 2H), 7.19 (d, 1H), 7.02-7.13 (m, 1H), 6.96 (dd, 1H), 7.08 (t, 1H), 6.01 (dd, 1H), 4.37 (s, 2H), 3.96 (s, 6H), 3.92 (d, 2H), 3.39 (dd, 1H), 3.22 (dd, 1H), 1.12-1.34 (m, 1H), 0.52-0.67 (m, 2H), 0.29-0.46 (m, 2H).
Reaction SMILES: [CH2:1]([OH:10])[C@@H:2]([C@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.S(=O)(=O)(O)O.Cl[CH:26]=[C:27]([Cl:29])Cl>O1CCOCC1>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:8]([OH:9])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]([OH:3])[C:1](=[CH:18][C:15]2[CH:14]=[CH:13][C:27]([Cl:29])=[CH:26][CH:16]=2)[OH:10])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: ClC=C(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: OC(=Cc1ccc(Cl)cc1)[C@@H](O)[C@H](O)[C@@H](O)C(O)=Cc1ccc(Cl)cc1
Yield: 92 %

Procedure:
A powdery reaction mixture is obtained in the same manner as in Example 8 with the exception of using 24.0 g of xylitol, 41.5 g of p-chlorobenzaldehyde, 0.5 g of 50% sulfuric acid, 60 ml of trichloroethylene and 18 ml of dioxane. The mixture is similarly after-treated, affording di-(p-chlorobenzylidene)xylitol in a yield of 92% with a purity of 97%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Br:16].[Cl:17][CH:18]([Cl:22])[C:19]([OH:21])=[O:20]>>[Br:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:18]([Cl:22])([Cl:17])[C:19]([OH:21])=[O:20]
Reactant: BrCCCCCCCCCCCCCCBr
Reactant: O=C(O)C(Cl)Cl
Product: O=C(O)C(Cl)(Cl)CCCCCCCCCCCCCCBr

Procedure:
Analogously to example 1 from 2.0 g (5.6 mmol) 1,14-dibromotetradecane and 2.3 g (22.5 mmol) dichloroacetic acid. Yield 0.58 g (23%), melting point 61-63° C.
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4](Cl)[CH:3]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>CN1C(=O)CCC1.O>[NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[CH:3]=1
Reactant: c1c[nH]cn1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1cc(-n2ccnc2)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1 mmol; see Example 154) in NMP (2 mL) was added with imidazole (5 mmol). The resulting mixture was subjected to microwave irradiation at 120° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with water (30 mL). The solid formed was collected by filtration, washed with water, and dried in vacuo. The product, 4-amino-2-imidazol-1-yl-N-(1H-indazol-6-yl)-5-nitro-benzamide, obtained as a yellow solid was used without any purification.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)=[O:3].O1CCOCC1.[Br:24]Br>[Cl-].[Al+3].[Cl-].[Cl-].O1CCCC1>[Br:24][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Yield: 76 %

Procedure:
After dissolving 4.0 g of 4-benzyloxyacetophenone into 20 ml of 1,4-dioxane and 20 ml of tetrahydrofuran, 0.1 g of anhydrous aluminum chloride and 3.1 g of bromine were added under ice cooling and stirring. Further, after stirring for 5 hours under ice cooling, the reaction solution was concentrated to solid. Water and chloroform were added to the residue to separate liquid layers. Then, the chloroform layer was dried over anhydrous sodium sulfate and then concentrated to solid followed by purification by silica gel column chromatography using benzene/n-hexane (1:1) as an elute, to obtain 4.1 g of 2-bromo-1-(4-benzyloxy-phenyl)-ethanone. Then, using 3.0 g of the thus obtained bromide, 2.2 g of (Z)-2-(4-methyl-piperazin-1-yl)-1-(4-benzyloxy-phenyl)-ethanone oxime hydrochloride with the melting point of from 208° to 210° C. (decomposition) and 0.7 g of (E)-2-(4-methyl-piperazin-1-yl)-1-(4-benzyloxy-phenyl)-ethanone oxime hydrochloride with the melting point of from 210° to 212° C. were obtained in the same manner as in Example 1.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:14]O>>[C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([O:10][CH3:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: CCC(C(=O)O)c1ccccc1
Agent: Cl
Product: CCC(C(=O)OC)c1ccccc1
Temperature: 25 °C

Procedure:
2-Phenylbutyric acid (10 g, 61 mmole) was dissolved in methanol (30 ml) treated with concentrated HCl (1 ml) and heated at reflux for 20 hours. The heating was stopped and the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the oily residue was treated with ethyl acetate (100 ml). The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a clear oil. Yield 10.61 g (97%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.81 (t, J=7.35 Hz, 3 H) 1.69 m, 1 H) 1.98 (m, 1 H) 3.53 (d, J=7.35 Hz, 1 H) 3.58 (s, 3 H) 7.30 m, 5 H).
Reaction SMILES: CC(C)C([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12]C(=O)C(C)C)[O:9][C@@H:8]([N:18]2[C:22]3[N:23]=[C:24]([NH:29]C=O)[N:25]=[C:26]([O:27]C)[C:21]=3[C:20]([I:32])=[CH:19]2)[CH2:7]1)=O>CC#N>[NH2:29][C:24]1[NH:25][C:26](=[O:27])[C:21]2[C:20]([I:32])=[CH:19][N:18]([C@@H:8]3[O:9][C@H:10]([CH2:11][OH:12])[C@@H:6]([OH:5])[CH2:7]3)[C:22]=2[N:23]=1
Reactant: COc1nc(NC=O)nc2c1c(I)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Solvent: CC#N
Product: Nc1nc2c(c(I)cn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1

Procedure:
The title compound (58) is prepared in analogy with Example 51 by proceeding from compound (46) (200 mg, 0.35 mmol). Colorless crystals (126 mg, 92%) are obtained from MeCN. Melting point: 218-220° C. UV (MeOH): λmax 266 (12,000), 285 (sh, 8400). 1H-NMR ([D6] DMSO): δ=2.08 (m, Hα—C(2′)), 2.30 (m, Hβ—C(2′)), 3.48 (m, H—C(5′)), 3.74 (m, H—C(4′)), 4.26 (m, H—C(3′)), 4.89 (t, 5′-OH), 5.18 (d, 3′-OH), 6.25 (dd, H—C(1′)), 6.34 (br., NH2), 7.09 (s, H—C(6)), 10.51 (br., NH). Anal. calculated for C11H13IN4O4 (392.2): C 33.69, H 3.34, N 14.29; found: C 33.78, H 3.42, N 14.29.
Reaction SMILES: C(OC([NH:11][CH2:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:19]=2)[CH2:14]1)=O)C1C=CC=CC=1.O.C(=O)([O-])[O-].[K+].[K+].[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CO.[C].[Pd]>[C:35]1([S:41]([NH:11][CH2:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:19]=3)[CH2:14]2)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)Cc1ccc2c(c1)CC(CNC(=O)OCc1ccccc1)C2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOC(=O)Cc1ccc2c(c1)CC(CNS(=O)(=O)c1ccccc1)C2
Reaction time: 2 h
Yield: 97 %

Procedure:
Dissolved in 30 ml of methanol were 1.80 g (4.90 mmol) of ethyl [2-(benzyloxycarbonylaminomethyl)indan-5-yl]acetate, and 500 mg of 10% palladium-carbon were added to the solution, followed by stirring for 2 hours under a hydrogen atmosphere. The catalyst was separated by filtration, and the filtrate was concentrated. The resultant residue was dissolved in 15 ml of ethyl acetate, and 10 ml of water and 1.18 g (8.51 mmol) of potassium carbonate were added to the solution. While vigorously stirring, 902 mg (5.11 mmol) of benzenesulfonyl chloride were then added dropwise. After the addition, the mixture was stirred for 1 hour, and an organic layer separated was taken out, dried and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform) to obtain 1.78 g of a colorless oily substance. Yield: 97%.
Reaction SMILES: FC1C=C(F)C=CC=1C(Cl)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([F:34])[CH:28]=1.[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44]>C1(C)C=CC=CC=1.C(O)C>[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44].[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[C:43]([NH:45][C:46]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][C:17]2[C:16]3[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=3)[N:20]=[CH:19][CH:18]=2)=[CH:28][C:29]=1[F:34])=[S:47])=[O:44]
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1F
Agent: O=C(N=C=S)c1ccc(F)cc1F
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4F)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
2,4-Difluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-difluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-difluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (56 mg, yield 68%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:29][O:30][C:31](=[O:44])[CH:32]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:34]Br>CN(C=O)C.C(OCC)(=O)C>[CH3:29][O:30][C:31](=[O:44])[CH:32]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:34][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:15]([O:14][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:16])=[CH:23][CH:24]=1
Reactant: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Reactant: COC(=O)C(CCBr)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(CCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 14 h
Yield: 82.6 %

Procedure:
Potassium carbonate (935 mg, 6.77 mmol) was added in one portion to a solution of 4-[4-(benzyloxycarbonylamino)butyl]phenol (506 mg, 1.69 mmol) and N-Boc bromide 30 (501 mg, 1.69 mmol) in anhydrous DMF (10 mL). The reaction mixture was stirred at 70° C. (oil bath) for 14 h, cooled to room temperature, and diluted with ethyl acetate (100 mL) and hexanes (20 mL). The mixture was washed with water (4×20 mL) and brine (40 mL) and concentrated under reduced pressure. Flash silica gel column chromatography using ethyl acetate/CH2Cl2 (1:25, 1:20, v/v) gave the desired product 31 as a thick yellow oil (718 mg, 83% yield). 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.48-1.68 (m, 4H), 2.12-2.38 (m, 2H), 2.48-2.60 (m, 2H), 3.10-3.24 (m, 2H), 3.75 (s, 3H), 3.97-4.06 (m, 2H), 4.41-4.52 (m, 1H), 4.70 (br s, 1H), 5.09 (s, 2H), 5.25-5.37 (m, 1H), 6.70-6.80 (m, 2H), 6.95-7.09 (m, 2H), 7.30-7.38 (m, 5H). m/z (ESI) 515 [C28H38N2O7+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C@@H:6]([O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[C:24]([CH3:36])[CH:23]=1)=[N:14][CH:15]=[N:16]2)[CH2:7][NH:8][CH3:9].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:9][N:8]([CH2:7][C@H:6]([O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[C:24]([CH3:36])[CH:23]=1)=[N:14][CH:15]=[N:16]2)[CH3:5])[C:1](=[O:3])[CH3:2]
Reactant: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
Acetyl chloride (24 μl, 0.33 mmol) was added drop wise to a solution of 5-[(1R)-1-methyl-2-(methylamino)ethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (129 mg, 0.30 mmol, obtained as described in Example 103, preparation of starting materials) and DIPEA (105 μl, 0.6 mmol) in DCM (5 ml). The mixture was stirred at room temperature for 2 hours and diluted with DCM. The solution was washed with water and brine, and dried over MgSO4. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 2 to 4% methanol in DCM) to give the title compound (84 mg, 60%) as a pale solid; NMR spectrum (CDCl3) 1.55 (d, 3H), 2.08 (s, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 3.08 (s, 3H), 3.56 (dd, 1H), 3.93 (dd, 1H), 5.09 (m, 1H), 6.92 (d, 1H), 7.12 (m, 3H), 7.50 (m, 2H), 7.65 (m, 1H), 7.70 (s, 1H), 8.27 (s, 1H), 8.62 (s, 1H); Mass spectrum: MH+ 472.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C(N(CC)CC)C.[CH3:19][Si:20]([CH3:23])([CH3:22])Cl>C(#N)C>[CH3:19][Si:20]([CH3:23])([CH3:22])[N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: C[Si](C)(C)Cl
Reactant: O=C1NC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)N1C(=O)c2ccccc2C1=O

Procedure:
250 g (1.7 moles) of phthalimide were suspended in 2.75 liter of acetonitrile and after 250 ml (1.8 moles) of triethylamine were added, the mixture was heated to gentle reflux. 250 ml (1.97 moles) of trimethylchlorosilane were added in 10 minutes and the reaction mixture was then concentrated to a thick paste. 2.5 liter of light petroleum (80°-110° C) were added, the triethylammonium hydrochloride was filtered off and washed with 500 ml of light petroleum. The filtrate ans washings were combined and concentrated until crystallization started. After cooling in the refrigerator for several hours, N-trimethylsilylphthalimide was isolated by filtraton, washed with a small portion of light petroleum (40°-60° C) and dried in vacuo. The compound was further purified by recrystallization from ligroin (80°-100° C). PMR: 0.51 (s, 9); 7.73 (centre of super imposed signals, 4).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.[C:17]([O:20][CH2:21][CH2:22]Br)(=[O:19])[CH3:18].O>CN(C)C=O>[C:17]([O:20][CH2:21][CH2:22][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=1)(=[O:19])[CH3:18]
Reactant: CCOC(=O)C=Cc1ccc(O)cc1
Reactant: CC(=O)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(OCCOC(C)=O)cc1
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a suspension of sodium hydride (60% active, 124 mg) in dimethylformamide (2 ml) at ambient temperature was added ethyl 4-hydroxycinnamate (500 mg) under nitrogen, and the mixture was stirred for 1 hour. 2-Bromoethyl acetate (522 mg) was added to the mixture at same temperature, and the mixture was allowed to stand for 19 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with chloroform to give ethyl 4-(2-acetoxyethoxy)cinnamate (716 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:33])[CH2:19][CH2:20][N:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)[CH3:22].[C:34](N1C=CN=C1)(N1C=CN=C1)=[O:35]>>[CH3:11][O:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]2[NH:1][C:34](=[O:35])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH3:33])[CH2:19][CH2:20][N:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=3)[CH3:22])[CH2:13][CH2:12][C:3]=2[CH:4]=1
Reactant: COc1ccc(N(C)CCN(C)CCCNCCc2cc(OC)c(OC)cc2N)cc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Product: COc1ccc(N(C)CCN(C)CCCN2CCc3cc(OC)c(OC)cc3NC2=O)cc1OC

Procedure:
The title compound is prepared from N-[3-(2-(2-amino-4,5-dimethoxyphenyl)-ethylamino)-propyl]-N-[2-(N-methyl-3,4-dimethoxy-phenylamino)-ethyl]-methylamine and carbonyldiimidazole analogously to Example 56.
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10].Cl.[NH2:19][C@H:20]([C:24]([NH:26][CH:27]([C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)=[O:30])[CH3:28])=[O:25])[CH:21]([CH3:23])[CH3:22].O>C(Cl)Cl>[O:11]([C:9]([NH:19][C@H:20]([C:24]([NH:26][CH:27]([C:29]([NH:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)=[O:30])[CH3:28])=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(NC(=O)[C@@H](N)C(C)C)C(=O)NCc1ccc(Cl)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CC(NC(=O)[C@@H](NC(=O)Oc1ccccc1)C(C)C)C(=O)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.4 %

Procedure:
0.55 g of N-methyhnorpholine, and subsequently 0.43 g of phenyl chloroformate were added to a suspension containing 0.95 g of L-valyl-N-(4-chlorobenzyl)-DL-alaninamide, hydrochloride suspended in 50 ml of methylene chloride at -15° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.9 g of the desired product in the form of white powder (yield: 75%).
Reaction SMILES: [CH:1]([C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1)=O.[C:11]1([C@@H:21]([NH2:23])[CH3:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.[C-:24]#[N:25].[K+].S([O-])(O)=O.[Na+]>C(O)C.O>[C:24]([CH:1]([NH:23][C@H:21]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:22])[C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1)#[N:25]
Reactant: [C-]#N
Reactant: CCOC(=O)C1(C=O)CC1
Reactant: C[C@H](N)c1cccc2ccccc12
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(C(C#N)N[C@@H](C)c2cccc3ccccc23)CC1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 72.2 %

Procedure:
An eggplant type flask was charged with 426 mg of ethyl 1-formylcyclopropane-1-carboxylate to which were further added 771 mg of (S)-1-(1-naphthyl)ethylamine dissolved in 5 ml of ethanol, 293 mg of potassium cyanide dissolved in 2 ml of water and 937 mg of sodium hydrogen sulfite in that order at 0° C. The reaction system was stirred for 3.5 hours at 50° C. After confirming completion of the reaction, the reaction solution was mixed with ice water and extracted with ethyl acetate. Next, the resulting organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate and, after removing insoluble matter by filtration, the solvent was evaporated under a reduced pressure. Thereafter, the resulting residue was subjected to a silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain 698 mg (72%) of a diastereomer mixture in the form of colorless oil. Formation ratio of the two diastereomers was calculated under the following analytical conditions.
Reaction SMILES: CN(C)C=O.[Na].[C:7]([O:10][CH2:11][C:12]1[CH2:19][S:18][CH:17]2[N:14]([C:15](=[O:21])[CH:16]2[NH2:20])[C:13]=1[C:22]([OH:24])=[O:23])(=[O:9])[CH3:8].Cl[CH2:26][O:27][C:28](=[O:31])[CH2:29][CH3:30]>C(OCC)(=O)C>[C:28]([O:27][CH2:26][O:23][C:22]([C:13]1[N:14]2[CH:17]([S:18][CH2:19][C:12]=1[CH2:11][O:10][C:7](=[O:9])[CH3:8])[CH:16]([NH2:20])[C:15]2=[O:21])=[O:24])(=[O:31])[CH2:29][CH3:30]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: CCC(=O)OCCl
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(=O)OCOC(=O)C1=C(COC(C)=O)CSC2C(N)C(=O)N12
Reaction time: 3 h

Procedure:
To 35 ml of dimethyl formamide is added 7.5 g of the sodium salt of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, and the solution is stirred at room temperature for about 30 minutes after which 8 ml of chloromethylpropionate is added. Stirring is continued at room temperature for about 3 hours. The mixture is dilutedwith ethyl acetate and washed with water. The organic layer is separated and evaporated to dryness. The residue is recrystallized from ethyl acetate to give 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid propionyloxymethyl ester.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[K+].CO.C(O)C>O>[CH2:1]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Yield: 90.3 %

Procedure:
A mixture of 120 g of methyl p-(tetradecyloxy)benzoate, 57.96 g of potassium hydroxide, 1-liter of methyl alcohol, 400 ml of ethyl alcohol and 60 ml of water is refluxed for 4.5 hours. A solid is formed and the reaction mixture partitioned between dilute hydrochloric acid and chloroform with some warming. The organic layer is washed with warm dilute hydrochloric acid and dried. The filtrate is evaporated to a volume of 600 ml and an equal volume of hexanes added to form a solid which is dried to give 104 g of the desired product as a white solid, m.p. 94°-96° C.