Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[N:16]=[C:15]([N:20]2[CH2:25][CH:24]=[CH:23][CH2:22][CH2:21]2)[N:14]=1>C(COC)OC>[NH2:19][C:17]1[N+:18]([O-:9])=[C:13]([NH2:12])[N:14]=[C:15]([N:20]2[CH2:21][CH:22]=[CH:23][CH2:24][CH2:25]2)[N:16]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1nc(N)nc(N2CC=CCC2)n1
Solvent: COCCOC
Product: Nc1nc(N2CC=CCC2)nc(N)[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
191 g. of m-chloroperbenzoic acid are dissolved in 800 ml. of dimethoxyethane and cooled to -5° C. 103 g. of 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]-s-triazine are then added in solid form within 2.5 hours. The mixture is left to warm to room temperature and then stirred overnight. The solvent is then concentrated at 20° C. under reduced pressure and 200 ml. of water are added. The pH value is then adjusted to 10 with sodium hydroxide and the solution is continuously extracted with chloroform for 20 hours. The solvent is then evaporated off and the crude product is chromatographed over silica gel, there being obtained pure 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]-s-triazine-3-oxide having a melting point of 261°-265° C.(decomposition).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=3)[N:12](C3CCCCO3)[N:11]=2)=[CH:6][CH:5]=1)[CH3:3].[N:27]([Sn](CCCC)(CCCC)CCCC)=[N+:28]=[N-:29].O1CCOCC1.Cl>C1(C)C=CC=CC=1.[OH-].[Na+]>[CH3:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[N:20]=[N:27][NH:28][N:29]=4)[CH:17]=3)[NH:12][N:11]=2)=[CH:8][CH:9]=1)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CC(C)c1ccc(-c2nn(C3CCCCO3)c3ccc(C#N)cc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)c1ccc(-c2n[nH]c3ccc(-c4nn[nH]n4)cc23)cc1
Yield: 80 %

Procedure:
The title compound was prepared from 3-[4-(methylethyl)phenyl]-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.095 g, 0.307 mmol), azidotributyl tin (0.744 g, 0.689 mL, 2.33 mmol) in toluene (10 mL) as described for the preparation of compound 167. Deprotection was effected by treating a dioxane solution (5 mL) with 5 mL of 6.0 N aqueous solution of hydrogen chloride. The solid obtained upon completion of the reaction was partially dissolved in 2.0 N aqueous sodium hydroxide and was extracted in ethyl acetate (4×15 mL). (0.260 g, 0.85 mmol, 80% yield over 2 steps): 1H NMR (DMSO-d6) δ 13.5 (br s, 1H), 8.7 (s, 1H), 8.1 (d, 1H), 7.9 (d, 2H), 7.8 (d, 1H), 7.4 (d, 2H), 3.0 (septet, 1H), 1.3 (d, 6H); ES-MS (m/z) 305 [M+1]+.
Reaction SMILES: [OH-].[NH4+:2].[N+:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11](Cl)(=[O:13])=[O:12])([O-:5])=[O:4]>O1CCCC1>[N+:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11]([NH2:2])(=[O:13])=[O:12])([O-:5])=[O:4]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1ccsc1S(=O)(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1sccc1[N+](=O)[O-]
Yield: 111.6 %

Procedure:
Ammonium hydroxide (28% aqueous, 2.4 mL, 17.57 mmol) was added to a stirred solution of 3-nitro-thiophene-2-sulfonyl chloride (1.00 g, 4.39 mmol) in tetrahydrofuran (50 mL) at room temperature. After 15 min the reaction mixture was concentrated under reduced pressure. The residue was triturated in methanol and dichloromethane. The solid was collected by filtration and dried to give 1.02 g (quantitative yield) of the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[CH:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@:8]3([OH:22])[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.[C:23](OC(=O)C)(=[O:25])[CH3:24].C([O-])(=O)C>N1C=CC=CC=1>[C:23]([O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[CH:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@:8]3([OH:22])[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@H](O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@]12O
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@]32O)C1

Procedure:
3β,14β-Dihydroxyandrostan-17-one-(70 mg.) was dissolved in 5 ml. of pyridine and treated with 1 ml. of acetic anhydride at room temperature for 15 hours. After evaporation of solvents, the residue was crystallized from ether to give 70 mg. of the acetate, m.p. 182°-184°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[F:21][C:22]([F:35])([F:34])[O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[Cl:19][C:6]1[CH:5]=[C:4]([NH:20][S:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:34])[F:35])=[CH:29][CH:28]=2)(=[O:32])=[O:31])[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Product: O=S(=O)(Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1)c1ccc(OC(F)(F)F)cc1

Procedure:
N-[3,5-Dichloro-4-(6-chlorobenzothiazol-2-yloxy)-phenyl]-4-trifluoromethoxy-benzenesulfonamide was synthesized (83%) from 3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (420) and 4-trifluoromethoxybenzenesulfonyl chloride (Maybridge) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.15 (d, J=2.2 Hz, 1H), 8.03-7.98 (m, 2H), 7.68 (d, J=8.7 Hz, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.46 (dd, J=8.7, 2.2 Hz, 1H), 7.31 (s, 2H). MS (EI): m/z 567 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2.[H-].[Na+].[CH3:27]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:27])[CH:20]=[CH:19]2
Reactant: CI
Reactant: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc4c(ccn4C)c3)c2cc1OC
Reaction time: 0.5 h
Yield: 62 %

Procedure:
6,7-Dimethoxy-4-[(1H-5-indolyl)oxy]quinoline (50 mg) was dissolved in N,N-dimethylformamide (1 ml), and 60% sodium hydride (7 mg) was added, followed by stirring for 30 min under ice cooling. Methyl iodide (0.0107 ml) was added to the reaction solution, and the mixture was stirred under ice cooling for additional one hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (32 mg, yield 62%).
Reaction SMILES: Cl.[C:2](=N)(OCC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O-]CC.[Na+].[CH3:17][C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]=1[C:29]([NH:31][NH2:32])=[O:30]>C(O)C.O1CCOCC1>[CH3:17][C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]=1[C:29]1[O:30][C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:32][N:31]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: CCOC(=N)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccccc2)o1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
To a solution of ethyl benzimidate hydrochloride (376 mg; 2.03 mmol) in ethanol (4 mL) was added at 0° C. sodium ethoxide (2.72 M in ethanol, 355 L, 0.99 mmol) and stirred for 15 min. The suspension was filtered off and 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was added and stirred for 90 h at 70° C. The reaction mixture was suspended in dioxane (4 mL) and heated in the microwave for 30 min at 180° C. Concentration and then purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (163 mg, 29%) as a white solid. MS: m/e=304.2 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2.[CH2:20]([O:22][C:23](=[O:33])[CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:21].C(N(CC)CC)C>C(#N)C>[CH2:20]([O:22][C:23](=[O:33])[CH2:24][N:25]([CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:21]
Reactant: CCOC(=O)CNCc1ccccn1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CN(Cc1ccccn1)Cc1cc([N+](=O)[O-])cc2nc(OC)c(OC)nc12

Procedure:
150 ml (0.46 mmol) of 5-bromomethyl-2,3-dimethoxy-7-nitro-quinoxaline, 98 mg (1.1 equiv.) of N-(2-pyridylmethyl)-glycine ethyl ester and 0.076 ml (1.2 equiv.) of triethylamine are stirred at reflux in 5 ml of acetonitrile for 20 hours. The mixture is concentrated by evaporation and the residue is suspended in diethyl ether and filtered. After drying, the title compound is obtained in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12]1[S:13][C:14](=[CH:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[CH:24][CH:23]=[CH:22]3)[C:15](=[O:17])[N:16]=1.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>CCO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([NH:11][C:12]2[S:13][C:14](=[CH:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][CH:23]=[CH:22]4)[C:15](=[O:17])[N:16]=2)[CH:4]=1
Reactant: O=C1N=C(Nc2cc([N+](=O)[O-])ccc2Cl)SC1=Cc1ccc2ncccc2c1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Cl)c(NC2=NC(=O)C(=Cc3ccc4ncccc4c3)S2)c1
Temperature: 25 °C
Yield: 20.5 %

Procedure:
A mixture of 2-(2-chloro-5-nitro-phenylamino)-5-quinolin-6-ylmethylene-thiazol4-one (100 mg, 0.42 mmol) and sodium sulfide nonahydrate (350 mg, 1-66 mmol) in 4 ml of EtOH was heated by microwave (SmithSynthesizer-Personal Chemistry) at 130 for 2 hours. The reaction mixture was cooled to room temperature and concentrated by vacuum distillation, then water was added and neutralized with aqueous ammonium chloride. Generated solid was collected by filtration and washed with water, followed by desiccation in vacuo to afford the title product (33 mg, 0.086 mmol). 1H NMR(DMSO-d6) δ 12.63 (s, 1H) 8.94 (m, 1H) 8.47 (d, 1H) 4.16 (s, 1H) 8.10 (d, 1H) 7.87 (dd, 1H) 7.84 (s, 1H) 7.56 (dd, 1H) 7.12 (d, 1H) 6.40 (d, 1H) 6.38 (s, 1H) 5.37 (s, 2H).:LC/MS: m/z 381 (M+1)
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C@H:23]2[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]2)[C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1.[H-].[Na+].[Cl:34][C:35]1[N:40]=[C:39](Cl)[CH:38]=[CH:37][N:36]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:31][C:2]([CH3:30])([CH3:1])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[C@H:23]2[CH2:28][CH2:27][C@H:26]([O:29][C:37]3[CH:38]=[CH:39][N:40]=[C:35]([Cl:34])[N:36]=3)[CH2:25][CH2:24]2)[CH:6]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](O)CC2)c(C(=O)O)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](Oc3ccnc(Cl)n3)CC2)c(C(=O)O)s1
Reaction time: 0.5 h

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (211 mg, 0.46 mmol) in DMF (2 mL) at 0 deg C. was treated with sodium hydride (110 mg, 2.8 mmol, 60% oil dispersion) in portions. The mixture was stirred for 30 minutes at 0 deg C. and a solution of 2,4-dichloropyrimidine (210 mg, 1.4 mmol) in DMF (1 mL) was added dropwise. The reaction mixture was allowed to warm and stir at room temperature. After completion, ethyl acetate (2-3 mL) was added and the mixture was carefully quenched with citric acid (10% aqueous solution, 2-3 mL). Water was added and the mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was passed through a plug of silica (0-5% MeOH:DCM eluent) and concentrated to yield 162 mg of 5-(3,3-dimethyl-but-1-ynyl)-3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(2-chloro-pyrimidin-4-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid as an impure black oil which was carried on without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[CH2:35](Br)[CH:36]=[CH2:37]>>[CH2:37]([O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1)[CH:36]=[CH2:35]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: C=CCBr
Product: C=CCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Method D, 9.53 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenyloxy)-propoxy]phenyl}piperidine-1 carboxylate and 3.42 ml of allylbromide are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.31 (1:2 EtOAc-heptane); Rt=6.03.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[C:15]([NH:21][C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:24]=3)[CH:16]=[CH:17][C:18]=2[O:19][CH3:20])=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[CH:14]=[C:15]([NH:21][C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:24]=3)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[N:10]=2
Reactant: N#C[S-]
Reactant: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc(N)cn1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
Potassium thiocyanate (1.26 g, 13.0 mmol) was suspended in acetic acid (15 mL), and the mixture was stirred at room temperature for 15 min. To the obtained solution was added a solution of N-{3-[(5-aminopyridin-2-yl)oxy]-4-methoxyphenyl}-3-(1-cyano-1-methylethyl)benzamide obtained above in acetic acid (25 mL), and the mixture was further stirred at room temperature for 15 min. A solution of bromine (690 mg, 4.32 mmol) in acetic acid (30 mL) was added dropwise to the obtained solution for 30 min or more. After the completion of the dropwise addition, the mixture was stirred at room temperature for 10 hr. The yielded yellow insoluble material was filtered off, and washed with acetic acid. The filtrate and the washing fluid were combined, and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (100 mL)/tetrahydrofuran (10 mL), and the suspension was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL) and aqueous ammonium chloride solution (50 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/80→0/100), and the obtained solution was concentrated under reduced pressure to give the title compound (1.00 g, 65%, 3 step yield) as a colorless amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=O)[C:4]=2[N:5]=[CH:6][N:7]=1.[F:23][C:24]([F:33])([F:32])[C:25]1[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([NH:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:32])[F:33])[CH:26]=3)=[O:18])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(C(=O)O)cc1/C=C/c1csc2c(N)ncnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1/C=C/c1csc2c(N)ncnc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.5 %

Procedure:
(E)-3-(2-(4-aminothieno[3,2-d]pyrimidine-7-yl)vinyl)-4-methylbenzoic acid (30 mg, 0.096 mmol) was dissolved in DMF (1 mL), 3-(trifluoromethyl)benzeneamine (16 mg, 0.096 mmol), HATU (110 mg, 0.289 mmol) and TEA (67 μL, 0.48 mmol) was added thereto and stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried with MgSO4, filtered and concentrated. The resulting mixture was purified by silica gel chromatography to obtain the title compound (36 mg, 82% yield).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:17])[NH:11]1.C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([NH:7][C:8]([N:11]2[CH:12]([C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:17])[CH2:13][CH2:14][CH2:15][NH:10]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NC1CCCCC1
Reactant: O=C(OCCCCc1ccccc1)C1CCCNN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCCCCc1ccccc1)C1CCCNN1C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
Cyclohexylisocyanate (0.38 g, 3.0 mmol) was added to a CH2Cl2 solution containing 4-phenylbutyl perhydropyridazinecarboxylate (0.72 g, 2.75 mmol) and triethylamine (0.42 ml, 3 mmol). The reaction was stirred overnight at room temperature under nitrogen atmosphere, and then diluted to 50 ml CH2Cl2. The organic layer was washed with water, dried, and concentrated. The crude material was purified by silica gel column to yield 0.95 g (89%) final product as clear oil. Rf=0.28 (2:1 hexane:EtOAc). 1H NMR (CDCl3, 400 MHz): δ 1.10 (m, 3H); 1.33 (m, 3H); 1.69 (m, 10H); 1.88 (m, 2H); 2.62 (m, 2H); 2.72 (m, 1H); 2.87 (m, 1H); 3.60 (m, 1H); 4.13 (m, 3H); 4.38 (m, 1H); 5.11 (d, 1H, J=8.3); 7.23 (m, 5H). Anal. Calcd. for C22H28N3O3-0.14H2O: C, 67.75; H, 8.60; N, 10.77. Found: C, 67.75; H, 8.45; N, 10.90.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:8][CH2:9][CH2:10][OH:11].[C:20](O)(=[O:22])[CH3:21]>>[C:20]([O:11][CH2:10][CH2:9][CH2:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:19])(=[O:22])[CH3:21]
Reactant: CC(=O)O
Reactant: Cc1ccccc1C(CCCO)c1ccccc1C
Product: CC(=O)OCCCC(c1ccccc1C)c1ccccc1C

Procedure:
The crude 2,2-di-(2-tolyl)-tetrahydrofuran 33a (28 g) was dissolved in acetic acid (250 mL). 5% palladium on Carbon black (3 g) was added and the mixture was hydrogenated in a Parr apparatus at 3 ato at 55° C. for 5 hrs. The catalyst was filtered off and the solvent was evaporated in vacuo. The remaining oil was subjected to CC (n-heptane/ethyl acetate--15:1) to give 4,4-di-(2-tolyl)-1-butanol (17 g). A solution of 4,4-di-(2-tolyl)-1-butanol (19 g) in acetic acid (400 mL) was boiled under reflux for 3 hrs. The cooled solution was evaporated in vacuo to give 4,4-di-(2-tolyl)-1-butyl acetate (17 g) as an oil. A solution of 4,4-di-(2-tolyl)-1-butyl acetate (9.2 g) in 57% aqueous iodic acid (150 mL) was boiled under reflux for 3 hrs. The cooled solution was poured into a mixture of ice and water and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with water and a saturated aqueous solution of NaCl, dried (Na2SO4) and evaporated in vacuo to give the title compound 34a (11.7 g) as an oil, which was used without further purification. 1H NMR (CDCl3) δ1.80-2.10 (m,4H), 2.28 (s,6H), 3.17 (t,2H), 4.26 (t,1H), 7.12 (s,8H)
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH:24]=[CH:25][CH:26]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].CS(C)=O.[NH2:40][CH2:41][C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1>C(#N)C>[CH3:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:40][CH2:41][C:42]4[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:22]=1
Reactant: NCc1cccnc1
Reactant: Cc1ccccc1-c1cccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)c1
Solvent: CC#N
Solvent: CS(C)=O
Product: Cc1ccccc1-c1cccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)c1
Yield: 77.1 %

Procedure:
To a solution of 2,2,2-trichloro-1-{10-[(2′-methyl-1,1′-biphenyl-3-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step C (0.600 g, 1.1 mmol) and dimethyl sulfoxide (0.41 mL, 5.8 mmol) in dry acetonitrile (5.5 mL) at room temperature under nitrogen was added 3-(aminomethyl)pyridine (0.23 mL, 2.2 mmol) and the reaction mixture heated to reflux for 45 hours. The cooled reaction mixture was concentrated in vacuo, the oily residue redissolved in ethyl acetate (25 mL), washed with 1 M sodium hydroxide (25 mL), water (25 mL) and brine (25 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a pale orange foam. Purification by flash chromatography using ethyl acetate as solvent afforded a pale yellow foam that was recrystallized from ethyl acetate/diethyl ether/hexane to give the title compound (0.435 g, 74%) as an off-white crystalline solid.
Reaction SMILES: [CH:1]([CH:3]1[CH2:7][N:6]([C:8]2[C:12]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:11][N:10]([CH3:21])[N:9]=2)[C:5](=[O:22])[C:4]1([CH3:24])[CH3:23])=O.[CH3:25][NH:26][CH3:27].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1.C(O)(=O)C>[CH3:25][N:26]([CH2:1][CH:3]1[CH2:7][N:6]([C:8]2[C:12]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[CH:11][N:10]([CH3:21])[N:9]=2)[C:5](=[O:22])[C:4]1([CH3:23])[CH3:24])[CH3:27]
Reactant: CNC
Reactant: Cn1cc(NC(=O)OC(C)(C)C)c(N2CC(C=O)C(C)(C)C2=O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)CC1CN(c2nn(C)cc2NC(=O)OC(C)(C)C)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (3-(4-formyl-3,3-dimethyl-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamate (173 mg) obtained in Step D of Example 4, 2M dimethylamine THF solution (0.39 mL) and acetic acid (30 μL) in THF (5.0 mL) was added sodium triacetoxyborohydride (220 mg). The reaction mixture was stirred at room temperature for 16 hr, saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and then HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)), and the obtained fraction was concentrated under reduced pressure to give the title compound (112 mg).