Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][C:8]([C:10]2[C:11]3[Se:23][CH:22]=[CH:21][C:12]=3[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1)=[O:4].C(OCC)(=O)C.O>[OH-].[Na+]>[OH:4][C:3]([C:5]1[O:9][C:8]([C:10]2[C:11]3[Se:23][CH:22]=[CH:21][C:12]=3[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1)=[O:2]
Reactant: COC(=O)c1ccc(-c2nn(-c3ccccc3)c3cc[se]c23)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(-c2nn(-c3ccccc3)c3cc[se]c23)o1
Yield: 78 %

Procedure:
Compound 34 (1.49 g, 0.004 mole) in 40 ml of 10% NaOH solution was heated under refluxing for 2 h. The progress of the hydrolysis reaction was monitored by TLC with ethyl acetate (EA). When the reaction was completed, the reaction mixture was poured into water to stop the reaction, and then was extracted with toluene. The aqueous layer was recovered, and acidified with 10% HCl solution, which was then extracted with EA. The organic layer was recovered and dried over MgSO4 and filtered. The solvent of the filtrate was evaporated under a reduced pressure, and the residue was then recrystallized from EA to afford compound 48 in brown columnar crystals (0.76 g). Yield: 78%; mp 234-237° C.
Reaction SMILES: [NH2:1][C:2]1([CH2:17][CH2:18][NH2:19])[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.C(N(CC)CC)C.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28].C(OCC)(=O)C>C1(C)C=CC=CC=1>[O:28]=[C:27]1[NH:19][CH2:18][CH2:17][C:2]2([CH2:3][C@H:4]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[CH2:5][CH2:6]2)[NH:1]1
Reactant: NCCC1(N)CC[C@@H](C(=O)OCc2ccccc2)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1NCCC2(CC[C@@H](C(=O)OCc3ccccc3)C2)N1
Temperature: 80 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
To a solution of (1R)-benzyl 3-amino-3-(2-aminoethyl)cyclopentanecarboxylate (from step D, 30 mg, 0.114 mmol) in toluene (2 mL) was added triethylamine (0.048 mL, 0.343 mmol) and 1,1′-Carbonyldiimidazole (37.1 mg, 0.229 mmol). The resulting mixture was stirred at 80° C. for 2 hours. To the reaction mixture was added ethyl acetate (10 mL) and the resulting mixture was washed with 1N hydrogen chloride (1 mL), water (2 mL), brine (2 mL), dried over Na2SO4 and concentrated under reduced pressure to yield (2R)-benzyl 7-oxo-6,8-diazaspiro[4.5]decane-2-carboxylate (20 mg, 0.069 mmol, 60.7% yield) as an oil. It was used as such for the subsequent step without further purification. MS (ESI+) m/z 288 M+
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[C:20]3[C:15]([CH:16]=[C:17]4[N:23]=[N:22][N:21]=[C:18]4[CH:19]=3)=[CH:14][NH:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Br[CH:25]([CH3:30])[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([N:12]2[C:20]3[CH:19]=[C:18]4[N:21]([CH:25]([C:26]([O:28][CH3:29])=[O:27])[CH3:30])[N:22]=[N:23][C:17]4=[CH:16][C:15]=3[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=1.[Cl:1][C:2]1[C:3]([N:12]2[C:20]3[CH:19]=[C:18]4[N:21]=[N:22][N:23]([CH:25]([C:26]([O:28][CH3:29])=[O:27])[CH3:30])[C:17]4=[CH:16][C:15]=3[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=1
Reactant: COC(=O)C(C)Br
Reactant: FC(F)(F)c1cnc(-n2[nH]cc3cc4nnnc4cc32)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)n1nnc2cc3c(cnn3-c3ncc(C(F)(F)F)cc3Cl)cc21
Product: COC(=O)C(C)n1nnc2cc3cnn(-c4ncc(C(F)(F)F)cc4Cl)c3cc21

Procedure:
To a solution of 5-(3-chloro-5-trifluoromethylpyridin-2-yl)[1,2,3]triazolo[4,5-f]indazole [Compound No. 48] (1.0 g) in N,N-dimethylformamide (10 g), methyl 2-bromopropionate (0.5 g) and potassium carbonate (1 g) were added, and the resultant mixture was stirred at 40° C. for 3 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give 5-(3-chloro-5-trifluoromethylpyridin-2-yl)-3-(1-methoxycarbonylethyl)[1,2,3]triazolo[4,5-f]indazole (0.3 g) and 5-(3-chloro-5-trifluoromethylpyridin-2-yl)-1-(1-methoxycarbonylethyl)[1,2,3]triazolo[4,5-f]indazole (0.1 g).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]1[C:23]2[CH:22]=[CH:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[CH:18]([C:28]#[N:29])[C:17]=2[CH:16]=[CH:15][CH:14]=1.Br[CH2:31][CH2:32][CH2:33][C:34]#[N:35]>C1COCC1>[C:34]([CH2:33][CH2:32][CH2:31][C:18]1([C:28]#[N:29])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:23]=2[CH:22]=[CH:21][C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]1=2)#[N:35]
Reactant: N#CCCCBr
Reactant: N#CC1c2ccccc2C=Cc2ccccc21
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#CCCCC1(C#N)c2ccccc2C=Cc2ccccc21
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 78.1 %

Procedure:
To a −5° C. solution of diisopropylamine (0.143 ml, 1 mmol) in THF (1 ml) was added dropwise nBuLi (0.67 ml, 1.06 mmol, 1.6 M in hexane). After 20 minutes stirring at −5° C., a solution of 5H-dibenzo[a,d]cycloheptene-5-carbonitrile (prepared according to: Regnier G. J. et al. J. Med. Chem. 1992, 35, 2481-2496) (0.2 g, 0.9 mmol) in THF (1 ml) was added dropwise. After 15 minutes at −5° C., a solution of 4-bromobutyronitrile (0.1 ml, 1 mmol) in THF (1 ml) was added slowly. The reaction mixture was allowed to warm up slowly to room temperature, stirred overnight and quenched with water and ether. Aqueous phase was extracted with ether and the combined organic phases were washed with water, dried with Na2SO4 and concentrated in vacuo. The residue was chromatographed over silica gel (hexane-ethylacetate 9:1) to provide 5-(3-cyano-propyl)-5H-dibenzo[a,d]cycloheptene-5-carbonitrile (0.2 g, 76%) as a colorless oil, MS: m/e=284 (M+).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[O:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.CC(C)([O-:29])C.[K+]>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16](/[CH:19]=[CH:23]/[C:22]([O:21][CH2:25][CH3:24])=[O:29])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)c1csc(-c2cc3cc(C=O)ccc3o2)n1
Reactant: C1CCOC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 0 °C

Procedure:
A mixture of 4-tert-butyl-2-(5-formylbenzofuran-2-yl)thiazole (1.83 g) and triethyl phosphonoacetate (1.53 ml) in the mixed solvent of tetrahydrofuran (10 ml) and N,N-dimethylformamide (10 ml) was stirred under ice-cooling. After several minutes, potassium tert-butoxide was added to the mixture, which was stirred for 1 hour at same temperature. The resulting mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate. The fractions containing the objective compound were combined and concentrated under reduced pressure to give ethyl (E)-3-[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]propenoate (0.68 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:22])([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[SH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[CH3:32].COC1C=CC(N)=C(C)C=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[S:21][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[CH3:32])([OH:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(I)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)ccc2S)CC1
Agent: COc1ccc(N)c(C)c1
Product: COc1ccc(Sc2ccc(F)cc2C2(O)CCN(C(=O)OC(C)(C)C)CC2)c(C)c1

Procedure:
Prepared from 4-hydroxy-4-(2-mercapto-5-fluoro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester and 1-iodo-4-methoxy-2-methyl-benzene (prepared from 4-methoxy-2-methyl-phenylamine by diazotization according to the general procedure by Tunney and Stille J. Org. Chem. 1987, 52, 748-753).
Reaction SMILES: C[N:2](/[CH:4]=[N:5]/[C:6]([C:8]1[S:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1)=O)C.O.[NH2:17]N>CC(O)=O>[N+:13]([C:10]1[S:9][C:8]([C:6]2[N:5]=[CH:4][NH:2][N:17]=2)=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: CN(C)/C=N/C(=O)c1ccc([N+](=O)[O-])s1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2nc[nH]n2)s1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
N-[(1E)-(Dimethylamino)methylene]-5-nitrothiophene-2-carboxamide (7.00 g, 30.8 mmol) was combined with AcOH (70 mL) and hydrazine hydrate (65% wt, 2.76 mL, 37.0 mmol) and stirred at 90° C. for 1.5 h. The yellow solution was cooled to room temperature and concentrated. The resulting slurry was diluted with CH2Cl2 and saturated NaHCO3 and stirred. The yellow precipitate was isolated by filtration and dried to provide the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][OH:7].C(N(CC)C(C)C)(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(#N)C>[S:25]([O:7][CH2:6][C:5]1[CH:8]=[C:9]([O:13][CH3:14])[C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:27])(=[O:26])[CH3:24]
Reactant: COc1cc(CO)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(COS(C)(=O)=O)cc(OC)c1OC
Reaction time: 2 h

Procedure:
Combine 3,4,5-trimethoxybenzyl alcohol (9.0 g, 45.4 mmol), N,N-diisopropylethylamine (12.9 g, 100 mmol), and acetonitrile (60 mL). Cool in an ice bath. Add methanesulfonyl chloride (6.76 g, 49.0 mmol). After 2 hours, partition the reaction mixture between water and ethyl acetate. Separate the layers and extract the organic layer with 1 M hydrochloric acid solution and them a saturated solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[NH:11][C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9]2.[C:23](=O)([OH:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].O1CCCC1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[N:11]([C:23]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29])[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9]2
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc([N+](=O)[O-])c2[nH]1
Reactant: CC(C)(C)OC(=O)O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(OCCOC)cc([N+](=O)[O-])c2n1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
To a mixture of ethyl 5-(2-methoxyethoxy)-7-nitro-1H-indole-2-carboxylate (3.08 g), t-butyl bicarbonate (4.37 g) and tetrahydrofuran (100 mL) was added N,N-dimethyl-4-aminopyridine (122 mg), and the mixture was stirred at 50° C. for 4 hr. The reaction mixture was diluted with ethyl acetate and water, and the organic layer was washed successively with 10% aqueous citric acid solution, aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography to give the title compound (3.93 g, yield 96%) as a yellow oil from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH2:10][OH:11].C([O-])([O-])=O.[K+].[K+].CC(C)=O>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: OCCOc1ccc(Br)cc1
Yield: 44.2 %

Procedure:
In a reactor, 10.0 g of 4-bromophenol, 7.95 g of ethylene bromohydrin, 16.0 g of K2CO3, and 300 ml of acetone were charged, and stirred and refluxed for 50 hours to give a reaction solution. The reaction solution was poured into water, extracted with toluene, washed with water, and thereafter dried over sodium sulfate anhydride, and the solvent was evaporated and the residue was distilled under reduced pressure in GTO (glass tube oven) to give 5.55 g (Y., 44.3%) of 1-bromo-4-(2-hydroxyethoxy) benzene.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH:18]4[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]([S:29]([NH2:31])=[O:30])([CH3:28])([CH3:27])[CH3:26].[CH2:32]([Mg]Cl)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>O1CCCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH2:32]([C:21]1([NH:31][S:29]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:30])[CH2:22][CH2:23][CH:18]([O:17][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[O:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:15]3)[CH2:19][CH2:20]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1CCC(Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Reactant: CC(C)(C)S(N)=O
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)S(=O)NC1(Cc2ccccc2)CCC(Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 43.5 %

Procedure:
To a solution of 352 mg of 4-(2-phenyl-chroman-6-yloxy)-cyclohexanone (1.1 mmol) in 10 ml of tetrahydrofuran at room temperature 0.46 ml of titanium(IV) ethoxide (2.18 mmol) and 139 mg of tert-butylsulfinamide (1.15 mmol) were added and the resulting solution heated to reflux for 16 h. The solution was cooled to 0° C. and 1.09 ml of benzylmagnesium chloride (2M in tetrahydrofuran, 2.18 mmol) were added. The mixture was stirred at room temperature for 16 h and additional 1.09 ml of benzylmagnesium chloride solution were added. After additional 16 h of stirring the reaction was stopped by careful addition of water. The suspension was filtered and the filter cake washed with dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and filtered, and the solvent removed by evaporation. The resulting oil was purified by chromatography over silica gel using a heptane/ethyl acetate gradient (0% ethyl acetate to 25% ethyl acetate). 248 mg of 2-methyl-propane-2-sulfinic acid [1-benzyl-4-(2-phenyl-chroman-6-yloxy)-cyclohexyl]-amide were isolated as a mixture of diastereomers (44%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](OC)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:15].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CC(=O)OCC>C1COCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:15]
Reactant: COC(=O)c1ccc2c(c1)nc(C)n2C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc2cc(CO)ccc2n1C
Reaction time: 1 h

Procedure:
To a solution of Methyl 1,2-dimethyl-1H-benzo[d]imidazole-5-carboxylate (500 mg, 2.448 mmol) in THF (24.5 ml) Lithiumaluminium hydride (1 M in THF, 2.44 ml) was added at 0° C. After 2 hours sodium sulfate decahydrate and citric acid was added to the reaction to destroy the excess of lithiumaluminiumhydride. After 1 hour, methanol (25 ml) was added and the fine suspension was filtered off. The filtrate was evaporated under reduced pressure to afford a brown solid. EA (50 ml) was added and the suspension was treated in an ultra sonic bath. The solid was filtered off and this procedure was repeated twice. The yellow filtrate was evaporated under reduced pressure to afford crude (1,2-Dimethyl-1H-benzo[d]imidazol-5-yl)methanol.
Reaction SMILES: [BH4-].[Li+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:27](OC)=[O:28])=[C:8]2[C:12]=1[N:11]=[C:10]1[N:13]([C:17]3[CH:18]=[N:19][C:20]([N:24]([CH3:26])[CH3:25])=[CH:21][C:22]=3[CH3:23])[CH2:14][CH2:15][CH2:16][N:9]21>O1CCCC1>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:18]=[N:19][C:20]([N:24]([CH3:25])[CH3:26])=[CH:21][C:22]=4[CH3:23])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH2:27][OH:28])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1cnc(N(C)C)cc1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(N(C)C)ncc1N1CCCn2c1nc1c(Cl)ccc(CO)c12
Temperature: 40 °C
Reaction time: 24 h
Yield: 99.7 %

Procedure:
Lithium borohydride (265 mg, 12.2 mmol) was added to a stirred solution of methyl 9-chloro-1-[6-(dimethylamino)-4-methylpyridin-3-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (1.22 g, 3.05 mmol) in tetrahydrofuran (20 ml) at room temperature, and the mixture was stirred at 40° C. for 24 hr. The reaction was quenched by aqueous saturated ammonium chloride at 0° C., concentrated in vacuo and the precipitate was collected by filtration, washed with water, diisopropyl ether to give the title compound as a colorless powder (1.13 g, 3.04 mmol, 99%).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>O1CCCC1>[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:35])[O:18][C:15]2[CH:16]=[C:17]3[C:12]([CH2:11][CH2:10][CH2:9][N:8]3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][CH:14]=2)=[CH:29][CH:28]=1
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (800 mg, 3.34 mM) and triethylamine (0.5 mL) in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 4-fluorophenyl isocyanate (570 mg/ml, 5.01 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was quenched with distilled water (1 mL) followed by the extraction with chloroform (3×15 mL). The combined fractions of chloroform was again washed with water and dried over sodium sulphate. Further concentration of chloroform fraction under vacuum afforded the crude product, which was cystallize with methanol-ether (1:5) to yield 8d as solid. Yield: 1.06 g, 84.23%.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]([OH:16])=O)[CH:7]=1.[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=1)[CH3:21].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:14]([CH2:13][O:12][C:8]2[CH:7]=[C:6]([CH2:5][CH:4]([O:17][CH3:18])[C:3]([OH:2])=[O:19])[CH:11]=[CH:10][CH:9]=2)=[O:16])=[CH:24][CH:23]=1)[CH3:21]
Reactant: COC(=O)C(Cc1cccc(OCC(=O)O)c1)OC
Reactant: CCc1ccc(CCN)cc1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCc1ccc(CCNC(=O)COc2cccc(CC(OC)C(=O)O)c2)cc1

Procedure:
The title compound was prepared from 3-(3-carboxymethoxy-phenyl)-2-methoxy-propionic acid methyl ester (PREPARATION 4, step 2) and 2-(4-ethyl-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C22H27NO5 [M+H]+: 386.
Reaction SMILES: [CH:1]([C:4]1[O:5][C:6]2[C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=[CH:18][C:7]=2[C:8]=1[CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)=[CH:2][CH3:3].[CH2:28]1[C:33](=[O:34])N(Br)C(=O)C1.[OH2:36]>C1C=CC=CC=1>[C:33]([O:34][CH2:3][CH:2]=[CH:1][C:4]1[O:5][C:6]2[C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=[CH:18][C:7]=2[C:8]=1[CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)(=[O:36])[CH3:28]
Reactant: O=C1CCC(=O)N1Br
Reactant: O
Reactant: CC=Cc1oc2c(OCC(=O)OC)cccc2c1CCOC1CCCCO1
Solvent: c1ccccc1
Product: COC(=O)COc1cccc2c(CCOC3CCCCO3)c(C=CCOC(C)=O)oc12
Reaction time: 4 h
Yield: 36 %

Procedure:
Methyl (2-(1-propenyl)-3-(2-tetrahydropyranyloxyethyl)benzofuran-7-yloxy)acetate (523 mg) was dissolved in benzene (5 ml) and NBS (299 mg) and azoisobutylonitrile (23 mg) were added, followed by stirring the mixture for 4 hours. The reaction solution was poured into water (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying the resultant over sodium sulfate. After removing sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was dissolved in DMF (4 ml). Potassium acetate (205 mg) was added to this solution and the solution was stirred at room temperature for 50 minutes. The reaction solution was added to water (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine and dried over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=2/1) using silica gel to obtain the desired compound (217 mg, yield: 36%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:7][C:8]([F:18])([F:17])[O:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[F:7][C:8]([F:17])([F:18])[O:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][C:2](=[O:3])[O:4][CH2:5][CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccccc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Nc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Ethyl chloroformate (4.4 mL, 0.046 mol) was added to a mixture of 2-(trifluoromethoxy)aniline (8.25 g, 0.0466 mol), sodium carbonate (15 g, 0.14 mol), 1,4-dioxane (70 mL) and water (70 mL) at 0° C. and the reaction mixture stirred at room temperature overnight. The reaction mixture was then washed with ether, acidified (pH 3) and the product extracted into EtOAc (3×40 mL). The combined extracts were washed with water (40 mL) and brine (40 mL), dried over Na2SO4 and the solvent removed in vacuo to give the desired product in a 84% yield. 1H NMR (400 MHz, CDCl3): δ 1.33 (t, J=5.2 Hz, 3H), 4.25 (q, J=6.8 Hz, 2H), 6.91 (br, 1H), 7.04 (m, 1H), 7.23 (m, 1H), 7.28 (m, 1H) and 8.2 (m, 1H). MS (ES+): m/z 250.12 [MH+].
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16]Cl)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1.[CH3:25][N:26]([CH3:28])O.[H-].[Na+]>CN(C)C=O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][N:26]([CH3:28])[CH3:25])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1
Reactant: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Reactant: CN(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CN(C)C)n1-2

Procedure:
In the manner given in Example 15, 8-methylthio-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine is treated with a cold mixture of N,N-dimethyl-hydroxylamine and sodium hydride in dimethylformamide to give 8-methylthio-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N1 -oxide.