Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[OH:2][CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH:8]=1
Reactant: COC(=O)CNCc1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2cc(CNCCO)ccn2)cc(OC)c1OC
Reaction time: 4 h

Procedure:
N-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-glycine methyl ester (6.54 g) was dissolved in THF (80 mL), and to the solution lithium aluminum hydride (717 mg) was gradually added portionwise at 0° C. under an argon atmosphere, and the mixture was stirred for 4 hours. A small amount of water was added to the reaction mixture. When bubbling ended, sodium sulfate was excessively added. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform:methanol=20:1) to obtain the title compound.
Reaction SMILES: [OH:1][CH:2]1[C@@H:6]2[CH2:7][C:8](=[O:9])[N:5]2[C:4]([C:10]([O:12][CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11])=[C:3]1[CH3:21].[C:22](OC(=O)C)(=[O:24])[CH3:23].N1C=CC=CC=1.C(=O)=O>CN(C)C1C=CN=CC=1.C(OCC)(=O)C.C(Cl)(Cl)Cl.C(Cl)Cl>[C:22]([O:1][CH:2]1[C@@H:6]2[CH2:7][C:8](=[O:9])[N:5]2[C:4]([C:10]([O:12][CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])=[O:11])=[C:3]1[CH3:21])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C[C@H]2C1O
Agent: CN(C)c1ccncc1
Agent: O=C=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)OC1C(C)=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C[C@@H]12
Reaction time: 2 h

Procedure:
To the freshly prepared methylene chloride solution of pivaloyloxymethyl 1-hydroxy-2-methylcarbapen-2-em-3-carboxylate of Example 4, cooled to -78° C. was added acetic anhydride (0.170 ml., 1.68 mmoles), pyridine (0.144 ml., 1.68 mmoles) and 4-dimethylaminopyridine (10.5 mg., 0.086 mmoles) in two aliquots over 2 hours. The reaction was monitored by tlc (3:1 chloroform:ethyl acetate). After maintaining the reaction mixture at dry ice temperature for approximately 16 hours, additional 4-dimethylaminopyridine (0.5 mg.) was added and reaction continued for 2 hours at -78° C. The reaction mixture was extracted twice with aqueous buffer (pH 7), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was chromatographed on 8 g. of silica gel (6:1 chloroform:ethyl acetate as eluant, monitored by tlc or ir spectral analysis) to yield pivaloyloxymethyl 1-acetoxy-2-methylcarbapen-2-em-3-carboxylate [15 mg.; ir (CH2Cl2) 1780, 1740 cm-1 ; Rf 0.75 (3:1 chloroform:ethyl acetate)].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:23]([O:25]C)=O)[C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])=[CH:11][C:12]=3[C:13]=2[N:14]=1.[NH3:27].CO>>[Br:1][C:2]1[CH:3]=[C:4]([C:23]([NH2:27])=[O:25])[C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:15]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[O:16])=[CH:11][C:12]=3[C:13]=2[N:14]=1
Reactant: N
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1ccc(C(=O)N3CCOCC3)cc12
Solvent: CO
Product: NC(=O)c1cc(Br)nc2c1[nH]c1ccc(C(=O)N3CCOCC3)cc12
Temperature: 105 °C
Yield: 96.7 %

Procedure:
Methyl 2-bromo-8-(morpholine-4-carbonyl)-5H-pyrido[3,2-b]indole-4-carboxylate (220 mg, 0.526 mmol) was mixed with NH3/MeOH(7N) (18 mL, 126 mmol) in a sealed microwave vial. The mixture was heated at 105° C. for 2.5 hrs in microwave. The mixture was concentrated to give 205 mg crude product. MS (ESI) m/z 402.95 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]([O:20][CH3:21])(=[O:19])[C:12]([CH2:14][C:15](OC)=[O:16])=[CH2:13].Cl.CCOCC>CO>[CH3:21][O:20][C:11]([CH:12]1[CH2:14][C:15](=[O:16])[N:8]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:13]1)=[O:19]
Reactant: COc1ccc(CN)cc1
Reactant: C=C(CC(=O)OC)C(=O)OC
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1CC(=O)N(Cc2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To 4-methoxybenzylamine (42 g, 0.306 mol) in methanol (40 mL) at 0° C. was added the dimethyl itaconate (48 g, 0.306 mol) in methanol (13 mL). The solution was stirred at room temperature for 4 days. 1N HCl was added to the solution followed by ether. The two layers were separated and the aqueous phase extracted with ether. The combined organic phases were dried (MgSO4). Upon filtration of the drying agent the desired material 79 precipitated from solution that was collected and dried under vacuum. 23.26 g, 29%. MS, m/z (relative intensity): 264 [M+H, 100%]. Anal. Calcd for C14H17N1O4: C, 63.87; H, 6.51; N, 5.32. Found: C, 63.96; H, 6.55; N, 5.29.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[CH:20]1([NH:26][NH2:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:26]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[N:27]=[C:8]2[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1
Reactant: COc1ccc(C(=O)c2cccc(Cl)c2F)cc1
Reactant: NNC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: COc1ccc(-c2nn(C3CCCCC3)c3c(Cl)cccc23)cc1
Yield: 92 %

Procedure:
Prepared according to Method C step A (3-chloro-2-fluorophenyl)-(4-methoxyphenyl)-methanone (0.55 g, 1.85 mmol), cyclohexylhydrazine hydrochloride (0.42 g, 2.7 mmol) and DMAP (0.225 g, 1.85 mmol) to give the product (0.58 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:3]=1[CH2:4][N:12]=[N+:13]=[N-:14]
Reactant: N#Cc1ccc(CBr)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN=[N+]=[N-])c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a stirred solution of 2-choro-4-cyanobenzyl bromide (6.9 g, 30.0 mmol) in DMF (150 ml), was added sodium azide (2.0 g, 30 mmol) The reaction was stirred overnight at room temperature, and then filtered. The DMF was removed from filtrate in vacuo. The residue was dissolved in EtOAc (300 ml), washed with water (200 ml×3), brine (200 ml×1), dried over sodium sulfate. Removed solvent in vacuo to give 5.8 g of raw 2-choro-4-cyanobenzyl azide.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f8) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1(O)[N:19]=[CH:18][N:17]=[C:16]2[C:3]1=[N:4][CH2:5][N:6]2[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[CH2:21]([O:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38](OC)OC)=[CH:34][CH:33]=1)[CH:22]=[CH2:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CN(C=O)C>[CH2:21]([O:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[O:11][CH:10]3[CH:12]([CH2:13][OH:14])[O:15][CH:7]([N:6]4[CH:5]=[N:4][C:3]5[C:16]4=[N:17][CH:18]=[N:19][C:2]=5[Cl:1])[CH:8]3[O:9]2)=[CH:34][CH:33]=1)[CH:22]=[CH2:23]
Reactant: OC[C@H]1O[C@@H](N2CN=C3C2=NC=NC3(O)Cl)[C@H](O)[C@@H]1O
Reactant: C=CCOC(=O)CCCCCOc1ccc(C(OC)OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCOC(=O)CCCCCOc1ccc(C2OC3C(CO)OC(n4cnc5c(Cl)ncnc54)C3O2)cc1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
A mixture of 6-chloroinosine (4, 32.5 g, 113 mmol) and the acetal linker 3 (47.5 g, 147 mmol) was dissolved in DMF (230 mL). p-Toluenesulfonic acid monohydrate (1.1 g, 5.7 mmol) was added, and the solution was placed on a Buechi R-134 rotavapor and agitated under reduced pressure (70 mbar) at 50° C. for 15 h. The solvent was removed in vacuo, the resulting residue was dissolved in EtOAc (1 L) and neutralized with triethyl amine (0.8 mL, 5.7 mmol). The solution was then washed with saturated aqueous NaCl (3×1 L), H2O (1 L), dried (MgSO4), filtered and concentrated. The resulting residue was taken up in EtOAc and triturated with hexanes, upon which the product precipitated as a white powder (5, 59.3 g, 109 mmol, 96%, mixture of two diastereomers): M.p.: 103-105° C.; 1H-NMR (400 MHz, CDCl3) δ=8.78 (s, 1H), 8.77 (s, 1H′), 8.41 (s, 1H), 8.33 (s, 1H′), 7.47 (d, J=8.6 ,2H), 7.37 (d, J=8.6, 2H′), 6.95 (d, J=8.5, 2H), 6.89 (d, J=8.5, 2H′), 6.24 (s, 1H), 6.19 (m, 1H, 1H′), 6.02 (s, 1H′), 5.91 (m, 1H, 1H′), 5.37-5.18 (m, 4H, 4H′), 4.77 (m, 1H, 1H′), 4.72 (s, 1H, 1H′), 4.58 (m, 2H, 2H′), 4.04-3.85 (m, 4H, 4H′), 2.37 (m, 2H, 2H′), 1.81 (m, 2H, 2H′), 1.71 (m, 2H, 2H′), 1.52 (m, 2H, 2H′); 13C -NMR (400 MHz, CDCl3) δ=173.4, 173.4, 160.5, 160.4, 152.0, 151.8, 150.8, 150.7, 132.8, 132.6, 132.3, 132.3, 132.1, 132.1, 128.2 (2C), 128.0 (2C), 127.5, 127.5, 118.3, 118.3, 114.8, 114.8, 114.6 (2C), 114.6 (2C), 108.0, 104.9, 93.5, 91.6, 86.4, 86.4, 84.3, 83.8, 83.3, 80.5, 67.9, 67.8, 65.1, 65.1, 63.2, 62.9, 34.2, 34.2, 28.9, 28.9, 25.7, 25.7, 24.7, 24.7; IR (film) ν=3233, 3109, 3073, 2934, 1727, 1595, 1396, 1245, 1194, 1167, 1101, 1073, 984, 832; HRMS (MALDI-FTMS) m/z 567.1627(567.1617 calculated for C26H29N4O7ClNa (M+Na)+).
Reaction SMILES: C(OC([O:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[CH3:9])C)C.[H-].[Na+].CO[C:17](=[O:28])[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=O)=[CH:20][CH:19]=1.Cl>O1CCCC1>[OH:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[CH2:9][C:22]([C:21]1[CH:20]=[CH:19][C:18]([C:17](=[O:28])[CH2:9][C:8](=[O:10])[C:7]([CH3:11])([OH:6])[CH3:12])=[CH:27][CH:26]=1)=[O:24]
Reactant: CCOC(C)OC(C)(C)C(C)=O
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(O)C(=O)CC(=O)c1ccc(C(=O)CC(=O)C(C)(C)O)cc1
Reaction time: 7 h
Yield: 49 %

Procedure:
In a 100 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 9.9 gm (57 mmol) of above-mentioned 3-(1-ethoxyethoxy)-3-methyl-butane-2-one, 2.3 gm (57 mmol) of 60% sodium hydride, 5.0 gm (25 mmol) of dimethylterephthalate and 50 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream, and the refluxing under heat was continued for 7 hours. After cooling the reaction mixture, 30 ml of 2N hydrochloric acid was added and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation. The reaction mixture was stirred at room temperature while adding 30 ml of methnol with ten drops of 2N hydrochloric acid. A mixed solvent of acetone-chloroform was added to the crude product, and recrystallization afforded 4.1 gm of the targe compound as pale yellow crystals (yield: 48%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[CH:11][C:12]([OH:14])=O)([O-:3])=[O:2].C(N(CC)CC)C.ClC(OCC)=O.[CH2:28]([NH2:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[CH2:28]([NH:36][C:12](=[O:14])[CH:11]=[CH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: O=C(O)C=Cc1ccccc1[N+](=O)[O-]
Reactant: CCCCCCCCN
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCNC(=O)C=Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 9.7 g. of 3-(2-nitrophenyl)propenoic acid, 5.6 g. of triethylamine and 240 ml. of dichloromethane was stirred at room temperature for 20 minutes, and then it was cooled in an ice-bath. To the mixture was then added, dropwise, during 15 minutes, a solution of 6.0 g. of ethyl chloroformate in 20 ml. of dichloromethane. After 15 minutes of stirring, a solution of 7.1 g. of octylamine in 20 ml. of dichloromethane was added dropwise, during 10 minutes. The reaction mixture was allowed to warm to room temperature, and then it was washed successively with 1 N potassium carbonate, 1 N hydrochloric acid, water and saturated sodium chloride. The resulting solution was dried and evaporated in vacuo, leaving 14.5 g. (95%) yield of the title compound as a tan solid.
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[CH:8]([C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1)[OH:9])(C)(C)C.[F-].C([NH3+])(C)(C)C.CCCCCC.C(OCC)(=O)C>C1COCC1>[N:20]1[CH:21]=[CH:22][C:17]([CH:7]([OH:6])[CH:8]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)[OH:9])=[CH:18][CH:19]=1
Reactant: Cc1cccc(C(O)C(O[Si](C)(C)C(C)(C)C)c2ccncc2)c1
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(C(O)C(O)c2ccncc2)c1

Procedure:
To a solution of 2-(tert-butyl-dimethyl-silanyloxy)-2-pyridine-4-yl-1-m-tolyl-ethanol (5 g, 14.5 mmole) in THF (50 mL) was added t-butylamonium fluoride (1M, 16 mL, 16 mmole) at 25° C. The solution was stirred at that temperature for 1 hr before evaporation of solvent and purification (silica gel, hexane/ethyl acetate) to give the title compound. MS (m/z): Calcd. C14H15NO2(M+): 229, found (M+H)+: 230.1, (M−H)−: 228.1
Reaction SMILES: C1N=C[N:3](C(N2C=NC=C2)=O)C=1.[F:13][C:14]1[CH:19]=[C:18]([C:20]2[C:25]([CH3:26])=[CH:24][N:23]=[C:22]([O:27][CH3:28])[C:21]=2[CH3:29])[CH:17]=[CH:16][C:15]=1[C:30]1[N:34]([C@H:35]2[CH2:39][CH2:38][O:37][CH2:36]2)[N:33]=[CH:32][C:31]=1[C:40]([OH:42])=O.N>CN(C=O)C>[F:13][C:14]1[CH:19]=[C:18]([C:20]2[C:25]([CH3:26])=[CH:24][N:23]=[C:22]([O:27][CH3:28])[C:21]=2[CH3:29])[CH:17]=[CH:16][C:15]=1[C:30]1[N:34]([C@H:35]2[CH2:39][CH2:38][O:37][CH2:36]2)[N:33]=[CH:32][C:31]=1[C:40]([NH2:3])=[O:42]
Reactant: COc1ncc(C)c(-c2ccc(-c3c(C(=O)O)cnn3[C@H]3CCOC3)c(F)c2)c1C
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Product: COc1ncc(C)c(-c2ccc(-c3c(C(N)=O)cnn3[C@H]3CCOC3)c(F)c2)c1C
Temperature: 25 °C
Reaction time: 1.58 h
Yield: 96.4 %

Procedure:
CDI (21.4 g) was added at one time to a solution of 5-[2-fluoro-4-(2-methoxy-3,5-dimethylpyridin-4-yl)phenyl]-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylic acid (38.7 g) in DMF (290 mL) at room temperature, and the mixture was stirred at room temperature for 95 minutes. 28% aqueous ammonia (95 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 35 minutes. 28% aqueous ammonia (95 mL) was added again to the reaction mixture, and the mixture was stirred at room temperature for 90 minutes. The reaction mixture was concentrated under reduced pressure. Chloroform (250 mL) and water (80 mL) were added to the resulting residue, and the organic layer was separated. The aqueous layer was re-extracted with chloroform (50 mL). The combined organic layers were sequentially washed with a saturated aqueous ammonium chloride solution (60 mL×3) and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was passed through a silica pad (NH-silica gel). The filtrate was concentrated under reduced pressure to give the title compound (37.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[O:5].[CH2:15]([CH:17]1[O:19][CH2:18]1)[Cl:16]>C(O)(=O)C>[Cl:16][CH2:15][CH:17]([OH:19])[CH2:18][NH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[O:5]
Reactant: ClCC1CO1
Reactant: Nc1ccccc1C(=O)c1cccs1
Solvent: CC(=O)O
Product: O=C(c1cccs1)c1ccccc1NCC(O)CCl

Procedure:
20.3 g. of 2-(2'-aminobenzoyl)thiophene were heated for 6 hours at 60°-70° C. together with 10.2 g. of epichlorohydrin and 6 g. of acetic acid. This reaction mixture was then poured onto water, and the mixture was extracted with methylene chloride. The organic phase was separated off, washed until neutral, dried and filtered, and the filtrate was evaporated. 25 g. of 2-(2'-[N-(3-chloro-2-hydroxylpropyl)-amino]-benzoyl)-thiophene were obtained as an oily crude product. This was heated without further purification, for 2.5 hours on a waterbath together with 32 ml. of formic acid and 16 ml. of 37% strength formaldehyde solution. The solution was then poured onto ice, and the mixture was extracted with chloroform. The organic phase was washed with saturated sodium carbonate solution until it had a neutral reaction. The chloroform phase was then dried and filtered, and the filtrate was evaporated. 24 g. of 2-(2'-[N-(3-chloro-2-hydroxypropyl)-methylamino]-benzoyl)-thiophene were obtained. This was reacted with 3.5 g. of sodium hydroxide and 6.8 ml. of water in 50 ml. of dioxane and 50 ml. of isopropanol for 10 hours at room temperature. After removal of the organic solvent in vacuo, the oily crude product was dissolved in methylene chloride, and the solution was washed with water until neutral, dried over sodium sulphate and filtered. The methylene chloride was distilled off, and 12 g. of 2-(2-[N-(2,3-epoxypropyl)-methylamino]-benzoyl)-thiophene were obtained. This was cyclised with 36 g. of ammonia in 1,200 ml. of methanol by heating for 10 hours at 150° C. in a steel autoclave. When the solvent had been distilled off, 9 g. of 1-methyl-3-hydroxy-6-thienyl-1,2,3,4-tetrahydro-1,5-benzodiazocine were obtained. Boiling for 2 hours with thionyl chloride under reflux produced 10 g. of crude 1-methyl-2-chloromethyl-5-(2'-thienyl)-1H-2,3-dihydro-1,4-benzodiazepine hydrochloride. After recrystallising from acetone/isopropanol, 8 g. of 1.methyl-2-chloromethyl-5-(2'-thienyl)-1H-2,3-dihydro-1,4-benzodiazepine hydrochloride having a melting point of 163°-164° C. were obtained.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:25]([O-:27])=[O:26])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.O1CCCC1.O.[OH-].[Li+]>O>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:25]([OH:27])=[O:26])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCC(=CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(=CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)O
Yield: 62.8 %

Procedure:
Ethyl, 7-(4,5-diphenyl-1H-imidazol-2-ylthio)-2-pentyl-2-heptenoate (0.37 g, 0.00078 mol) was combined with methanol (5 ml), tetrahydrofuran (2 ml) and lithium hydroxide monohydrate (0.16 g, 0.0038 mol) dissolved in water (3 ml), under a nitrogen atmosphere at ambient temperature. The reaction was heated to 50° for 4 hours, allowed to cool, concentrated then partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give an oil. The product was purified by flash chromatography eluting toluene: ethyl acetate: acetic acid (80:20:2) to give the title compound (0.22 g, 0.00049 mol, 63% yield) as a white foam. 1H NMR (CDCl3) δ7.5-7.4(d, 4H), 7.32-7.17(m, 7H), 6.77(t, 1H), 3.08(t, 2H), 2.3-2.15(m, 4H), 1.76-1.68(m, 2H), 1.57-1.50(m, 2H), 1.4-1.2(m, 6H), 0.87(t, 3H).
Reaction SMILES: [CH:1]([CH:4]([N:8]=[CH:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=1OC)[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH:22]([Li])([CH3:24])[CH3:23]>C1COCC1>[CH:22]([C:11]1[CH:12]=[C:13]([O:18][CH3:19])[C:14]([O:16][CH3:17])=[CH:15][C:10]=1[CH:9]=[N:8][CH:4]([CH:1]([CH3:2])[CH3:3])[CH:5]([CH3:6])[CH3:7])([CH3:24])[CH3:23]
Reactant: COc1cc(OC)c(OC)cc1C=NC(C(C)C)C(C)C
Reactant: [Li]C(C)C
Solvent: C1CCOC1
Product: COc1cc(C=NC(C(C)C)C(C)C)c(C(C)C)cc1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1-isopropyl-2-methyl-propyl)-(2,4,5-trimethoxy-benzylidene)-amine (1.024 g, 3.5 mmol) in 35 ml THF at −78° C. was added isopropyllithium (6.0 mL, 0.7 M in pentane) drop-wise over 5 minutes. The solution was allowed to stir 30 min at −78° C. After warming to room temperature over 45 minutes the mixture was quenched by the addition of 5 mL of 10% NH4Cl and concentrated in vacuo. 100 mL of H2O was added and the mixture was extracted with ethyl acetate, washed with H2O and then brine. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give (2-isopropyl4,5-dimethoxy-benzylidene)-(1-isopropyl-2-methyl-propyl)-amine as a yellow oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[F:10][C:11]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[C:12]=1[NH2:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:13][C:12]1[C:11]([F:10])=[CH:17][C:16]([F:18])=[CH:15][C:14]=1[F:19])=[O:8]
Reactant: O=C(Cl)CCCCCBr
Reactant: Nc1c(F)cc(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CCCCCBr)Nc1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
6-Bromohexanoyl chloride (234 mg, 1.1 mmols) was gradualy added dropwise to a chloroform (3 ml) solution of 2,4,6-trifluoroaniline (147 mg, 1.0 mmol) and triethylamine (11 mg, 1.1 mmols) cooling in ice bath, and stirred for 1 hour at room temperature. The reaction mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with 1N-HCl, an aqueous saturated solution of sodium hydrogencarbonate, water, and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. Then, the resulting solid was recrystallized from hexan-ether, and 6-bromo-N-(2,4,6-trifluorophenyl)hexan amide 283 mg(yield 87%) was obtained as colorless needle-like crystals. Potassium carbonate (45 mg, 0.33 mmols) and 18-crown-6 (8 mg, 0.03 mmols) were added to DMF (2 ml) solution of the resulting anilide (97 mg, 0.3 mmols) and 2-mercaprbenzoxzole (45 mg, 0.3 mmol), and stirred for 1.5 hours at 80° C. The mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. And the resulting crystals were recrystallized from hexane-ether, and colorless needle-like crystals 106 mg (yield: 90%) of the intended product as crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[N:8][O:9][CH:10]=1)=[O:5])C.Cl>C(O)(=O)C>[C:12]1([CH3:17])[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][N:8]=1
Reactant: CCOC(=O)c1conc1-c1ccccc1C
Agent: Cl
Solvent: CC(=O)O
Product: Cc1ccccc1-c1nocc1C(=O)O
Yield: 80.2 %

Procedure:
A solution of 3-o-tolyl-isoxazole-4-carboxylic acid ethyl ester (1.32 g, 5.71 mmol, 1.0 equiv), 6M HCl aqueous solution (40 mL) and acetic acid (24 mL) was heated to reflux for 5 hours. After cooling, the mixture was partitioned between water and ethyl acetate and separated. The organic phase was sequentially washed with water and saturated aqueous sodium chloride solution. The collected organic was then dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 930 mg (80%) of crude 3-o-tolyl-isoxazole-4-carboxylic acid which was used without purification.