Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[N:38]([C:39]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:37]=[N:36][N:35]=2)=[CH:24][CH:23]=1.O>CS(C)=O>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38]([C:39]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:37]=[N:36][N:35]=3)=[CH:26][CH:27]=2)[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc2ccccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
0.87 g (5 mmol) of 2-n-butyl-benzimidazole is dissolved in 20 ml of dimethylsulphoxide and 0.61 g (5.5 mmol) of potassium tert.butoxide is added with stirring. After 1/2 hour, 4'-bromomethyl-2-(1-triphenylmethyl-1H-tetrazol-5-yl)-biphenyl is added and the mixture is stirred for 3 hours at ambient temperature. It is poured into about 50 ml of iced water and extracted by shaking 3 times using 30 ml of ethyl acetate each time. The ethyl acetate phase is extracted by shaking using 30 ml of water, dried over sodium sulphate and evaporated to dryness. The crude product is purified over a silica gel column (grain size: 0.063-0.2 mm, eluting agent: methylene chloride/ethanol=100:1).
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][N:5]([CH3:11])[CH2:6][CH:7]([CH3:10])[CH2:8][Cl:9].[CH3:12][N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][C:16](=[O:24])[C:15]2=[CH:25][S:26][CH:27]=[C:14]12.Cl>CCOCC.CN(C)C=O>[ClH:9].[CH3:4][N:5]([CH3:11])[CH2:6][CH:7]([CH3:10])[CH2:8][N:17]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:13]([CH3:12])[C:14]2=[CH:27][S:26][CH:25]=[C:15]2[C:16]1=[O:24]
Reactant: CC(CCl)CN(C)C
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(CN(C)C)CN1C(=O)c2cscc2N(C)c2ccccc21
Reaction time: 18 h

Procedure:
A mixture of 0.47 g. of 55% sodium hydride-mineral oil dispersion and 0.91 g. of 3-dimethylamino-2-methylpropylchloride hydrochloride in 35 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.6 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water and extracted with chloroform. The dried chloroform extracts are concentrated to an oil, which is chromatographed on silica gel preparative thin layer chromatographic (tlc) plates with 10:1 benzene:methanol to give an oil. An ethanolic solution of the oil is treated with anhydrous hydrogen chloride and diluted with ether to give a white solid, m.p. 231°-233°C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1.O1CCCC1.C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O>[NH2:9][C:3]1[N:4]=[C:5]([NH:8][C:21](=[O:22])[O:23][CH2:24][CH3:25])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Nc1ccc(Cl)c(N)n1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Nc1ccc(Cl)c(N)n1
Temperature: 0 °C

Procedure:
A solution of 3-chloro-2,6-diaminopyridine (129 g. 0.9 mole) in 1000 ml. of tetrahydrofuran and 250 ml. of water containing sodium bicarbonate (84 g., 1.0 mole) is stirred at 0° C. while adding ethyl chloroformate (114 g. 1.05 mole) dropwise over 1/2 hour. The mixture is stirred at 0° C. over night. The dark solution is filtered through activated carbon and the organic layer of the filtrate is separated, dried and concentrated in vacuo. The residual oil is taken up in ether, washed with 5 N sodium hydroxide and with saturated sodium chloride solution, dried and concentrated in vacuo. A light amber oil (162 g.) which solidifies when triturated in petroleum ether is obtained. The solid is purified by extracting into boiling hexane (10×300 ml) and cooling the extracts to give 131.6 g. of white solid, m.p. 66°-70°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=[C:4]([CH3:10])[CH:3]=1.[O:11]1[CH2:15][CH2:14]OC1=O>N1C=CN=C1>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[CH:5]=[C:6]([Cl:9])[C:7]=1[O:8][CH2:14][CH2:15][OH:11]
Reactant: Cc1cc(Cl)c(O)c(Cl)c1
Reactant: O=C1OCCO1
Agent: c1c[nH]cn1
Product: Cc1cc(Cl)c(OCCO)c(Cl)c1
Temperature: 160 °C
Yield: 74.9 %

Procedure:
In a three-necked flask equipped with a gas droplet counter and an efficient cooling system, a mixture of 2,6-dichloro-p-cresol (20.0 g, 113 mmol), [1,3]dioxolan-2-one (9.95 g, 113 mmol) and imidazole (115 mg, 1.70 mmol) was heated to 160° C. for 25 h. The mixture was allowed to cool to rt. Purification by FC (Et2O/heptane 1.1) yielded the title compound (18.7 g, 75%). LC-MS: tR=0.88 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[NH3:26]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:10]([C:11](=[O:13])[NH2:26])[CH:9]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[O:25]
Reactant: N
Reactant: Nc1ncc(-c2cccc(C(=O)O)c2)cc1C(=O)Nc1ccncc1
Product: NC(=O)c1cccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)c1

Procedure:
Reaction of 3-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with ammonia gives “A99”; method 2: HPLC/MS: 1.64 min, [M+H]=334.
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.Cl.Cl[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.[H-].[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][O:1][C:2]2[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:3]=2)[CH:16]=1
Reactant: CCOC(=O)c1c[nH]nc1O
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2cccnc2)nc1OCc1cccnc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.5 %

Procedure:
To a mixture of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (1.06 g), 3-chloromethylpyridine hydrochloride (2.79 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 1.36 g) at 0° C. The mixture was stirred at room temperature for 15 hrs. Saturated aqueous sodium hydrogen carbonate was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, from a fraction eluted with ethyl acetate-methanol (10:1, v/v), ethyl 3-(pyridin-3-ylmethoxy)-1-(pyridin-3-ylmethyl)-1H-pyrazole-4-carboxylate as colorless crystals (1.23 g, yield 53%). Recrystallization from ethyl acetate-hexane gave colorless needle crystals. melting point: 120-121° C.
Reaction SMILES: IC1C=CC=CC=1C(O)=O.[NH2:11][CH2:12][C@@H:13]1[C@H:18]([CH3:19])[CH2:17][CH2:16][CH2:15][N:14]1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1)=[O:21].F[C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][N:36]=1>>[CH3:19][C@@H:18]1[CH2:17][CH2:16][CH2:15][N:14]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[O:21])[C@@H:13]1[CH2:12][NH:11][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][N:36]=1
Reactant: C[C@@H]1CCCN(C(=O)c2ccccc2-c2ncccn2)[C@@H]1CN
Reactant: Fc1ccc(C(F)(F)F)cn1
Agent: O=C(O)c1ccccc1I
Product: C[C@@H]1CCCN(C(=O)c2ccccc2-c2ncccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A230 using 2-iodobenzoic acid to make ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-(pyrimidin-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 456 [M+1]+. 1H NMR (500 MHz, DMSO-d6) δ 8.90-6.60 (m, 11H), 4.85-2.85 (m, 5H), 2.00-0.65 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:26][CH2:27][CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[CH2:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:26][CH2:27][CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCn1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCn1ccnc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 0.17 g (0.34 mmol) t-butyl 8-(p-chlorophenylsulfonamido)-4-[3-(1-imidazolyl)propyl]-octanoate in 5 ml methylene chloride is added 1 ml trifluoroacetic acid and the solution is stirred at room temperature for 1.5 h. The solvent is evaporated and the residue taken up in 5 ml water. The pH of the solution is adjusted to 6.5 using 1N aqueous sodium hydroxide. Then the aqueous solution is extracted twice with ethyl acetate. The combined organic layer is washed with water and brine, dried, filtered and concentrated to give a pale yellow oil. The product is triturated five times with 2 ml ether each and finally dried to yield 8-(p-chlorophenylsulfonamido)-4-[3-(1-imidazolyl)propyl]-octanoic acid, m.p. 136°-138°.
Reaction SMILES: [NH2:1][NH2:2].[C:3]([N:7]=[C:8]=[O:9])([CH3:6])([CH3:5])[CH3:4]>CCOCC>[C:3]([NH:7][C:8]([NH:1][NH2:2])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: NN
Reactant: CC(C)(C)N=C=O
Solvent: CCOCC
Product: CC(C)(C)NC(=O)NN
Reaction time: 2 h
Yield: 71.7 %

Procedure:
To a vigorously stirred mixture of 0.33 g (0.0103 mol) of anhydrous hydrazine in 50 ml of dry ether was added 1 g (0.01 mol) of t-butyl isocyanate. The resulting mixture was stirred for 2 hr. at room temperature then was kept overnight at 4° C. The crystals formed were filtered off, washed with a small portion of ether and dried to give 0.94 g (72% yield) of (t-butylamino)carbonylhydrazine melting at 192-193° C. When this was substituted for t-butyl carbazate in Step A of Example 1, the identical process afforded 1-(t-butylamino)carbonyl-2-isopropylhydrazine in 58% yield as a white solid; NMR (CDCl3): 1.03 (d, 6H, isopropyl CH3); 1.33 (s, 9H, t-butyl CH3); 3.9 (broad s. 1H, NH); 6.02 (broad s, 2H, NH amide). When this was substituted for t-butyl 3-isopropylcarbazate in Step B of Example 19 the identical process afforded 1-(t-butylamino)carbonyl-2-[(2S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]-2-isopropylhydrazine in 68% yield, as a white solid; NMR (CDCl3): 1.0 (m, 6H, isopropyl CH3); 1.3 (s, 9H, t-butyl CH3); 2.33-4.22 (m, BH, butyl CH2 -1,4, CH-2,3, OH, isopropyl CH); 5.05 (s, 2H, methoxy CH2); 5.3 (m, 2H, NH); 5.91(m 1H, NH); 7.2, 7.35 (m, s, 5H, 5H, aromatic). When this was substituted for t-butyl 3-isopropyl-[(2R, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]carbazate in Example 3, the identical process afforded the title compound in 67% yield; melting point=119-125° C.; Rf (C)=0.06; Rf (D)=0.43; NMR(CDCl3): 1.0 (m, 6H, isopropyl CH3); 1.32 (s, 9H, t-butyl CH3); 2.24-3.38 (m, 7H, butyl CH2 -1,4, CH-3, asn CH2); 3.38-4.63 (m, 3H, butyl CH-2, OH, isopropyl CH); 5.09 (m, 1H, asn CH); 5.63-8.4 (m, 16H, aromatic, NH); 9.0 (d, 1H, asn NH).
Reaction SMILES: [CH2:1]([N:8]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:19]3[C:20]4[CH:26]=[CH:25][N:24](S(C5C=CC(C)=CC=5)(=O)=O)[C:21]=4[N:22]=[CH:23][C:18]3=[N:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[CH2:37]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]2[N:19]3[C:20]4[CH:26]=[CH:25][NH:24][C:21]=4[N:22]=[CH:23][C:18]3=[N:17][CH:16]=2)[CH2:11][CH2:10]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2ncc(C4CCC(N(Cc5ccccc5)Cc5ccccc5)CC4)n23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@@H](c3cnc4cnc5[nH]ccc5n43)CC2)cc1
Temperature: 60 °C

Procedure:
N,N-dibenzyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohexanamine (5.6 g, 9.5 mmol) was dissolved in 1,4-dioxane (80 mL). Aqueous NaOH (2 N, 47.5 mL, 95 mmol) was added and the reaction mixture was heated at about 60° C. for about 120 min. The organic solvent was removed under reduced pressure and the residue was extracted with 2-methyl tetrahydrofuran (300 mL). The aqueous layer was extracted with 2-methyl tetrahydrofuran (3×50 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4 and concd under reduced pressure. To the residue was added EtOAc (500 mL). The solid was removed by filtration and the filtrate was dried over anhydrous Na2SO4 and concd under reduced pressure. Purification by silica gel flash chromatography eluting with a gradient of 1-8% MeOH in EtOAc yielded (cis)-N,N-dibenzyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohexanamine (1.0 g, 24%): LC/MS (Table 1, Method a) Rt=2.48 min; MS m/z 436 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>>[F:26][C:27]([F:32])([F:31])[C:28]([O:30][C:4]1([N:7]=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:29]
Reactant: ON=C1CCOCC1
Reactant: O=C(O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: O=NC1(OC(=O)C(F)(F)F)CCOCC1

Procedure:
4-Nitrosotetrahydro-2H-pyran-4-yl 2,2,2-trifluoroacetate was prepared from tetrahydro-pyran-4-one oxime, lead tetraacetate and trifluoroacetic acid using conditions of General Method 3. 1H NMR (250 MHz, chloroform-d) δ 4.18 (2H, m), 3.75 (2H, m), 2.53 (2H, m), 1.92 (2H, m).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[C:14]([F:24])=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[C:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28]>CN1C(=O)CCC1.CCOC(C)=O>[F:24][C:14]1[C:13]([C@@H:11]([C:8]2[N:6]3[N:7]=[C:2]([N:33]4[CH2:34][CH2:35][N:30]([C:27](=[O:29])[CH3:28])[CH2:31][CH2:32]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:21]([F:22])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[CH3:23]
Reactant: CC(=O)N1CCNCC1
Reactant: C[C@@H](c1c(F)cc2c(cnn2C)c1F)c1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2ccc3ncc([C@@H](C)c4c(F)cc5c(cnn5C)c4F)n3n2)CC1
Temperature: 180 °C
Reaction time: 3.5 h

Procedure:
6-Chloro-3-[(S)-1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (Intermediate Q, 36.6 mg, 0.105 mmol), KF (30.6 mg, 0.526 mmol) and 1-acetylpiperazine (40.5 mg, 0.316 mmol) were suspended in NMP (0.4 mL). The RM was stirred at 180° C. for 3.5 h. The mixture was diluted with EtOAc and washed with NaHCO3 10% (2×) and water (4×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and afforded the title compound as a light brown foam (tR 3.80 min (conditions 5), tR 13.31 min (conditions 3), MH+=440.3, 1H-NMR in DMSO-d6: 8.12 (s, 1H); 7.79 (d, 1H); 7.52 (s, 1H); 7.39 (d, 1H); 7.04 (d, 1H); 4.84 (m, 1H); 3.96 (s, 3H); 3.36 (m, 8H); 1.99 (s, 3H); 1.79 (d, 3H)).
Reaction SMILES: [CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([OH:7])=[O:6])[CH2:2][CH3:3].C1(C)C=CC=CC=1.[OH-].[Na+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>CN(C)C=O>[CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([O:7][CH2:20][CH:22]1[O:24][CH2:23]1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCC(CCC)C(=O)O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCC(CCC)C(=O)OCC1CO1
Reaction time: 6 h

Procedure:
Into a flask were introduced 70 g (0.48 mol) of di-n-propylacetic acid, 250 ml of toluene and 30 ml of N,N-dimethylformamide. After this operation, 40 g of 50%-aqueous solution of sodium hydroxide were added. This mixture was heated to 60°-80° C. and 138.7 g (1.5 mol) of epichlorhydrine were introduced. The reaction medium was maintained under stirring for 6 hours at 70°-80° C. and then concentrated in a rotary evaporator. After extraction with ethyl ether, the organic fractions were collected and distilled under 1 mm Hg.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH2:14])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].C(N[C@@H](C(O)=O)CC(C)C)(=O)C>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([NH2:14])[CH2:9][CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CCC2N
Agent: CC(=O)N[C@H](CC(C)C)C(=O)O
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)CC[C@H]2N
Temperature: 65 °C

Procedure:
5-tert-Butyl-2,3-dihydro-1H-inden-1-ylamine (11.70 g, 44.4% ee), N-acetyl-(D)-leucine (11.78 g), and methanol (120 mL) were combined and heated at 65° C. for 1 hour. The solution was allowed to cool to ambient temperature. The solids were filtered and washed with toluene. The solid was then resuspended in methanol (125 mL) and brought to reflux. The solution was allowed to cool to ambient temperature and the solids were filtered. The solid was dried at 40° C. under reduced pressure to provide the title compound (98.7% ee).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=[C:26]([O:36][CH2:37][O:38][CH3:39])[C:25]=1[O:40][CH3:41].CN(C)CCN(C)C.C([Li])CCC.[Br:55]N1C(=O)CCC1=O>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH3:41][O:40][C:25]1[C:26]([O:36][CH2:37][O:38][CH3:39])=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:30][CH2:31][O:32][CH3:33])[C:24]=1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:4]1[C:5]([O:15][CH2:16][O:17][CH3:18])=[C:6]([O:13][CH3:14])[C:7]([Br:55])=[C:8]([O:9][CH2:10][O:11][CH3:12])[C:3]=1[O:2][CH3:1]
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Reactant: O=C1CCC(=O)N1Br
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)c(Br)c(OC)c2OCOC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
998 Milligrams of 2,2'-pentamethylenebis[1,4-dimethoxy-3,6-bis(methoxymethoxy)benzene] was dissolved in a mixed solvent of 30 ml of tetrahydrofuran with 3 ml of hexamethylphosphoric triamide, to this solution was added 1.03 ml of N,N,N',N'-tetramethylethylenediamine, was cooled to -78° C. on a dry ice-acetone mixture bath. 4.56 Milliliters of n-butyllithium (1.6 M, n-hexane solution) was added dropwise to the reaction mixture and stirred for 30 minutes. Next, 15 ml of tetrahydrofuran solution containing 1.22 g of N-bromosuccinimide was added dropwise and the reaction mixture was stirred overnight. The solvent was removed under reduced pressure, and the residue obtained was extracted twice with 50 ml of diethyl ether, and the diethyl ether layer was washed twice with 50 ml of water, and washed twice with 50 ml of a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate. The diethyl ether solution was concentrated under reduced pressure, the residue obtained was purified by means of a preparative thin layer chromatography (thickness: 2 mm, adsorbent: Merck 5717 silica gel, developing solvent: 40% ethyl acetate-n-hexane). There were obtained 155 mg of 1-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]-5-[2,5-dimethoxy- 3,6-bis(methoxymethoxy)-4-bromophenyl]pentane, as well as 22 mg of 2,2'-pentamethylenebis[1,4-dimethoxy-3,6-bis(methoxymethoxy)-5-bromobenzene].
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH:24][C:25](=O)[CH3:26])[CH:21]=4)[C:16](C=O)=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.NO.[C:35]([O-])(=[O:37])[CH3:36].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][N:24]5[CH2:25][CH2:26][CH2:36][C:35]5=[O:37])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:12][CH2:13]2)=[CH:30][CH:31]=1
Reactant: CC(=O)[O-]
Reactant: CC(=O)NCc1ccc2c(C=O)cn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CO
Product: O=C1CCCN1Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
A liquid mixture of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-3-formyl-6-acetamidomethylindole (0.09 g) obtained in Example 370, hydroxylamine hydrochloride (0.02 g) and anhydrous sodium acetate (0.03 g) in methanol (10 ml) was stirred at room temperature for 1 hr. Then the reaction mixtures were concentrated and the residue was partitioned between ethyl acetate (20 ml) and a 1 N aqueous solution (10 ml) of sodium hydroxide. The ethyl acetate layer was washed successively with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. Then the residue was crystallized from ether/hexane, collected by filtration, washed with hexane and dried to give the title compound (0.08 g) as a pale yellow powder (yield: 88.5%).
Reaction SMILES: [CH:1]1([N:7]([CH2:13][CH3:14])[C:8](=[O:12])[O:9][CH2:10]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:15][C@@H:16]([C@H:18]1[C:38](=[O:39])[N:20]2[C:21]([C:35]([O-:37])=[O:36])=[C:22]([S:25]/[CH:26]=[CH:27]\[C:28]3[S:32][CH:31]=[N:30][C:29]=3[CH2:33][OH:34])[C@H:23]([CH3:24])[C@H:19]12)[CH3:17].[Na+]>>[OH:15][C@@H:16]([C@H:18]1[C:38](=[O:39])[N:20]2[C:21]([C:35]([O:37][CH2:10][O:9][C:8]([N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:13][CH3:14])=[O:12])=[O:36])=[C:22]([S:25]/[CH:26]=[CH:27]\[C:28]3[S:32][CH:31]=[N:30][C:29]=3[CH2:33][OH:34])[C@H:23]([CH3:24])[C@H:19]12)[CH3:17]
Reactant: CCN(C(=O)OCCl)C1CCCCC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CCN(C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12)C1CCCCC1
Yield: 67.9 %

Procedure:
In the same manner as in step b) in Example 125, 285 mg of the title compound was prepared from 190 mg of chloromethyl N-cyclohexyl-N-ethylcarbamate and 300 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethyl-thiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Br:7][C:8]1[CH:13]=[CH:12][C:11](CC(O)=O)=[CH:10][CH:9]=1.C(Cl)Cl>CN(C)C=O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:1][C:2]([Cl:4])=[O:3])=[CH:10][CH:9]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
Initially, oxalyl chloride is added to an equimolar amount of p-bromophenylacetic acid (C) in an inert solvent, preferably methylene chloride, at about room temperature, with a catalytic amount of dimethylformamide. The mixture is stirred for about 30 minutes, after which the product, p-bromophenylacetyl chloride (D), is isolated by conventional means.