Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH3:21]>CO>[CH2:8]([OH:7])[CH2:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH3:21]
Reactant: CC/C=C\C/C=C\CCCC#CCCOC1CCCCO1
Solvent: CO
Product: CC/C=C\C/C=C\CCCC#CCCO
Yield: 83 %

Procedure:
A solution of 6 (2.2 g, 7.5 mmol) in methanol (50 mL) was stirred with DOWEX™ 50W-X8 (Dow Chemical, Midland, Mich.) ion exchange resin (2 g) and the formation of 7 was monitored by TLC. The resin was removed by filtration and washed with methanol (3×20 mL). The alcohol 7 was purified by flash chromatography (1.3 g, 83% yield). 13H NMR (200 MHz) δ: 5.36 (m, 4H, CH=CH), 3.66 (t, J=6.1, 6.4 Hz, 2H, CH2 -1), 2.78 (t, J=6.4, 6.7 Hz, 2H, =CH--CH2 --CH=), 2.42 (tt, J=2.1, 2.4, 6.1, 6.4 Hz, 2H, CH2 -2), 2.16 (tt, J-2.1, 2.4, 7.0, 7.3 Hz, 2H, CH2 -5), 2.15 (m, 2H, CH2 -7), 2.06 (dq, J=7.3, 7.0, 7.3, 7.6 Hz, 2H, CH2 -13), 1.55 (tt, J=7.1, 7.3, 7.3, 7.3 Hz, 2H, CH2 -6), 0.96 (t, J=7.3, 7.6 Hz, 3H, CH3 -14). 13C NMR (100.6 MHz) δ: 131.9(12), 129.0(11), 128.8(9), 127.2(8), 82.3(3), 76.6(4), 61.3(1), 28.8(7), 26.2(6), 25.5(10), 23.1(5), 20.5(2), 18.2(13), 14.2(14). MS [EI, m/z(%)] 161(15), 159(20), 145(30), 133(25), 131(27), 119(34), 117(42), 105(42), 95(17), 93(27), 91(83), 79(76), 77(37), 69(22), 67(78), 65(29), 55(46), 53(39), 44(29), 43(24), 42(34), 41(100), 40(61).
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:18][C:19]([O:21]CC)=[O:20])([O-:3])=[O:2].[OH-].[Na+:25]>O>[N+:1]([C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:18][C:19]([O-:21])=[O:20])([O-:3])=[O:2].[Na+:25]
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2Cl)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])Cc1cccc(Oc2ccccc2Cl)c1[N+](=O)[O-]

Procedure:
A mixture of ethyl 2-[2-nitro-3-(2-chlorophenoxy)phenyl]acetate and sodium hydroxide in water was treated in a similar manner to that of Example 5-(2) to give sodium 2-[2-nitro-3-(2-chlorophenoxy)phenyl]acetate.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[NH:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br-].[CH3:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].O>CN(C)C=O>[CH2:1]([N:8]([CH2:9][C:10]1[NH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:19][CH:20]=2)[N:14]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCC
Reactant: c1ccc(CNCc2nc(-c3ccc(-c4ccccc4)cc3)c[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCN(Cc1ccccc1)Cc1nc(-c2ccc(-c3ccccc3)cc2)c[nH]1
Reaction time: 3 h
Yield: 13 %

Procedure:
N-benzyl(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)methanamine (1 g; 0.0024 mol; prepared under experimental conditions similar to those previously and using suitable starting reagents and reaction products) is diluted in 15 ml of dimethylformamide. Potassium carbonate (1 g; 0.0073 mol) is added at 23° C. then hexane bromide (0.34 ml; 0.0024 mol) is added fairly slowly. The reaction mixture is brought to about 70° C. for 3 hours before being poured into ice-cooled water. The mixture is extracted with ethyl acetate and the organic phase is washed with water. After drying over magnesium sulphate, the solvents are concentrated using a rotary evaporator. After purification on a silica column (eluent: ethyl acetate-heptane/7-3), a light yellow-coloured solid is obtained in the form of a paste (yield of 13%). Free base. Melting point: 120-122° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][C:7]([CH3:15])=[N:6]1.[OH-].[Na+].Cl.C(OCC)(=O)C>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]([CH3:15])=[N:6]1
Reactant: CCOC(=O)c1cc(C)nn1CCOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCn1nc(C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
To a suspension of sodium hydride (310 mg, 7.8 mmol) in N,N-dimethylformamide (10 mL) was slowly added a solution of ethyl 3-methyl-1H-pyrazole-5-carboxylate (1000 mg, 6.5 mmol) in N,N-dimethylformamide (5 mL) under ice-cooling, and the mixture was stirred at 0° C. for 10 min, then at room temperature for 20 min. To the reaction mixture was added a solution of 1-bromo-2-methoxyethane (1090 mg, 7.8 mmol) in N,N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 7 hr. The solvent was evaporated under reduced pressure, and ethyl acetate/tetrahydrofuran and water were added to the residue. The aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×3). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→70/30) to give ethyl 1-(2-methoxyethyl)-3-methyl-1H-pyrazole-5-carboxylate (430 mg, 2.0 mmol) as a colorless liquid. To a solution of the obtained ethyl 1-(2-methoxyethyl)-3-methyl-1H-pyrazole-5-carboxylate (430 mg, 2.0 mmol) in tetrahydrofuran (6 mL) was added 8N aqueous sodium hydroxide solution (1.3 mL), and the mixture was stirred at room temperature for 3 hr. 1N Hydrochloric acid (13 mL) and ethyl acetate were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (×3). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give the title compound (310 mg, 83%) as a white solid.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH:12]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:11][CH2:10][CH2:9][C:8]2=1)C=C.[CH:24]1[C:29](Cl)=CC=C(Cl)[CH:25]=1>>[CH2:29]([C:6]1[C:5]([OH:4])=[CH:17][CH:16]=[C:15]2[C:7]=1[C:8]1[CH2:9][CH2:10][CH2:11][CH:12]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]=1[NH:14]2)[CH:24]=[CH2:25]
Reactant: C=CCOc1ccc2[nH]c3c(c2c1)CCCC3CC(=O)OCC
Reactant: Clc1ccc(Cl)cc1
Product: C=CCc1c(O)ccc2[nH]c3c(c12)CCCC3CC(=O)OCC

Procedure:
The product of Step 3 (400 mg) is heated in dichlorobenzene at 210° C. for 10 hours. Evaporation of the solvent and chromatography of the residue over silica gel using EtOAc-hexane yields ethyl 5-allyl-6-hydroxy-1,2,3,4-tetrahydrocarbazol-1-ylacetate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[N-:11]=[N+:12]=[N-:13].[Na+]>CC(C)=O>[N:11]([CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])=[N+:12]=[N-:13]
Reactant: N#Cc1ccccc1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Product: N#Cc1ccccc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A mixture of 2-bromomethyl-benzonitrile (300 mg, 1.53 mmol) and sodium azide (129 mg, 1.99 mmol) in acetone was stirred overnight at rt. The solvent was removed, and the resulting residue was chromatographered using hexane/ethyl acetate (6:1) to give the title compound (212 mg, 88%). MS (DCI/NH3) m/z 176 (M+18)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.69 (s, 2H) 7.58 (td, J=7.67, 1.23 Hz, 1H) 7.66 (d, J=7.67 Hz, 1H) 7.76 (td, J=7.67, 1.23 Hz, 1H) 7.91 (dd, J=7.67, 1.53 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1)#[N:2].C(=O)([O-])[O-].[Na+].[Na+].[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][C:22]=1[S:30](=[O:33])(=[O:32])[NH2:31]>O1CCOCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([Cl:20])=[C:22]([S:30](=[O:32])(=[O:33])[NH2:31])[CH:23]=2)[NH2:10])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(NN)c([N+](=O)[O-])c1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ccc(N(N)C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)c([N+](=O)[O-])c1
Yield: 20.8 %

Procedure:
The process described in Example 1(B) was followed and 8.1 g of 4-cyano-2-nitrophenylhydrazine (prepared as described in: Beilst. 9 Vol. II page 289), 114 ml of dioxane, 46 ml aqueous solution of 2.4 g of crystalline sodium carbonate and 11.6 g of 4-chloro-3-sulfamoylbenzoyl chloride dissolved in 53 ml of dioxane were used as starting materials. After evaporating the reaction mixture, the residue was thoroughly mixed with water, the yellow precipitate was filtered by suction, washed with water and dried at 80° C. Thus, 3.75 g (65%) of 4-cyano-2-nitro-N-(4'-chloro-3'-sulfamoylbenzoyl)-phenylhydrazine were obtained, m.p.: 292°-295° C. (with decomposition) after recrystallization from acetic acid.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(Cl)(Cl)Cl>[C:1]1([S:7][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCl
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: OCCCCSc1ccccc1
Yield: 3.1 %

Procedure:
A mixture of thiophenol (121.2 g, 1.10 mole), 4-chloro-1-butanol (100.0 g, 0.921 mole), and potassium carbonate (138.2 g, 1.0 mole) was heated overnight at gentle reflux in dimethoxyethane. The reaction mixture was filtered and solvent removed by rotary evaporator. The residue obtained was dissolved in chloroform and extracted with 10% sodium hydroxide. The chloroform layer was dried, filtered, and solvent removed to give an oil which crystallized to a white solid. The solid was vacuum distilled at 134°-140° C./0.55 mm. A six-gram sample of the distilled oil was subjected to flash chromatography on silica gel using ethyl acetate-hexanes for elution. This gave a clear oil which was dried at 80° C. overnight in vacuo. The process produced 5.2 g (57.8%) of clear oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:19]([OH:20])[C@H:18]([OH:21])[C@H:13]2[NH:14][C:15](=[O:17])[O:16][C@H:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.CCOC(C)=O>[C:22]([O:21][C@@H:18]1[C@H:13]2[NH:14][C:15](=[O:17])[O:16][C@H:12]2[CH2:11][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[C@H:19]1[O:20][C:9](=[O:8])[C:10]1[CH:19]=[CH:18][CH:13]=[CH:12][CH:11]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](O)[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 178.8 %

Procedure:
To a solution of (3aR,4R,5R,6R,7aS)-6-(((tert-butyldimethylsilyl)oxy)methyl)-4,5-dihydroxyhexahydrobenzo[d]oxazol-2(3H)-one (2.21 g, 7.00 mmol) and 4-dimethylaminopyridine (30 mg, 0.24 mmol) in pyridine (20 mL) at 0° C. was added benzoyl chloride (3.92 g, 27.9 mmol) dropwise. The mixture was stirred at room temperature for 20 h. The reaction was diluted with EtOAc (300 mL), washed with saturated aqueous NaHCO3 water (2×150 mL), 0.5 N HCl (2×100 mL) and brine and dried over MgSO4. The solvent was evaporated to give the crude product. This was purified by basic alumina column, eluted with 10-30% EtOAc in hexanes to provide (3aS,4R,5R,6R,7aS)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxooctahydrobenzo[d]oxazole-4,5-diyl dibenzoate (3.29 g, 90%). 1H NMR (400 MHz, CDCl3) δ 7.92-7.97 (m, 4H), 7.49-7.53 (m, 2H), 7.35-7.39 (m, 4H), 6.07 (s, 1H), 5.53 (t, J=10.1 Hz, 1H), 5.13 (dd, J=9.6 Hz, 6.6 Hz, 1H), 4.91-4.94 (m, 1H), 3.89 (t, J=7.0 Hz, 1H), 3.79 (dd, J=10.0 Hz, 4.0 Hz, 1H), 3.61 (dd, J=10.0 Hz, 2.6 Hz, 1H), 2.40 (dt, J=15.5 Hz, 3.0 Hz, 1H), 2.27-2.36 (m, 1H), 2.03-2.11 (m, 1H), 0.87 (s, 9H), −0.03 (s, 3H), −0.07 (s, 3H).
Reaction SMILES: [CH2:1]([S:3][CH:4]1[NH:7][C:6](=[O:8])[CH2:5]1)[CH3:2].C([O:11][CH:12](O)[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:14])C>C1C=CC=CC=1>[CH2:1]([S:3][CH:4]1[N:7]([CH:12]([OH:11])[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)=[O:14])[C:6](=[O:8])[CH2:5]1)[CH3:2]
Reactant: CCSC1CC(=O)N1
Reactant: CCOC(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Product: CCSC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 16 h

Procedure:
A solution of 12.3 g. of 4-ethylthio-2-oxoazetidine and 25.5 g. of p-nitrobenzyl glyoxylate ethyl hemiacetal in 900 ml. of benzene was heated under reflux for 16 hours. During the heating for 16 hours, water and ethanol were removed from the reaction mixture by azeotropic distillation using a Dean-Stark trap. At this point, the benzene was removed by evaporation in vacuo, and the residue was dissolved in 700 ml. of dichloromethane. The dichloromethane solution was washed three times with water, and then dried with anhydrous sodium sulfate. Evaporation in vacuo afforded 32.5 g of the title compound as a yellow semi-solid. The IR spectrum of the product in chloroform showed an absorption at 5.65 microns. The NMR spectrum of the product in deuterochloroform showed peaks at 1.25 (t, 3H); 2.35-3.62 (m, 4H); 4.3 (s, 1H); 4.85 (m, 1H); 5.22 and 5.54 (ss, 1H); 5.38 (s, 2H); 7.5 (d, 2H); and 8.2 (d, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[CH3:14][N:15]([CH3:32])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]3[N:24]([N:28]=[C:29]([NH2:31])[N:30]=3)[CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1>>[CH3:14][N:15]([CH3:32])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]3[N:24]([N:28]=[C:29]([NH:31][CH:10]4[CH2:11][CH2:12][N:7]([C:5]5[S:4][N:3]=[C:2]([CH3:1])[N:6]=5)[CH2:8][CH2:9]4)[N:30]=3)[CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1
Reactant: CN(C)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Product: Cc1nsc(N2CCC(Nc3nc4c(-c5ccc(N(C)C)cc5)cccn4n3)CC2)n1

Procedure:
Prepared in analogy to example 1h employing 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (see example 1c) and 8-(4-dimethylamino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (prepared in analogy to example 66a-c). The title compound was obtained as white foam. MS ISP (m/e): 435.3 (100) [(M+H)+].
Reaction SMILES: [CH3:1][O-].[Na+].[Na].[N:5]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:16]([OH:25])[C:15]=3[CH:26]=2)[CH:9]=[CH:8][N:7]=[CH:6]1>CO>[N:5]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:16]([O:25][CH3:1])[C:15]=3[CH:26]=2)[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: On1c(-c2ccccc2)nc2ccc(Cn3ccnc3)cc21
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COn1c(-c2ccccc2)nc2ccc(Cn3ccnc3)cc21
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a stirred sodium methoxide solution previously prepared starting from 0.46 parts of sodium and 32 parts of methanol were added 6.16 parts of 6-(1H-imidazol-1-ylmethyl)-2-phenyl-1H-benzimidazol-1-ol. After stirring for a while, the whole was concentrated and 2 portions of 18 parts of methylbenzene were added. After evaporation, there were added successively 27 parts of N,N-dimethylformamide and a solution of 2.84 parts of iodomethane in 9 parts of N,N-dimethylformamide. The whole was stirred first for 10 minutes at room temperature and then for 30 minutes at 60° C. The reaction mixture was evaporated and 50 parts of water were added to the residue. The precipitated product was filtered off, washed with water and purified by filtration over silica gel using a mixture of trichloromethane and methanol (92.5:7.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybisproprane. The product was filtered off and dried, yielding 5.4 parts (88.7%) of 6-(1H-imidazol-1-ylmethyl)-1-methoxy-2-phenyl-1H-benzimidazole; mp. 142.1° C. (compound 227).
Reaction SMILES: [C:1]1([C@H:7]2[C:12]3[NH:13][C:14]4[C:19]([C:11]=3[CH2:10][C@H:9]([C:20](OC)=[O:21])[NH:8]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([N:30]2[C:20](=[O:21])[C@H:9]3[N:8]([C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:12]4[NH:13][C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=5[C:11]=4[CH2:10]3)[C:31]2=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C=NC1CCCCC1
Reactant: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@H](c2ccccc2)N1
Product: O=C1[C@@H]2Cc3c([nH]c4ccccc34)[C@H](c3ccccc3)N2C(=O)N1C1CCCCC1

Procedure:
The same method as employed in the preparation of Example 1 but starting from trans methyl 1,2,3,4-tetrahydro-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate and cyclohexyl isocyanate gave after recrystallisation from methanol, the title compound as white crystals m.p.: 248-250° C.
Reaction SMILES: [C:1]([OH:5])(=O)[C:2]#[CH:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>ClCCl.C(O)C>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:1](=[O:5])[C:2]#[CH:3])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: C#CC(=O)O
Reactant: COc1ccc(-c2ccc(N)cc2)cc1
Solvent: CCO
Solvent: ClCCl
Product: C#CC(=O)Nc1ccc(-c2ccc(OC)cc2)cc1

Procedure:
Prepared analogously to Example 1.1.b. from propynoic acid and 4′-methoxybiphenyl-4-ylamine. Yield: 1.3 g (17.2% of theory); C16H13NO2 (M=251.28); calc.: molecular ion peak (M+H)+: 252; found: molecular ion peak (M+H)+: 252; Rf value: 0.6 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: C(S([NH:7][C:8]1([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][O:10][CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>CO.O1CCOCC1>[CH2:26]([O:25][C:23]([NH:7][C:8]1([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][O:10][CH2:11]1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)C1(NS(=O)C(C)(C)C)COC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)C(C)C1(NC(=O)OCc2ccccc2)COC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-{3-[(tert-butylsulfinyl)amino]oxetan-3-yl}propanoate (Preparation 34, 40 g, 140 mmol) in methanol (400 mL) at 0° C. was added a 4M solution of hydrogen chloride in 1,4-dioxane (72 mL). After 2 hours, a 4M aqueous solution of sodium hydroxide (400 mL) was added drop-wise until pH 7 was achieved whilst maintaining the temperature at 0° C. The methanol was removed in vacuo. The resulting solution was stirred with tetrahydrofuran (150 mL) and a 1M aqueous solution of sodium hydrogen carbonate (180 mL) at 0° C. Benzyl chloroformate (33.7 g, 187 mmol) was added and the reaction mixture stirred at room temperature for 18 hours. The organics were removed in vacuo and the resulting solution extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:36]/[O:37][CH3:38])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[CH:32][N:33]=[C:29]4[N:28]=[C:27](OC)[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.NC1SC=C(/C(=N/OC)/C(N[C@@H]2C(=O)N3[C@@H]2SCC(CSC2N4N=C(N)N=C4N=C(C)C=2)=C3[C:58]([OH:60])=[O:59])=O)N=1>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:36]/[O:37][CH3:38])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:58]([OH:60])=[O:59])[N:33]=[C:29]4[N:28]=[CH:27][CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3cc(OC)nc4ncnn34)CS[C@H]12)c1csc(N)n1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3cc(C)nc4nc(N)nn34)CS[C@H]12)c1csc(N)n1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3ccnc4nc(C(=O)O)nn34)CS[C@H]12)c1csc(N)n1

Procedure:
(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(5-methoxy-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Compound 17: (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-amino-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[CH3:16][S:17]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)Cn1ccc2cc(N)ccc21
Solvent: c1ccncc1
Product: COC(=O)Cn1ccc2cc(NS(C)(=O)=O)ccc21

Procedure:
To a solution of methyl 2-(5-amino-1H-indol-1-yl)acetate (730 mg, 3.54 mmol) in pyridine (15 ml), methanesulfonyl chloride (418 μl, 5.36 mmol) was added, and the mixture was reacted for 2 hours at room temperature. The solvent was evaporated and the resulting crude was partitioned between 1N HCl and ethyl acetate; the aqueous phase was extracted with ethyl acetate (3×30 ml) and dried over sodium sulfate. The solvent was removed obtaining crude methyl 2-(5-(methylsulfonamido)-1H-indol-1-yl)acetate that was used in the next step without any additional purification (1 g, 3.54 mmol, quantitative yield). MS/ESI+ 283.3 [MH]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[BH3-]C#N.[Na+].[F:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.CS(O)(=O)=O>CO>[F:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:1][C@H:2]2[CH2:6][CH2:5][NH:4][C:3]2=[O:7])=[CH:20][CH:19]=1
Reactant: N[C@H]1CCNC1=O
Reactant: O=Cc1ccc(OCc2cccc(F)c2)cc1
Agent: CS(=O)(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C1NCC[C@@H]1NCc1ccc(OCc2cccc(F)c2)cc1
Reaction time: 0.17 h

Procedure:
To a 2M solution of (S)-3-aminopyrrolidin-2-one (1.47 g, 14.6 mmol), prepared as described in Example 5, in anhydrous methanol 2.0 g of 3 Å molecular sieves and 0.77 g NaBH3CN (12 mmol) were added; after 10 minutes, 3.4 g (14.8 mmol) of 4-(3-fluorobenzyloxy)benzaldeyde in 40 ml of anhydrous methanol were added. The reaction was carried out for 3 hours, then the mixture filtered, the solution was evaporated yielding a residue which was directly flash-chromatographed on silica gel (eluant: CHCl3:CH3OH:NH3 (30%) 97:3:0.3, v:v:v) to give a white solid (3.4 g; 74%). The free base thus obtained was treated with a stoichiometric amount of methanesulfonic acid to give the title compound m.p. 140.5-143.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5]2[O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:4]=2[CH:3]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)(Cl)Cl>[C:23]([NH:1][C:2]1[C:7](=[O:8])[NH:6][C:5]2[O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:4]=2[CH:3]=1)(=[O:25])[CH3:24]
Reactant: Nc1cc2c([nH]c1=O)OCc1ccccc1-2
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc2c([nH]c1=O)OCc1ccccc1-2

Procedure:
To 2.0 gm of 2-amino-4,6-dihydro-3H-[2]benzopyrano[3,4-b]pyridin-3-one, in 100 ml of chloroform containing 1 ml of pyridine, add 0.80 gm of acetyl chloride. Stir the reaction at room temperature for 5 hours. Filter and wash the solution with water. Remove the solvent by stripping to give the title compound.