Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:6])=[CH:3][CH2:4]Cl.[C:7]([O-:16])(=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13].[K+].[K+].[I-].[K+]>C(N(CC)CC)C>[Cl:1][CH:2]([Cl:6])[CH:3]=[CH:4][O:13][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([O:16][CH:4]=[CH:3][CH:2]([Cl:6])[Cl:1])=[O:15]
Reactant: ClCC=C(Cl)Cl
Reactant: O=C([O-])CCCCC(=O)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: O=C(CCCCC(=O)OC=CC(Cl)Cl)OC=CC(Cl)Cl

Procedure:
62 g of 1,1,3-trichloro-propene, prepared according as described in Example 1, were reacted with 36.6 g of potassium adipate for 6 hours at 135° C. in the presence of 2 g of triethylamine and 0.3 g of potassium iodide. The reaction product was then washed and freed of the low-boiling components by means of distillation under vacuum. By a successive molecular distillation (120° C./10-4 mm Hg) 47 g of a substance were obtained which on elementary analysis showed the following composition:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:13])[CH:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].O.B([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH3:14][C:3]1[CH:4]=[C:5]([C:8]2[N:9]([CH3:13])[CH:10]=[CH:11][N:12]=2)[CH:6]=[CH:7][C:2]=1[C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(-c2nccn2C)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2nccn2C)ccc1-c1ccc(C(=O)O)cc1
Yield: 88.7 %

Procedure:
2-(4-Bromo-3-methylphenyl)-1-methylimidazole (D89, 600 mg, 2.39 mmol) was dissolved in dimethoxyethane (15 ml) and H2O (15 ml) and treated with 4-boronobenzoic acid (397 mg, 2.39 mmol), sodium carbonate (1.01 g, 9.56 mmol), tetrakis (triphenylphosphine)palladium (O) (60 mg) and heated at reflux for 36 hours. The dimethoxyethane was removed in vacuo, the aqueous residue treated with 10% Na2CO3 (approx. 10 ml) and washed with ethyl acetate. The aqueous phase was acidified with 5N HCl and the solid that formed collected by filtration and dried in vacuo to yield the title compound as an off-white solid (620 mg, 89%).
Reaction SMILES: C[O-].[Na+].[Cl:4][CH2:5][C:6]1([CH3:24])[O:10][N:9]=[C:8]([S:11][CH2:12][C:13]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][N:16]([CH3:19])[C:17]=2F)[CH2:7]1.O.[C:26](OCC)(=[O:28])C>CO>[Cl:4][CH2:5][C:6]1([CH3:24])[O:10][N:9]=[C:8]([S:11][CH2:12][C:13]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][N:16]([CH3:19])[C:17]=2[O:28][CH3:26])[CH2:7]1
Reactant: CCOC(C)=O
Reactant: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(CSC2=NOC(C)(CCl)C2)c(C(F)(F)F)nn1C

Procedure:
0.9 g (4.4 mmoles) of sodium methoxide (in the form of a 28% methanol solution) was added, at room temperature, into a solution of 1.0 g (2.9 mmoles) of 5-chloromethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline dissolved in 10 ml of methanol. The mixture was heated for refluxing for 5 hours, to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order, and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 3.3 g (yield: quantitative) of 5-chloromethyl-3-(5-methoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmeth-ylthio)-5-methyl-2-isoxazoline.
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5OCC[O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.OC1C=C(NC2N=C(NC3C=CC=C(O)C=3)C(Br)=CN=2)C=CC=1.[CH2:58]1[O:66]C2C=CC(B(O)O)=CC=2[O:59]1>>[OH:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:28])[CH:20]=3)[C:15]([C:29]3[CH:34]=[CH:33][C:32]4[O:59][CH2:58][O:66][C:31]=4[CH:30]=3)=[CH:14][N:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: Oc1cccc(Nc2ncc(Br)c(Nc3cccc(O)c3)n2)c1
Product: Oc1cccc(Nc2ncc(-c3ccc4c(c3)OCO4)c(Nc3cccc(O)c3)n2)c1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine, N2,N4-bis(3-hydroxyphenyl)-5-bromo-2,4-pyrimidinediamine and 3,4-methylenedioxyphenylboronic acid were reacted to yield N2,N4-bis(3-hydroxyphenyl)-5-(3,4-methylenedioxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.82 (s, 1H), 7.13–7.06 (m, 3H), 7.04–7.01 (m, 2H), 6.97 (dt, 1H, J=1.2 and 8.7 Hz), 6.94–6.88 (m, 3H), 6.52 (ddd, 1H, J=1.2, 2.4, and 6.9 Hz), 6.42 (dt, 1H, J=2.1 and 7.5 Hz), 6.01 (s, 2H); LCMS: ret. time: 21.11 min.; purity: 99%; MS (m/e): 415 (MH+).
Reaction SMILES: [CH2:1]([P:5]([O:10][CH2:11][CH3:12])(=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH:3][CH3:4].O1CCCC1.C([Li])CCC.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>Cl.CCCCCC>[CH2:23]([CH:1]([P:5]([O:6][CH2:7][CH3:8])(=[O:9])[O:10][CH2:11][CH3:12])[CH:2]=[CH:3][CH3:4])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC=CCP(=O)(OCC)OCC
Reactant: ClCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC=CC(Cc1ccccc1)P(=O)(OCC)OCC
Temperature: -70 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
1.92 g of diethyl 2-butenephosphonate was placed in 10 ml. of dry tetrahydrofuran, and the solution was cooled to -70° C. in an atmosphere of argon. 7 ml. of n-butyl lithium (as a 15% by weight n-hexane solution) was gradually added, and the mixture was stirred at -70° C. for 1 hour. The reaction mixture was turbid assuming a pale yellow color. When 1.7 g of benzyl chloride was added to this mixture, it became clear. The temperature of the reaction mixture was gradually elevated to room temperature, and it was stirred for an additional 2 hours. The reaction mixture was then diluted with dilute hydrochloric acid, and extracted with ether. The extract was washed with a solution of sodium hydrogen carbonate, washed with water, and dried. The solution was concentrated, and then the residue was distilled at reduced pressure to afford 2.33 g of diethyl 1-benzyl-2-butenephosphonate having a boiling point of 144° C. (0.3 mmHg) in a yield of 93%. The analysis values of the product were as follows:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:17][C:18](=[O:28])[NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH2:10]([O:17][C:18]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][O:27][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:24][CH:25]=1)=[O:28])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1ccc(CO)cc1)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.1 %

Procedure:
Diisopropylethylamine (0.19 ml, 1.17 mmol) was added to a cool (0° C.) solution of (4-Hydroxymethyl-phenyl)-carbamic acid benzyl ester (0.25 g, 0.97 mmol) in DCM (8 ml) and the reaction stirred at this temperature for 5 minutes. After this time, methane sulfonyl chloride (0.09 ml, 1.07 mmol) was added dropwise and the mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was then diluted with DCM (20 ml) and washed sequentially with saturated sodium bicarbonate solution (10 ml), saturated ammonium chloride (10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to afford the title compound (0.29 g, 89% yield) as a yellow oil which was taken forward without further purification.
Reaction SMILES: C(O[C@H:5]1[O:27][C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[CH:38]1[CH:43]=[N:42][CH:41]=[N:40][CH:39]=1.C[Si](N[Si](C)(C)C)(C)C.Cl[Si](C)(C)C.Cl[Sn](Cl)(Cl)Cl>CC#N>[C:8]([O:7][C@H:6]1[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:27][C@@H:5]1[C:41]1[N:42]=[CH:43][CH:38]=[CH:39][N:40]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1cncnc1
Reactant: CC(=O)O[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC#N
Product: O=C(OC[C@@H]1O[C@H](c2ncccn2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1

Procedure:
To a mixture of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-L-ribofuranose (1 mol) and pyrimidine base (1 mol) in anhydrous MeCN are successively added HMDS (1 mol), ClSiMe3 (0.8 mol) and SnCl4 (1.2 mol). The resulting clear solution is refluxed for 1 hour when TLC indicates completion of the reaction. The solvent is evaporated and the residue dissolved in EtOAc, washed with NaHCO3 and H2O. The EtOAc layer is dried, filtered and evaporated to give the crude product, which is either crystallized or purified on a silica gel column to obtain the pure 2,3,5-tri-O-benzoyl-β-L-ribofuranosyl pyrimidine compounds. These compounds are stirred with NH3 /MeOH to give pure β-L-ribofuranosyl pyrimidines after purification and crystallization.
Reaction SMILES: [CH2:1]([Cl:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>CCOCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][Cl:7]
Reactant: OCCCCCCl
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Product: ClCCCCCOC1CCCCO1
Reaction time: 4.5 h
Yield: 62.5 %

Procedure:
A stirred solution of pentamethylene chlorohydrin (10.0 g, 0.0816 mol) in Et2O (165 ml) under nitrogen was treated with 3,4-dihydro-2H-pyran (10.3 g, 0.122 mol) and p-toluenesulfonic acid hydrate (0.5 g) and kept at ambient temperature for 4.5 hours. The mixture was washed with aqueous NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was distilled to give 4.06 g, bp 79°-82° C. (0.1-0.07 mm Hg) and 10.54 g, bp 82°-84° C. (0.1-0.07 mm Hg) of 5-chloropentyl 2-tetrahydropyranyl ether.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][S:11][CH:10]([CH2:13][CH2:14][O:15]C2CCCCO2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO>[C:1]([O:5][C:6]([CH:8]1[CH2:12][S:11][CH:10]([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C1CSC(CCOC2CCCCO2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C1CSC(CCO)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To a stirred solution of 4-tert-butoxycarbonyl-2-(2-tetrahydropyranyloxyethyl)tetrahydrothiophene (0.67 g) in methanol (20 ml), p-toluenesulfonic acid monohydrate (40 mg) was added and the mixture was stirred for 3 hours at room temperature. Saturated aqueous sodium bicarbonate solution was added to the mixture and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 470 mg (96%) of the titled compound (compound No. 2-1).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:22]([O:24][C:25](=[O:31])[C:26](OCC)=[O:27])[CH3:23]>CCOCC>[CH2:22]([O:24][C:25](=[O:31])[C:26](=[O:27])[CH:9]1[C:8](=[O:11])[CH2:7][CH2:6][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:10]1)[CH3:23]
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C1CCC2(CC1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Product: CCOC(=O)C(=O)C1CC2(CCC1=O)OCCO2

Procedure:
According to the procedure of Example 2, a solution of 1,4-dioxaspiro[4.5]decane-8-one Compound 22a in ether was added to a solution of LHMDS in ether at −78° C. The diethyloxalate Compound 2b was added to the mixture and reacted to produce an oxo-(8-oxo-1,4-dioxa-spiro[4.5]dec-7-yl)-acetic acid ethyl ester Compound 22b.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:40])[N:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:27]([CH2:30][CH:31]([OH:33])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:41]([NH:51][C@H:52]([C:54](O)=[O:55])[CH3:53])([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:40])[N:26]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:27]([CH2:30][C@H:31]([O:33][C:54](=[O:55])[C@@H:52]([NH:51][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])[CH3:53])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CC(C)O)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)[C@H](C)NC(=O)OCc5ccccc5)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a mixture of (R)—N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl-1-(2-hydr-oxypropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (2.0 g, 3.68 mmol), (S)—N-Cbz-alanine (1.647 g, 7.36 mmol, Shanghai Hanhong Chemical CO., LTD.) and DMAP (0.90 g, 7.36 mmol, Aladdin) in CH2Cl2 (30 mL) was added EDC solid (2.116 g, 11.04 mmol, Aladdin) in portions at 0° C. After stirring at 0° C. for 2 hrs, the reaction mixture was warmed up to room temperature and continued to stir at rt for 20 hrs. The mixture was diluted with 180 mL of CH2Cl2. The resulted mixture was washed with 30 mL of 0.1 N HCl, followed by 50 mL of saturated NaHCO3 solution. The aqueous phase was extracted with EtOAc (50 mL×3), and the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to give the desired compound as a pale yellow solid (2.1 g, 73.1%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[CH:19]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25](O)=[O:26])([CH3:21])[CH3:20].C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:25]([C:24]3[CH:28]=[C:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:30]=[CH:31][C:23]=3[O:22][CH:19]([CH3:21])[CH3:20])=[O:26])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1 (b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride and 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a yellowish foam.
Reaction SMILES: [CH2:1]([NH:3][CH3:4])[CH3:2].[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:33])[C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=4)=[CH:22][CH:21]=3)[CH:14]=2)[NH:9][CH:8]=1)#[N:6]>>[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:33])[C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([N:3]([CH2:1][CH3:2])[CH3:4])[N:27]=4)=[CH:22][CH:21]=3)[CH:14]=2)[NH:9][CH:8]=1)#[N:6]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: CCNC
Product: CCN(C)c1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using ethylmethylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 1.15 (t, 3H, J=7 Hz); 2.99 (bt, 2H); 3.17 (s, 3H); 3.56 (m, 2H); 3.73 (m, 2H); 7.20 (m, 2H); 7.50 (m, 2H); 7.94 (d, 2H, J=7 Hz); 8.20 (m, 3H); 8.44 (d, 1H, J=5 Hz); 8.69 (bs, 1H); 12.14 (bs, 1H). MS (ion spray) m/z 425 (M+H)+.
Reaction SMILES: [I:1]N1C(C)(C)C(=O)N(I)C1=O.[CH3:12][C:13]([NH:19][C:20]([C:22]1[CH:34]=[CH:33][CH:32]=[CH:31][C:23]=1[C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])=[O:21])([CH3:18])[CH2:14][S:15]([CH3:17])=[O:16]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C(=O)C>[CH3:12][C:13]([NH:19][C:20]([C:22]1[C:34]([I:1])=[CH:33][CH:32]=[CH:31][C:23]=1[C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])=[O:21])([CH3:18])[CH2:14][S:15]([CH3:17])=[O:16]
Reactant: CCCCOC(=O)c1ccccc1C(=O)NC(C)(C)CS(C)=O
Reactant: CC1(C)C(=O)N(I)C(=O)N1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Product: CCCCOC(=O)c1cccc(I)c1C(=O)NC(C)(C)CS(C)=O
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Into the same reactor as in Example 1 were charged 1.32 mg of palladium acetate, 0.78 g of 1,3-diiodo-5,5-dimethylhydantoin, n-butyl 2-(1,1-dimethyl-2-methylsulfinylethylaminocarbonyl)benzoate and 5 ml of N,N-dimethylacetamide. After stirring the mixture at 90° C. for 30 minutes, 0.56 g of 1,3-diiodo-5,5-dimethylhydantoin was added, and the mixture thus obtained was stirred at 90° C. for 3.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, an aqueous solution of sodium thiosulfate was added, and the mixture thus obtained was extracted twice with toluene. The organic layer was washed successively with 0.5N aqueous hydrochloric acid, an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The crude product thus obtained was washed with hexane-ether mixture to obtain 2.26 g of n-butyl 2-(1,1-dimethyl-2-methylsulfinylethylaminocarbonyl)-3-iodobenzoate (yield 82%, melting point 57.5–66.3° C.). Regioselectivity of iodination into the 3-position was 100%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=O)[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C@H:20]([C@@H:28]([OH:34])[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([NH:19][C@H:20]([C@@H:28]([OH:34])[CH2:29][CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)=[O:18])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CC(C)CC[C@H](O)[C@@H](N)CC1CCCCC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a solution of N-t-butoxycarbonyl-L-histidine (363 mg) and 2(S)-amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (294 mg) in dry N,N-dimethylformamide (30 ml) which was cooled to 0° C., were added a solution of diphenyl phosphorylazide (390 mg) in dry N,N-dimethylformamide (5 ml) and triethylamine (144 mg). The mixture was stirred overnight at ambient temperature. After evaporation of the solvent, the residue was dissolved in ethyl acetate (30 ml) and the solution was washed with 10% citric acid solution, saturated sodium bicarbonate solution and water successively, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (chloroform as eluent) to give 2(S)-(N-t-butoxycarbonyl-L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (384 mg) as an amorphous powder.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:14][C:15](=[O:27])/[CH:16]=[CH:17]/[CH2:18][C@@H:19]([CH3:26])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH3:13]>C(Cl)Cl>[CH2:12]([O:14][C:15](=[O:27])[CH:16]=[CH:17][CH2:18][C@H:19]([CH3:26])[CH2:20][CH2:21][CH:22]1[C:23]([CH3:25])([CH3:24])[O:9]1)[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)/C=C/C[C@@H](C)CCC=C(C)C
Solvent: ClCCl
Product: CCOC(=O)C=CC[C@H](C)CCC1OC1(C)C
Temperature: 0 °C
Yield: 101.3 %

Procedure:
13.54 g of 3-chloro-perbenzoic acid (MCPBA, 70%) was dissolved in 30 ml of CH2Cl2 and cooled to 0°. 8.84 g of (E)-(S)-5,9-dimethyl-deca-2,8-dienoic acid ethyl ester dissolved in 15 ml of CH2Cl2, was slowly added and the mixture kept for an additional 0.5 h in the ice bath. The reaction was then quenched by pouring onto crushed ice/sodium pyrosulfite, extracted twice with AcOEt, washed with 2N NaOH, water and brine, dried over sodium sulfate and evaporated to dryness to yield 9.59 g of (5R)-7-((RS)-3,3-dimethyl-oxiranyl)-5-methyl-hept-2-enoic acid ethyl ester as 1/1 epimeric mixture, sufficiently pure for the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)([O-])=O>CO.CCOC(C)=O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[NH2:17])[O:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccncc2)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(Oc2ccncc2)cc1N
Temperature: 25 °C
Reaction time: 42 h

Procedure:
4-(3,4-Dinitro-phenoxy)-pyridine (1.36 g, 5.21 mmol) was dissolved in 20 mL MeOH and 40 mL EtOAc. To the argon-degassed solution was added 10% by weight Pd/C (0.35 g). The reaction was vigorously stirred for 42 h at RT under 1 atm of H2 gas. The reaction was filtered through a Celite® plug. The solvent was removed under reduced pressure to obtain the title compound.
Reaction SMILES: Cl.CN([CH2:5][CH:6]1[C:18](=[O:19])[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:20])[C:9]=2[CH2:8][CH2:7]1)C.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1>O>[CH3:20][N:10]1[C:9]2[CH2:8][CH2:7][CH:6]([CH2:5][N:23]3[CH:24]=[CH:25][N:26]=[C:22]3[CH3:21])[C:18](=[O:19])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: Cc1ncc[nH]1
Reactant: CN(C)CC1CCc2c(c3ccccc3n2C)C1=O
Agent: Cl
Solvent: O
Product: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Yield: 82.2 %

Procedure:
A solution of 3-[(dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one hydrochloride (1.7 g) in water (17 ml) was treated with 2-methylimidazole (1.4 g) and then heated under reflux for 20 h. The cooled mixture was filtered and the residue washed with water (3×15 ml) to give crude product (1.7 g) m.p. 221°-221.5°. This material was recrystallized from methanol to give the title compound (1.4 g) m.p. 231°-232°.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([CH:11]=O)[NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2>>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[C:23]2=[CH:11][C:9]1[NH:10][C:6]2[CH2:5][CH2:4][NH:3][C:2](=[O:1])[C:7]=2[C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: O=Cc1[nH]c2c(c1-c1ccccc1)C(=O)NCC2
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1[nH]c2c(c1-c1ccccc1)C(=O)NCC2
Yield: 31.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 41 with 4-oxo-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-chloro-1,3-dihydro-indol-2-one as starting materials to give 2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-phenyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (22 mg, 31.9%) as a yellow solid.