Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:36][O:37][CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[C:8]([NH:10][C@@H:11]2[C:34](=[O:35])[N:13]3[C:14]([C:31]([O-:33])=[O:32])=[C:15]([CH2:18][N+:19]([CH3:30])([CH3:29])[CH2:20][C:21]4[NH:22][CH:23]=[C:24]([OH:28])[C:25](=[O:27])[CH:26]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:36][O:37][CH2:38][C:39]([OH:41])=[O:40])[C:8]([NH:10][C@@H:11]2[C:34](=[O:35])[N:13]3[C:14]([C:31]([O-:33])=[O:32])=[C:15]([CH2:18][N+:19]([CH3:29])([CH3:30])[CH2:20][C:21]4[NH:22][CH:23]=[C:24]([OH:28])[C:25](=[O:27])[CH:26]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+](C)(C)Cc3cc(=O)c(O)c[nH]3)CS[C@H]12)c1csc(N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Product: C[N+](C)(CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1)Cc1cc(=O)c(O)c[nH]1
Yield: 56.6 %

Procedure:
To a suspension of 7β-[2-(2-aminothiazol-4-yl) -2-tert-butoxycarbonylmethoxyiminoacetamido]-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4-carboxylate (syn isomer) (0.54 g) in anisole (2 ml) was dropwise added trifluoroacetic acid (8 ml) under ice-cooling with stirring. After being stirred at ambient temperature, the mixture was poured into diisopropyl ether (100 ml). The resulting precipitate was collected by filtration, washed with diisopropyl ether and dried under reduced pressure. The precipitate was dissolved in water (30 ml) at pH 7.0 and acidified to pH 1.0 with 6N hydrochloric acid. After removal of precipitated materials, the aqueous solution was subjected to column chromatography on Diaion HP-20 (50 ml). The column was washed with water and the elution was carried out with 30% aqueous methanol. The active fractions were collected and lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl )methyl}ammonio]methyl-3-cephem-4-carboxylate (syn isomer) (0.28 g).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]5[C:27](=[O:28])[CH2:26][CH2:25][C:24]5=[O:29])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:32])[CH:3]=1.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[CH:45]1([NH2:48])[CH2:47][CH2:46]1>C1COCC1.CCOC(C)=O>[CH:45]1([NH:48][C:37]([NH:1][C:2]2[CH:31]=[CH:30][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:13]=[C:14]([C:16]5[CH:17]=[CH:18][C:19]([CH2:22][N:23]6[C:24](=[O:29])[CH2:25][CH2:26][C:27]6=[O:28])=[CH:20][N:21]=5)[S:15][C:8]=34)=[C:4]([F:32])[CH:3]=2)=[O:43])[CH2:47][CH2:46]1
Reactant: NC1CC1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5C(=O)CCC5=O)cn4)sc23)c(F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5C(=O)CCC5=O)cn4)sc23)c(F)c1)NC1CC1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 16.7 %

Procedure:
To a solution of 139 (101 mg, 0.225 mmol) in THF (6 mL) at −35° C. was added TEA (0.094 mL, 1.126 mmol) and triphosgene (80 mg, 0.270 mmol) in THF (1 mL) and the mixture was warmed to −10° C. over an hr. Cyclopropylamine (64.3 mg, 1.126 mmol) was added and the reaction mixture was stirred at RT for 1.5 hrs. The reaction mixture was diluted with EtOAc then washed with saturated NH4Cl solution. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. Purification by column chromatography (10% MeOH in EtOAc) afforded title compound 140 (20 mg, 17% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.69 (s, 1H), 8.53 (s, 1H), 8.50 (d, J=5.48 Hz, 1H), 8.32 (s, 1H), 8.22 (d, J=8.021, 1H), 7.81 (m, 1H), 7.70 (m, 1H), 7.36 (t, J=9.19 Hz, 1H), 7.18 (m, 1H), 6.62 (d, J=4.89 Hz, 1H), 6.55 (s, 1H), 4.62 (s, 2H), 2.68 (s, 4H), 2.53 (m, 1H), 0.63 (m, 2H), 0.41 (m, 2H). M (m/z)=532.543 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH2:23][CH:22]([CH2:24][S:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:21][C:20]3=[O:33])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C[O:35]C1C=CC(C2C=CC(S(NC(CC3OC3)C(OC)=O)(=O)=O)=CC=2)=CC=1.C([O-])(O)=O.[Na+].CCN(CC)CC.C(S)C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH:18][CH:19]([CH2:23][CH:22]([OH:35])[CH2:24][S:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:20]([OH:21])=[O:33])(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(S(=O)(=O)NC3CC(CSCc4ccccc4)OC3=O)cc2)cc1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: SCc1ccccc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSCc3ccccc3)C(=O)O)cc2)cc1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
3-[(4′-Methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-2-oxo-5-[(benzylthio)methyl]-tetrahydrofuran: To a solution of methyl 2-[(4′-methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-4,5-epoxypentanoate 1d (0.5 g, 1.28 mmol) in benzene (3 mL), NaHCO3 (0.32 g, 3.84 mmol) and Et3N (0.23 mL, 1.6 mmol) at room temperature is added slowly benzyl mercaptan (0.62 mL, 4.99 mmol). The reaction mixture is heated at 70° C. for 3 h, and stirred two days at room temperature. The resulting mixture is diluted with water, and then the mixture is extracted three times with EtOAc. The combined EtOAc layer is washed with water, brine, dried over MgSO4 and concentrated to an oil which is purified by column chromatography eluting with hexane/EtOAc (4:1) to give the desired product.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][C:15]([C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C:25]([CH2:26][C@@H:27]([OH:37])[CH2:28][CH2:29]2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1)=[CH:16][CH3:17]>CC(C)=O>[CH3:14][C:15]([C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C:25](=[CH:26][C:27](=[O:37])[CH2:28][CH2:29]2)[C:24](=[O:3])[CH2:23]3)[CH2:20][CH2:19]1)=[CH:16][CH3:17]
Reactant: CC(C)=O
Reactant: CC=C(C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC=C(C)[C@H]1CC[C@H]2[C@@H]3CC(=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.75 h
Yield: 29 %

Procedure:
Jones reagent (2.67M, 2.0 mL. 5.3 mmol) was added to a solution of 20,21 -dimethylpregna-5,20-dien-3β-ol (6, 460.1 mg, 1.400 mmol) in 50 mL of acetone and the reaction was stirred 45 min. After quenching with 2-propanol (1.0 mL) the mixture was poured into 100 mL of water and extracted three times with 50 mL of ethyl acetate. The combined organic extracts were washed with 50 mL of saturated sodium bicarbonate+50 mL of brine, dried over magnesium sulfate, and filtered through Celite. The residue was washed with 25 mL of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Flash chromatography (25% ethyl acetate/hexanes on silica gel) and recrystallization of the residue from 95% ethanol gave yellow needles (138.2 mg, 0.4059 mmol, 29%), m.p. 172°-178° C. (NA-1993B-73)
Reaction SMILES: CON(C)[C:4](=[O:12])[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH2:7].[F:14][C:15]([F:28])([F:27])[C:16]1[CH:17]=[C:18](Br)[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.C([Li])CCC>O1CCCC1>[F:14][C:15]([F:27])([F:28])[C:16]1[CH:17]=[C:18]([C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[NH2:7])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CON(C)C(=O)c1ccccc1N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1ccccc1C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -78 °C
Yield: 97.1 %

Procedure:
Then, in a nitrogen atmosphere, N-methoxy-N-methyl-anthranilamide (0.62 g, 3.4 mmol), and 3,5-bis(trifluoromethyl)-1-bromobenzene (1.00 g, 3.4 mmol) were dissolved in tetrahydrofuran (20 mL), followed by stirring at −78° C. To the solution, 1.66 mol/L n-butyl lithium (4.11 mL, 6.8 mmol) was gradually added dropwise, followed by stirring for 30 minutes. The reaction was terminated by adding 1 mol/L hydrochloric acid. The reaction solution was extracted with ethyl acetate. The organic layer was washed with a sodium chloride solution and then dried with magnesium sulfate, followed by filtration. The filtrate was concentrated using a rotary evaporator. The residue was purified by recrystallization (hexane). Thus, 3′,5′-bis(trifluoromethyl)-2-aminobenzophenone (1.1 g, 3.3 mmol) was obtained in a yield of 96%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:20][CH2:19]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:29]C(=O)OCC1C=CC=CC=1.C(O)C>O1CCCC1.[C].[Pd]>[NH2:29][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:7][C:2]=1[F:1]
Reactant: O=C(Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCCC4)CC3)c2)cc1F)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCCC4)CC3)c2)cc1F
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of benzyl (2-fluoro-4-{2-[(4-pyrrolidin-1-ylpiperidine-1-carbonyl)amino]pyridin-4-yloxy}phenyl)carbamate (91 mg) in tetrahydrofuran (10 ml) was 10% palladium carbon (36.4 mg), followed by stirring under a hydrogen atmosphere at room temperature for 3.5 hrs. Ethanol (5.0 ml) was added thereto, followed by stirring under a hydrogen atmosphere at room temperature for 1.5 hrs. The reaction mixture was filtered to remove the catalyst, and washed with a small amount of tetrahydrofuran to give a solution of the titled compound in tetrahydrofuran. The solution was concentrated to almost dryness, which was then used for succeeding reactions without further purification.
Reaction SMILES: FC1C=CC=CC=1C=[O:5].[Na].[BH4-].[Na+].Br[C:14](O)([S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[C:39](=[O:41])[CH3:40]>>[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[C:39](=[O:41])[CH2:40][C:27]1[CH:26]=[CH:25][C:24]([S:21]([C:14]2[CH:15]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:16][OH:5])(=[O:22])=[O:23])=[CH:29][CH:28]=1
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: O=Cc1ccccc1F
Reactant: O=S(=O)(c1ccccc1)C(O)(Br)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [Na]
Product: O=C(Cc1ccc(S(=O)(=O)c2ccccc2CO)cc1)c1ccc(F)cc1F

Procedure:
2-Fluorobenzaldehyde was reacted with sodium 4-bromophhenylsulfinate by the procedure of Example 113 Step 1, then the aldehyde group reduced using sodium borohydride by the procedure of Example 41. The resulting bromophenylsulfonylbenzyl alcohol was reacted with 2′,4′-difluoroacetophenone as described in Example 132 to provide the title compound. δH (500 MHz, d6 DMSO): 8.07 (1H, d, J=7.8 Hz), 7.96 (1H, q, J=8.0 Hz), 7.82-7.77 (3H, m), 7.72 (1H, t, J=7.5 Hz), 7.54 (1H, t, J=7.5 Hz), 7.48 (2H, d, J=8.2 Hz), 7.45-7.41 (1H, m), 7.23 (1H, td, J=2.2, 7.7 Hz), 5.41 (1H, t, J=5.7 Hz), 4.69 (2H, d, J=5.7 Hz), 4.45 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.[N+:11]([C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O)([O-])=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([N:7]2[CH:16]=[C:15]3[C:14]([CH:21]=[CH:20][CH:19]=[CH:18]3)=[N:11]2)=[C:5]([CH3:10])[CH:4]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COc1ccc(N)c(C)c1
Solvent: C1CCOC1
Product: COc1ccc(-n2cc3ccccc3n2)c(C)c1
Yield: 62.9 %

Procedure:
A mixture of 4-methoxy-2-methylaniline (1.37 g, 10.0 mmol) and 2-nitrobenzaldehyde (1.51 g, 10.0 mmol) in tetrahydrofuran (30 mL) was stirred at reflux for 4 hours. The reaction was concentrated. To the residue was added triethyl phosphite (10 mL) and the mixture was stirred at reflux for 40 hours. The reaction was concentrated and purification by flash column chromatography gave 2-(4-methoxy-2-methylphenyl)-2H-indazole (1.5 g, 63%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 8.05 (s, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.31-7.35 (m, 2H), 7.12-7.16 (m, 1H), 6.82-6.88 (m, 2H), 3.87 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH:14]1([CH:20]=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([CH:20]2[NH:1][C:2]3[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=3[S:10](=[O:12])(=[O:11])[NH:13]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Nc1c(Br)cc(Br)cc1S(N)(=O)=O
Reactant: O=CC1CCCCC1
Product: O=S1(=O)NC(C2CCCCC2)Nc2c(Br)cc(Br)cc21

Procedure:
2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 166-167° C.
Reaction SMILES: CS[C:3]1[S:4][CH2:5][C:6](=[O:8])[N:7]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1>CO>[O:8]=[C:6]1[CH2:5][S:4][C:3]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]2)=[N:7]1
Reactant: O=C(O)C1CCNCC1
Reactant: CSC1=NC(=O)CS1
Solvent: CO
Product: O=C1CSC(N2CCC(C(=O)O)CC2)=N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-methylsulfanyl-thiazol-4-one (4.4 g, 30 mmol) in MeOH (60 mL) was added piperidine-4-carboxylic acid (3.9 g, 30 mmol). The mixture was stirred at room temperature for 16 hours. The resulting solid was collected by filtration and washed with fresh MeOH.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18](Cl)[N:17]=[C:16]([C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C>CC(O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:15]=[C:16]([C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)[N:17]=[CH:18][N:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc(-c3ccsc3)n2)CC1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(-c3ccsc3)n2)CC1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(4-chloro-6-thiophen-3-yl-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (169 mg, 0.29 mmol) in 2-propanol/EtOAc (10:1, 11 mL) at room temperature was added DIEA (0.5 mL). The resulting solution was vacuum-flushed with N2 and then treated with 10% Pd/C (50 mg). The resulting suspension was exposed to H2 via balloon and heated to 65° C. After 3 h, 10% Pd/C (50 mg) was added, and the reaction mixture was heated at 65° C. overnight under H2. The resulting mixture was filtered to remove catalyst; the filtrate was concentrated and the residue was purified by preparative TLC (EtOAc/hexanes, 1:2) to yield a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1)#[N:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:21](=[O:31])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH3:29])=[C:24]([NH2:30])[CH:23]=1>ClCCl.CO>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:21]([C:22]1[CH:27]=[CH:26][C:25]2[N:28]([CH3:29])[C:11]([CH2:10][NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[N:30][C:24]=2[CH:23]=1)=[O:31]
Reactant: CCOC(=O)CN(C(=O)c1ccc(NC)c(N)c1)c1ccccn1
Reactant: N#Cc1ccc(NCC(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccn1
Yield: 24 %

Procedure:
Prepared analogously to Example 25c from N-(4-cyanophenyl)glycine and 3-amino-4-methylaminobenzoic acid-N-(2-pyridyl)-N-ethoxycarbonylmethylamide. Yield: 24% of theory; Rf value: 0.56 (silica gel; dichloromethane/methanol=4:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[C:36]3[C:31](=[C:32]([Cl:38])[CH:33]=[C:34]([Cl:37])[CH:35]=3)[NH:30][CH:29]=2)[CH:9]([C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[CH3:39]C(N(C)C)=O>CC([O-])(C)C.[K+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[C:36]3[C:31](=[C:32]([Cl:38])[CH:33]=[C:34]([Cl:37])[CH:35]=3)[N:30]([CH3:39])[CH:29]=2)[CH:9]([C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC)cc1)C(c1ccc(Cl)cc1)c1c[nH]c2c(Cl)cc(Cl)cc12
Reactant: CC(=O)N(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCC(c1ccc(C(=O)NCCC(=O)OC)cc1)C(c1ccc(Cl)cc1)c1cn(C)c2c(Cl)cc(Cl)cc12

Procedure:
A solution of KOtBu (1.0M THF, ca. 3 drops, 0.045 ml) was added to a dimethylacetamide solution (2 ml) of the intermediate from EXAMPLE 1, Step C (faster eluting enantiomer on ChiralPak AD 10% EtOH/Heptane, 4 mg, 0.007 mmol). Methyl iodide (three drops, excess) was then added dropwise. The progress of the reaction during the addition was monitored by MS-HPLC in order to minimize over alkylation. The reaction was quenched with aqueous 1N HCl. The mixture was extracted with EtOAc and the combined organics washed with water and brine. The solution was then dried over Na2SO4, filtered and concentrated to give the title compound which was used without further purification. LCMS1 4.40 min. (M+H)=585. The procedure was also carried out as described on the intermediate from Example 1, Step C (slower eluting enantiomer). LCMS1 4.39 min. (M+H)=585
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH:9]=O.[N+:22]([CH3:25])([O-:24])=[O:23].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.O>[F:5][C:6]1[CH:7]=[C:8](/[CH:9]=[CH:25]/[N+:22]([O-:24])=[O:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(OCc2ccccn2)c(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])/C=C/c1ccc(OCc2ccccn2)c(F)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To an acetic acid (25.0 mL) solution of 3-fluoro-4-(pyridin-2-ylmethoxy)-benzaldehyde (2.80 g, 12.1 mmol) described in Manufacturing Example 87-1-1 were added nitromethane (3.69 g, 60.5 mmol) and ammonium acetate (1.87 g, 24.2 mmol) under nitrogen atmosphere at room temperature, which was stirred for 2 hours at 110° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.00 g) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH:3]=1.F[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH:3]=1
Reactant: Oc1ccc2nc(N3CCCc4ccccc4C3)cc(Cl)c2c1
Reactant: Fc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Clc1cc(N2CCCc3ccccc3C2)nc2ccc(Oc3ccccn3)cc12
Temperature: 130 °C
Reaction time: 0.67 h
Yield: 44.4 %

Procedure:
The mixture of 4-chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-6-ol (200 mg, 0.617 mmol), 2-fluoro-pyridine (180 mg, 1.85 mmol), potassium carbonate (73 mg, 0.53 mmol) and dry dimethylsulfoxide was heated with stirring in a sealed tube for 40 minutes at 130° C. under microwave irradiation. The resulting mixture was cooled to room temperature, then diluted with water (10 mL) and extracted with ethyl acetate (10 mL×2). The combined organic layer was washed with brine (10 mL×3), and then dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 1:5) to give 110 mg of product as a yellow solid (yield was 45%).
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=[O:14])[O:3]1.[CH2:15]([SH:19])[CH2:16][CH2:17][SH:18].B(F)(F)F.CCOCC.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl>[S:18]1[CH2:17][CH2:16][CH2:15][S:19][CH:2]1[C:10]1[CH:9]=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[C:4]([OH:3])=[O:14]
Reactant: SCCCS
Reactant: O=C1OC(O)c2ccc([N+](=O)[O-])cc21
Agent: FB(F)F
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: O=C(O)c1cc([N+](=O)[O-])ccc1C1SCCCS1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cooled mixture of the Compound 3a (5.00 g, 25.6 mmol) and propane-1,3-dithiol (2.92 g, 27 mmol) in chloroform (75 mL) was added boron trifluoride etherate (2 mL). The mixture was stirred and allowed to warm to room temperature. After stirring for 3 hours, most of the solid had dissolved. Magnesium sulfate was added to dry the solution, and stirring was continued overnight. Filtration and evaporation of the solvent afforded a light yellow solid. This material was triturated with butyl chloride to give the Compound 3b; m.p. 192°-194° C.; 1H NMR (CDCl3 +MeSO-d6 +D2O)δ1.8-2.3 (m, 2H, CH2CH2CH2, 2.9-3.2 (m, 4H, --CH2CH2CH2 --), 6.56 (s, 1H, --SCHS--), 7.6-8.8 (m, 3H, ArH).
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:5][C:6](=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH3:19])SC)#[N:4]>C(O)C>[C:3]([NH:5][C:6]([NH:2][CH3:1])=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH3:19])#[N:4]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: CN
Solvent: CCO
Product: CNC(=NCCSCc1[nH]cnc1C)NC#N
Reaction time: 2.5 h

Procedure:
A solution of methylamine in ethanol (33%, 75 ml.) was added to a solution of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (10.1 g.) in ethanol (30 ml.). The reaction mixture was set aside at room temperature for 2.5 hours. Following concentration under reduced pressure, the residue was recrystallised twice from isopropyl alcohol/petroleum ether, affording N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (8.6 g.), m.p. 141°-143°. (Found: C, 47.5; H, 6.3; N, 33.2; S, 12.9. C10H16N6S requires: C, 47.6; H, 6.4; N, 33.3; S, 12.7).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[C:18]4[N:19]=[C:20](Cl)[N:21]=[CH:22][C:17]=4[S:16][CH:15]=3)=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C@@H:24]1([NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH2:30].O.ClCCl>O1CCOCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[C:18]4[N:19]=[C:20]([NH:30][C@@H:25]5[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]5[NH2:31])[N:21]=[CH:22][C:17]=4[S:16][CH:15]=3)=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc2ncccc2c1)c1csc2cnc(Cl)nc12
Reactant: N[C@@H]1CCCC[C@@H]1N
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: N[C@H]1CCCC[C@H]1Nc1ncc2scc(C(=O)Nc3ccc4ncccc4c3)c2n1
Yield: 55.4 %

Procedure:
To a solution of 0.0794 g (0.233 mmole) 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid quinolin-6-ylamide in 2.33 mL of dioxane was added 0.168 mL (1.4 mmole) of cis-cyclohexane-1,2-diamine. The mixture was heated at 100 degrees for 2 hours. Water and dichloromethane were added, separated. The aqueous layer was washed with dichloromethane twice. The organic layer was washed with aqueous sodium carbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-0.7 N ammonia solution in methanol (gradient 100:0-90:10) gave 0.054 g of 2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid quinolin-6-ylamide as a light yellow solid. MH+/Z=419.