Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[O:30][CH3:31])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O-:26])=[S:25])=[C:15]([CH2:18][CH:19]4[CH2:23][CH2:22][O:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:33]([O:39][CH2:40]I)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].O>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[O:30][CH3:31])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O:26][CH2:40][O:39][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[S:25])=[C:15]([CH2:18][CH:19]4[CH2:23][CH2:22][O:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C([O-])=S)=C(CC3CCOC3)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OCOC(=O)C(C)(C)C)=C(CC3CCOC3)CS[C@H]12)c1csc(N)n1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(tetrahydrofuran-3-yl)methylthio-3-cephem-4-carboxylate (71 mg) was dissolved in dimethylformamide (1 ml) and the solution was cooled to -20° C. The solution, after addition of iodomethyl pivalate (66 mg) thereto, was stirred at a temeprature of -20° to 10° C. for 30 minutes, after which cold water (10 ml) was added to the reaction solution. The resulting mixture was extracted with ethyl acetate (10 ml) and the organic layer separated was washed with an aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to leave a yellow oil. The oily residue was purifed by a column chromatography on a silica gel column (40 g) with elution using ethyl acetate as eluent to collect fractions containing the titled compound. Concentration of the fractions so collected under reduced pressure gave the titled compound (77 mg; 92%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:28]3[N:32]([CH3:33])[CH:31]=[N:30][CH:29]=3)([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:28]4[N:32]([CH3:33])[CH:31]=[N:30][CH:29]=4)([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)[OH:20])[CH:8]=3)[N:3]3[N:34]=[N:35][N:36]=[C:2]3[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(C(O)(c2ccc3nc(Cl)nc(-c4cccc(Cl)c4)c3c2)c2cncn2C)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(O)(c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)c2cncn2C)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
A mixture of intermediate 24 (0.0105 mol) and sodium azide (0.031 mol) in DMF (70 ml) was stirred at 90° C. for 2 hours then cooled and poured out into ice water. The precipitate was filtered and taken up in DCM. The organic layer was washed with water, separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (15-40 μm) (eluent: DCM/MeOH/NH4OH; 95/5/0.1). The pure fractions were collected and the solvent was evaporated, yielding 3.68 g (quantitative) of 5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-α-(4-methylphenyl)-tetrazolo[1,5-a]quinazoline-7-methanol (intermediate 25), mp. 200° C.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[C:15](=[O:16])[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][NH:12]2)[CH:6]=1.[C:23](O)(=[O:27])[CH2:24][CH2:25][CH3:26].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[ClH:1].[O:16]=[C:15]1[N:11]([C:7]2[CH:6]=[C:5]([CH2:4][NH:3][C:23](=[O:27])[CH2:24][CH2:25][CH3:26])[CH:10]=[CH:9][N:8]=2)[NH:12][CH:13]=[C:14]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Reactant: CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80.0 mg (235 μmol) of the compound from Example 35 and 22.8 mg (259 μmol) butyric acid are dissolved in 5 ml DMF, 119 mg (1.18 mmol) triethylamine and 90.2 mg (470 μmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added, while cooling with ice, and the mixture is stirred overnight at RT. The reaction mixture is then purified directly by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid).
Reaction SMILES: [CH2:1](I)[CH3:2].[Br:4][C:5]1[CH:6]=[CH:7][C:8]([F:13])=[C:9]([Zn]I)[CH:10]=1>CN(P(N(C)C)(N(C)C)=O)C>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([F:13])=[C:9]([CH2:1][CH3:2])[CH:10]=1
Reactant: Fc1ccc(Br)cc1[Zn]I
Reactant: CCI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCc1cc(Br)ccc1F
Temperature: 100 °C
Yield: 109.4 %

Procedure:
Ethyl iodide (0.14 ml, 1.8 mmol) was added to a solution of (5-bromo-2-fluorophenyl)(iodo)zinc (0.5M in tetrahydrofuran) (5.4 ml, 2.7 mmol) in HMPA (10 ml). The reaction mixture was heated to 100° C. for 48 hrs. After which time the reaction mixture was cooled to room temperature and partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was separated and dried over anhydrous sodium sulfate, filtered and the solvent was removed in vacuo. The crude oil was purified by column chromatography on silica gel eluting with 80:20 hexanes:ethyl acetate, to afford the title compound as a yellow oil (0.4 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)=[O:6])[CH3:2].[BH4-].[Na+]>CCO>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([OH:6])[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(SC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(O)c1ccc(SC)cc1
Reaction time: 0.5 h

Procedure:
To a solution of (4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (Described in J. Med. Chem. 1981, 407) (1.0 eq) in EtOH (0.22M) at −78° C. was added NaBH4 (0.5 eq). The resulting mixture was stirred for 30 min then quenched at −78° C. by adding saturated aqueous NH4Cl. The residual mixture was concentrated, filtered on silica gel using EtOAc. The combined organic extracts were concentrated and the residual solid was recrystallised in Et2O/Hex to afford the desired compound as a yellow solid.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[C:6]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[S:8][N:7]=1>C(#N)C>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]2[S:8][N:7]=[C:6]([NH:3][CH2:2][CH2:1][NH2:4])[C:10]=2[CH:11]=1)([O-:17])=[O:16]
Reactant: NCCN
Reactant: O=[N+]([O-])c1ccc2snc(Cl)c2c1
Solvent: CC#N
Product: NCCNc1nsc2ccc([N+](=O)[O-])cc12
Yield: 35 %

Procedure:
Ethylenediamine (1.5 mL, 24 mmol) was added dropwise to a solution of 3-chloro-5-nitrobenzo[d]isothiazole (250 mg, 1.2 mmol) in acetonitrile (1 mL). The reaction mixture was microwaved at 120° C. for 10 min. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with water and the aqueous mixture was extracted with ethyl acetate. The organic extract was concentrated under reduced pressure and the crude product was purified by column chromatography, on silica gel, eluting with a mixture of 2% methanol in dichloromethane and selected fractions were combined and concentrated under reduced pressure to yield N1-(5-nitrobenzo[d]isothiazol-3-yl)ethane-1,2-diamine (100 mg) as a yellow solid.
Reaction SMILES: [CH:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[C:4](OCC)=O)=[O:2].C[O-].[Na+].[N+:21]([NH:24][C:25]([NH2:27])=[NH:26])([O-:23])=[O:22]>CO>[N+:21]([NH:24][C:25]1[NH:27][C:1](=[O:2])[C:3]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:4][N:26]=1)([O-:23])=[O:22]
Reactant: CCOC(=O)C(C=O)Cc1cccc(OC)c1
Reactant: N=C(N)N[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)c1
Yield: 29.2 %

Procedure:
Ethyl 2-formyl-3-(3-methoxyphenyl)propionate (10 g) was added dropwise to a stirred and boiling mixture of sodium methoxide (from 1.15 g sodium) and nitroguanidine (25% wet, 5.5 g) in methanol (250 ml) and the mixture was heated under reflux for 20 hours and evaporated to dryness. The residue was dissolved in water (100 ml), the solution was extracted with ether and the aqueous phase was adjusted to pH 4: the solid which separated was recrystallized from ethanol to give 2-nitroamino-5-(3-methoxybenzyl)-4-pyrimidone (3.41 g, 29%), m.p 178°-9°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1.Cl[C:14]1[NH:19][C:18]2[N:20]=[CH:21][CH:22]=[CH:23][C:17]=2[C:16](=[O:24])[N:15]=1.CC([O-])(C)C.[K+].CC#N>CS(C)=O.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][O:12][C:14]2[NH:15][C:16](=[O:24])[C:17]3[CH:23]=[CH:22][CH:21]=[N:20][C:18]=3[N:19]=2)=[CH:5][CH:4]=1
Reactant: O=c1nc(Cl)[nH]c2ncccc12
Reactant: COc1ccc(CCCO)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CCCOc2nc3ncccc3c(=O)[nH]2)cc1
Temperature: 120 °C

Procedure:
In a screw-capped glass tube, 3-(4-methoxyphenyl)-1-propanol ([5406-18-8], 137 mg, 0.826 mmol) was added to a mixture of 2-chloropyrido[2,3-d]pyrimidin-4(1H)-one ([93049-38-8], 50 mg, 0.28 mmol) and KOtBu (62 mg, 0.55 mmol) in DMSO (2 ml). The mixture was heated (3 days, 120° C.) and the title compound was isolated from the product mixture by reversed-phase, preparative HPLC (Agilent Zorbax XdB C18 column, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 7 min, flow rate 30 ml/min). MS: m/e=310.5 [M−H−], 1H NMR (d6-DMSO): δ 2.02 (dd, 2H), 3.36 (d, 2H), 3.71 (s, 3H), 4.42 (d, 2H), 6.86 (d, 2H), 7.15 (d, 2H), 7.36 (dd, 1H), 8.38 (d, 1H), 8.79 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:21][CH2:20][CH2:19][C:10]3[CH:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:11]=3)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)n(-c2ccccc2)n1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)cc4)CC3)nn2-c2ccccc2)cc1

Procedure:
77 mg (65%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (70 mg, 0.225 mmol), 1-(4-chlorophenyl)piperazine (61 mg, 0.225 mmol), DIPEA (0.059 mL, 0.338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([OH:30])=O)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O: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.[NH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[OH:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][CH2:35][NH:34][C:28](=[O:30])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([CH2:24][CH:19]3[CH2:20][CH2:21][CH2:22][CH:23]=[C:18]3[C:9]3[O:10][C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH:26]=2)=[CH:38][CH:39]=1
Reactant: O=C(O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: NCCc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCCc1ccc(O)cc1)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
To a mixture of (±)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoic acid (300 mg, 0.690 mmol) and tyramine (123 mg, 0.897 mmol) in DMF (5 ml) was added 1-hydroxybenzotriazole (140 mg, 1.04 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (265 mg, 1.38mmol). After stirring the resulting mixture at room temperature for 3 hours, the reaction mixture was diluted with EtOAc (30 ml), washed with 1N-hydrochloric acid, water, saturated sodium hydrogencarbonate solution, water and brine successively, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 3:2 elution) to give (±)-N-[2-(4-hydroxyphenyl)ethyl]-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzamide (358.4 mg, 94%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]([CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=O)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH2:16][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1c(-c2ccccc2)[nH]c2ccccc12)C1CCCNC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(-c2[nH]c3ccccc3c2CC2CCCNC2)cc1
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
To a solution of 7.5 g (24.7 mmol) of (2-phenyl-1H-indol-3-yl)piperidin-3-ylmethanone in anhydrous tetrahydrofuran (100 ml) under an atmosphere of nitrogen was added cautiously over 5 min a solution of lithium aluminium hydride (50 ml of a 1M solution in tetrahydrofuran, 50 mmol) at 0° C. The mixture was heated at reflux for 3 hr, after which it was cooled and quenched by the careful addition of water (2 ml), 4N NaOH (2 ml), and water (6 ml). The mixture was stirred for 10 min then filtered through hyflo and evaporated in vacuo to afford 5.6 g (19.3 mmol; 78%) of 2-phenyl-3-(piperidin-3-ylmethyl)-1H-indole as a clear oil. δH (360 MHz; CDCl3) 1.00-1.13 (1H, m, aliphatic), 1.28-1.40 (1H, m, aliphatic), 1.44-1.62 (2H, m, aliphatics), 1.74-1.86 (1H, m, aliphatic), 2.27 (1H, t, J 10.3, aliphatic), 2.44-2.52 (1H, m, aliphatic), 2.75 (2H, dd, J 7.2 and 3.3, aliphatics), 2.91-3.03 (2H, m, aliphatics), 7.12 (1H, t, J 7.9 and 7.1, indole H5), 7.19 (1H, t, J 7.9 and 7.0, indole H6), 7.32-7.39 (2H, m, aromatics), 7.42-7.50 (2H, m, aromatics), 7.54 (2H, dd, J 8.5 and 1.4, aromatics), 7.62 (1H, d, J 7.1, indole H4), 8.10 (1H, br s, NH); m/z (ES+) 291 (M++H, 100%).
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][C:3]=1[O:10][CH3:11].BrC[C:14]([NH:16]C1C=CC(Br)=CC=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].C(#N)CC>C(OCC)(=O)C>[O:10]([CH2:11][C:14]([NH2:16])=[O:15])[C:3]1[CH:2]=[CH:9][CH:8]=[CH:5][CH:4]=1
Reactant: O=C(CBr)Nc1ccc(Br)cc1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC#N
Solvent: CCOC(C)=O
Product: NC(=O)COc1ccccc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 190 %

Procedure:
To 4-hydroxy-3-methoxybenzaldehyde (2.02 g, 13.3 mmol), 2-bromo-N-(4-bromophenyl)acetamide (3.00 g, 10.2 mmol) and potassium carbonate (2.12 g, 15.4 mmol) was added propionitrile (10 ml), and the mixture was stirred at 80° C. for one day. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by alumina column chromatography (developing solvent; ethyl acetate), and powderized with ethyl acetate-diisopropyl ether (1:5) to give a phenoxyacetamide derivative (2.93 g). The title compound was obtained by similar operations as in Reference Example 43 and Example 6 and using this compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[S:13][CH:14]=[C:15]([CH2:17]Cl)[N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:19]1([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH:23]=[N:22][N:21]=[N:20]1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[S:13][CH:14]=[C:15]([CH2:17][O:30][C:27]3[CH:28]=[CH:29][C:24]([N:19]4[CH:23]=[N:22][N:21]=[N:20]4)=[CH:25][CH:26]=3)[N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(-n2cnnn2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(c2nc(CCl)cs2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)C1

Procedure:
A mixture of 3-(4-chloromethyl-thiazol-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (From Step 1) (386 mg, 1.34 mmol), 4-tetrazol-1-yl-phenol (217 mg, 1.34 mmol), Cs2CO3 (655 mg, 2.01 mmol) and KI (22 mg, 0.13 mmol) in acetonitrile (5 mL) was heated under reflux for 4 hours. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on silica gel (EtOAc-hexanes, 1:1) to afford the desired product. 1H NMR (CDCl3): δ 8.92 (1H, s), 7.61 (2H, d), 7.32 (1H, s), 7.19 (2H, d), 5.25 (2H, s), 4.39 (2H, m), 4.18 (2H, m), 4.14 (1H, m), 1.46 (9H, s).
Reaction SMILES: Cl[CH:2]([C:13](=O)[CH2:14][CH2:15][CH3:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[C:18]([NH2:21])(=[S:20])[CH3:19]>C(OCC)(=O)C>[CH3:19][C:18]1[S:20][C:2]([CH2:3][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)=[C:13]([CH2:14][CH2:15][CH3:16])[N:21]=1
Reactant: CC(N)=S
Reactant: CCCC(=O)C(Cl)Cc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Product: CCCc1nc(C)sc1Cc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 5.9 of 2-chloro-1-(4-nitrophenyl)hexan-3-one and 1.7 g of thioacetamide is heated at 90°-100° C. for 6 hours and then cooled and taken up with ethyl acetate. The precipitate formed is filtered off and washed with ethyl acetate and then with ether to give 5.6 g of 2-methyl-4-propyl-5-(4-nitrobenzyl)thiazole in the form of crystals melting at 124° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:4][N:3]=1.[CH3:19][S-:20].[Na+].C(OCC)C>CN(C)C=O>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([S:20][CH3:19])=[N:3][CH:4]=1)=[O:18]
Reactant: O=C(Cc1ccc(F)cc1F)c1ccc(Cl)nc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CSc1ccc(C(=O)Cc2ccc(F)cc2F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.3 %

Procedure:
A solution of the product of part (ii) (23.9 g, 89 mmol) in N,N-dimethylformamide (DMF) (105 ml) was treated with sodium methanethiolate (6.6 g, 94 mmol) and the resulting suspension was stirred for 2 hours at room temperature. The mixture was poured into diethyl ether (1000 ml) and the suspension was washed with water (2×500 ml). The organic phase was dried (MgSO4) and evaporated under reduced pressure. The crude product was triturated with diethyl ether to afford the title compound as a yellow solid, (3.3 g).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][C@H:6]([CH3:8])[CH2:5][N:4]1[CH2:9][CH2:10][C:11]#[N:12].C(N(CC)[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C>>[OH:1][CH2:2][C@H:3]1[CH2:7][C@H:6]([CH3:8])[CH2:5][N:4]1[CH2:9][CH2:10][C:11]1[NH:12][C:16](=[O:25])[C:17]2[C:18]([CH:24]=1)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: C[C@H]1C[C@H](CO)N(CCC#N)C1
Product: Cc1cccc2c(=O)[nH]c(CCN3C[C@@H](C)C[C@@H]3CO)cc12

Procedure:
(2R,4S)-4-Methylpyrrolidine-2-carboxylic acid described in J. Chem. Soc. C, pp. 514-522 (1971) is reacted with di-tert-butyl dicarbonate to give (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid. (2R,4S)-1-tert-Butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid is reacted with methyl iodide in the presence of potassium carbonate in acetonitrile solvent to give methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate. Methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate is reduced with lithium borohydride to give (2R,4S)-1-tert-butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine. (2R,4S)-1-tert-Butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine is reacted with 4N hydrogen chloride-dioxane to give (2R,4S)-2-hydroxymethyl-4-methylpyrrolidine hydrochloride. (2R,4S)-2-Hydroxymethyl-4-methylpyrrolidine hydrochloride is reacted with acrylonitrile to give 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile. In the same manner as in Example 1b (e) and using 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-{2-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]ethyl}-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[Cl:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=1[NH2:39]>>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[C:4]3[CH:3]=[C:2]([NH:39][C:32]4[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:31]=4[Cl:30])[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Reactant: COc1ccc(N)c(Cl)c1
Product: COc1ccc(Nc2cc3c(cn2)cc(-c2cnn(C(=O)OC(C)(C)C)c2)n3C(=O)OC(C)(C)C)c(Cl)c1
Yield: 72 %

Procedure:
The title compound was prepared in 72% yield from compound (10) and 2-chloro-4-methoxyphenylamine using the method described for Preparation 35. 1H-NMR (CDCl3, 500 MHz): δ 1.49 (s, 9H), 1.69 (s, 9H), 3.82 (s, 3H), 6.58 (d, J=0.95 Hz, 1H over br s, 1H), 6.86 (dd, J=2.84, 8.83 Hz, 1H), 7.03 (d, J=2.84 Hz, 1H), 7.38 (m, 1H), 7.73 (d, J=9.14 Hz, 1H), 7.82 (d, J=0.63 Hz, 1H), 8.21 (d, J=0.63 Hz, 1H), 8.46 (d, J=0.63 Hz, 1H).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][C:9]1[O:13][C:12]([N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[CH3:19])=[N:11][C:10]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=O)=O.O[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]#[N:36])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH:18]=[CH:17][N:16]=[C:15]3[CH3:19])[O:13][C:9]=2[CH2:8][CH2:7][CH2:6][O:5][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]#[N:36])=[CH:30][CH:29]=2)=[CH:21][CH:22]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOS(C)(=O)=O)o1
Reactant: N#CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccc(CC#N)cc2)o1

Procedure:
3-[4-(4-Chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyl methanesulfonate (400 mg), 4-hydroxyphenylacetonitrile (200 mg), potassium carbonate (276 mg) and N,N-dimethylformamide (10 ml) was stirred at 100° C. for 4 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml×2). The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, and 2-[4-[3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyloxy]phenyl]acetonitrile was obtained as a yellow oil (380 mg, 89%) from an ethyl acetate-hexane (2:1, v/v)-eluted fraction.