Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:10]1[CH2:20][CH2:19][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11]1>>[CH2:17]([O:16][C:14]([CH:13]1[CH2:19][CH2:20][N:10]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:11][CH2:12]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C1CCNCC1
Reactant: N#Cc1ccccc1F
Product: CCOC(=O)C1CCN(c2ccccc2C#N)CC1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and ethyl isonipecotate.
Reaction SMILES: [CH3:1][C:2]([N+:14]([O-:16])=[O:15])([CH3:13])[CH2:3][CH2:4][CH:5]=[C:6]1[NH:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].[OH-].[Na+].[H][H]>[C].[Pd].CO>[CH3:13][C:2]([N+:14]([O-:16])=[O:15])([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]1[NH:10][C:9](=[O:11])[NH:8][C:7]1=[O:12]
Reactant: CC(C)(CCC=C1NC(=O)NC1=O)[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(CCCC1NC(=O)NC1=O)[N+](=O)[O-]
Yield: 72.8 %

Procedure:
Methanol (200 ml) was added to 5-(4-methyl-4-nitropentylidene)hydantoin (25.85 g, 114 mmol) and 27% aqueous sodium hydroxide solution was added to adjust the pH to 10 for dissolution. Palladium-carbon (1.1 g) and hydrogen were added for reduction. After the reaction, palladium-carbon was filtered off and methanol was evaporated by concentration under reduced pressure. Water (50 ml) was added and the pH was adjusted to 2 with concentrated hydrochloric acid. The precipitated crystals were separated and dried to give 5-(4-methyl-4-nitropentyl)hydantoin (19.02 g, 83 mmol, yield 72.9%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[NH:22])[NH:20][OH:21])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.O.[CH:35](=O)[CH3:36]>C(O)C>[CH:1]1([C:4]2[C:5]([N:24]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)=[C:9]([C:19]4[NH:22][CH:35]([CH3:36])[O:21][N:20]=4)[C:8]=3[CH:23]=2)[CH2:2][CH2:3]1
Reactant: CC=O
Reactant: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(C(=N)NO)c2cc1C1CC1)S(C)(=O)=O
Solvent: CCO
Solvent: O
Product: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(C3=NOC(C)N3)c2cc1C1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 144 h
Yield: 47.7 %

Procedure:
A mixture of Example 10F (0.040 g, 0.084 mmol) and Amberlite® IRP-64 H-form (0.010 g) in ethanol (1 mL) and H2O (0.5 mL) was treated with acetaldehyde (1 mL, 17.7 mmol) and stirred in a sealed microwave tube at room temperature for 6 days. The mixture was filtered through a bed of diatomaceous earth that was washed thoroughly with ethyl acetate. The filtrate was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on an Isco silica gel cartridge (12 g) eluting with a gradient of hexane to 3:1 hexane/ethyl acetate to afford the title compound as a white foam (0.020 g, 47%). 1H NMR (DMSO-d6) δ ppm 0.48-0.61 (m, 1H), 0.78-0.88 (7H), 1.00-1.05 (m, 2H), 1.22-1.31 (m, 1H), 1.38 (dd, J=5.04, 2.90 Hz, 4H), 1.55-1.66 (m, 1H), 2.34-2.44 (m, 1H), 3.13 (s, 3H), 3.59-3.79 (m, 2H), 5.74-5.80 (m, 1H), 7.22 (s, 1H), 7.30 (dd, J=4.20, 2.37 Hz, 1H), 7.42 (t, J=8.85 Hz, 2H), 7.88 (s, 1H), 8.00-8.04 (m, 2H); MS (ESI+) m/z 500 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:26]1[C:35]2[C:30](=[CH:31][C:32]([C:36]([F:39])([F:38])[F:37])=[CH:33][CH:34]=2)[N:29]=[CH:28][CH:27]=1>>[F:39][C:36]([F:37])([F:38])[C:32]1[CH:31]=[C:30]2[C:35]([C:26]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([S:8]([N:11]4[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[CH2:13][CH2:12]4)(=[O:10])=[O:9])=[CH:4][CH:3]=3)=[CH:27][CH:28]=[N:29]2)=[CH:34][CH:33]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccc(S(=O)(=O)N2CCN(C(=O)OCC(Cl)(Cl)Cl)CC2)cc1
Product: O=C(OCC(Cl)(Cl)Cl)N1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1

Procedure:
In the manner given in Example 4C, 1-(p-aminophenylsulfonyl)-4-(2,2,2-trichloroethoxycarbonyl)piperazine is heated with 4-chloro-7-trifluoromethylquinoline to give 1-[[4-[(7-trifluoromethyl-4-quinolinyl)amino]phenyl]-sulfonyl]-4(2,2,2-trichloroethoxycarbonyl)piperazine.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6]([CH:8]=[O:9])[S:5][CH:4]=1)#[N:2].O1C[CH2:13][CH2:12][CH2:11]1.C([Mg]Cl)(C)C.C(OCC)(=O)C>CCOCC>[C:1]([C:3]1[CH:7]=[C:6]([CH:8]([OH:9])[CH:12]([CH3:13])[CH3:11])[S:5][CH:4]=1)#[N:2]
Reactant: N#Cc1csc(C=O)c1
Reactant: C1CCOC1
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)C(O)c1cc(C#N)cs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
3-Cyano-5-thiophenecarboaldehyde (2.00 g) was dissolved in anhydrous ether (100 ml) and anhydrous tetrahydrofuran (THF) (20 ml), and an ether solution (10.9 ml) of (2.0 M) isopropylmagnesium chloride was added thereto. After stirring at 0° C. for 2 hours, ethyl acetate was added thereto. The mixture was washed with an aqueous saturated ammonium chloride and further brine, dried over anhydrous magnesium sulfate and then evaporated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system), to give the title compound as a pale yellow oil (1.25 g, 47%).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH:19]([NH2:22])([CH3:21])[CH3:20]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:22][CH:19]([CH3:21])[CH3:20])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: CC(C)N
Solvent: O
Product: C=CCNc1nc(NC(C)C)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
A mixture of 250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 694 mg (11.74 mmol) of isopropylamine was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and crystals thus precipitated were filtered to give 270 mg (yield: 99.4%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:16][C:17]([F:27])([F:26])[C:18]1[N:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:21]3[CH:22]=[N:23][C:18]([C:17]([F:26])([F:16])[F:27])=[N:19][CH:20]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1cnc(C(F)(F)F)nc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2cnc(C(F)(F)F)nc2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyrimidine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11].N12CCN(CC1)CC2.Cl>C(OCC)(=O)C.O>[CH3:14][O:13][C:9](=[O:12])[C:10](=[CH2:11])[CH:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: O=Cc1ccccc1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C(=O)OC)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 119 h

Procedure:
A mixture of benzaldehyde (63.67 g; 600 mmol), methyl acrylate (60 ml; 667 mmol) and 1,4-diazabicyclo[2.2.2]octane (13.46 g; 120 mmol) is stirred at ambient temperature for 119 hours. To the reaction solution is added water (60 ml), 37 % hydrochloric acid (60 ml) and ethyl acetate (120 ml), and then, the organic phase is extracted. The resulting organic phase is washed twice with saturated saline (60 ml), dried over anhydrous sodium sulfate and filtered, then concentrated under reduced pressure, to give a crude product of the title compound at a yield of 108.8 g.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[N+](=[CH2:15])=[N-]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:15])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of indole-6-carboxylic acid (2.0 g, 12.4 mmol), prepared as described in step 1, in tetrahydrofuran (20 mL) at 0° C. was added excess diazomethane (0.30M solution in ether). After 10 min the solution was warmed to room temperature and nitrogen was bubbled through the solution for 30 min. The solution was concentrated in vacuo and the residue purified by flash chromatography (SiO2, 85:15 hexane:ethyl acetate) to afford methyl indole-6-carboxylate (2.1 g, 98 %) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:4][C:3]=1[S:8]([C:11]([F:12])([F:13])[F:14])(=[O:9])=[O:10]
Reactant: O=S(=O)(O)Cl
Reactant: O=S(=O)(c1ccccc1F)C(F)(F)F
Product: O=S(=O)(Cl)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1

Procedure:
reacting 1-fluoro-2-((trifluoromethyl)sulfonyl)benzene, and chlorosulfonic acid to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride and isolating or not isolating the 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride;
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[CH3:13][C:14]1([CH3:21])[NH:18][C:17](=[S:19])[NH:16][C:15]1=[S:20]>CCO>[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][S:19][C:17]1[N:16]=[C:15]([S:20][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]([CH3:12])[CH3:2])[C:14]([CH3:21])([CH3:13])[N:18]=1
Reactant: CC1(C)NC(=S)NC1=S
Reactant: CN(C)c1ccccc1CCl
Agent: Cl
Solvent: CCO
Product: CN(C)c1ccccc1CSC1=NC(C)(C)C(SCc2ccccc2N(C)C)=N1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Initially, a solution of 9.1 g of 2-dimethylaminobenzylchloride hydrochloride in 50 mL of EtOH was added to a solution of 7 g of 5,5-dimethyl-2,4-dithiohydantoin in 100 mL of ethanol (EtOH). The reaction mixture was stirred for 1.5 hour at the room temperature and concentrated in vacuo. To the residue, there was added 100 mL of chloroform (CHCl3). The residue was then washed with an aqueous solution of potassium carbonate (CaCO3), dried over magnesium sulfate (MgSO4), and concentrated in vacuo. The residue was chromatographed on a column of silica gel (CHCl3). From the earlier fractions, 2,4-bis(2-dimethylaminobenzylthio)-5,5-dimethyl-5H-imidazole was isolated as a syrup. The yield of this compound was 1.1 g with a yield ratio of 5.9%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]([CH:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([O-:3])=[O:2].[H-].[Na+].I[CH3:32].Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:32][C:20]([CH:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22]
Reactant: CI
Reactant: COC(=O)C(C(=O)OC)C(Cc1ccccc1[N+](=O)[O-])c1ccc(OC)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C(=O)OC)C(Cc1ccccc1[N+](=O)[O-])c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of [2-(2-nitrophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (4.0 g, 10.33 mmol) in 19 ml of dimethylformamide (0° C., argon) was added sodium hydride dispersion (0.5 g, 12.40 mmol). Stirring at 0° C. was continued for 5 minutes. Iodomethane was added (3.21 ml, 51.63 mmol) and the reaction was carried out at room temperature for 2 hours, 15 minutes. Ethyl acetate and 1M hydrochloric acid were added, the aqueous layer was washed with ethyl acetate, the combined ethyl acetate layers were washed with 1M hydrochloric acid (two times), saturated aqueous potassium carbonate solution, brine, dried over magnesium sulfate and evaporated in vacuo to yield 4.61 g of a viscous yellow oil. The oil was washed with several portions of hexane. Recrystallization of the residue (3.88 g of a sticky yellow solid) from methanol two times, (1 crop each) yielded 2.69 g of a white crystalline solid, melting point 82°-84° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[O:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[C:27](Cl)[CH:26]=[C:25]([Cl:30])[N:24]=2)[CH2:19][CH2:18]1>O1CCCC1>[Cl:30][C:25]1[N:24]=[C:23]([N:20]2[CH2:21][CH2:22][O:17][CH2:18][CH2:19]2)[N:28]=[C:27]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:26]=1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)nc(N3CCOCC3)n2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.5 %

Procedure:
To a solution of N-Boc-4-hydroxy piperidine (2.58 g, 12.81 mmol) in tetrahydrofuran at 0° C. under argon, was added sodium hydride (60%, 512 mg, 12.81 mmol). After stirring for 20 minutes, a solution of 2-morpholino-4,6-dichloropyrimidine (2.0 g, 8.54 mmol) in tetrahydrofuran (20 mL) was added through a syringe. The solution was stirred for 14 hours as the ice bath warmed to room temperature. At this time, the reaction mixture was quenched with water (2 mL), and was partitioned between EtOAc (350 mL) and Na2CO3(sat.) (75 mL). The organic layer was separated, washed with brine (50 mL), dried over Na2SO4, filtered, concentrated and the residue was purified by SiO2 chromatography (15-20% EtOAc in hexanes) to yield tert-butyl 4-(6-chloro-2-morpholinopyrimidin-4-yloxy)piperidine-1-carboxylate as a white solid (2.64 g, 77%). LCMS (m/z): 399.1 (MH+). 1H NMR (CDCl3): δ 6.00 (s, 1H), 5.18 (m, 1H), 3.74 (s, 8H), 3.64-3.74 (m, 2H), 3.28-3.38 (m, 2H), 1.86-1.96 (m, 2H), 1.68-1.78 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [C:1]1([C:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][C:9]([NH:11][CH2:12][C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[OH-].[Na+]>CO>[C:29]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:8][C:9]([NH:11][CH2:12][C:13]([NH:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:14])=[O:10])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)CCNC(=O)CNC(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)CNC(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
1.7 Grams of ethyl 3-(2-{(3,3,3-triphenylpropanoyl)amino}acetylamino)propionate was dissolved in a mixed liquid consisting of 70 ml of tetrahydrofuran and 20 ml of methanol. To the solution 5.0 ml of 4N aqueous sodium hydroxide solution was added at room temperature, followed by an hour's stirring at the same temperature. The reaction liquid was distilled off under reduced pressure, and the residue was rendered acidic by addition of 1N hydrochloric acid, extracted with ethyl acetate, washed with saturated saline solution and dried over anhydrous magnesium sulfate. Upon distilling the solvent off under reduced pressure, 1.10 g of the title compound was obtained.
Reaction SMILES: N.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17](C1NC=CN=1)(C1NC=CN=1)=[S:18]>C(Cl)Cl.CCCCCC>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([N:13]=[C:17]=[S:18])[CH:14]=[CH:15][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Agent: N
Solvent: CCCCCC
Solvent: ClCCl
Product: S=C=Nc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
The final product, Compound 1 is obtained by treatment of Z with thiocarbonyl di-imidazole followed by ammonia. 3-Benzyloxyaniline (5 g, 25 mmol) is added dropwise over a one minute period to 4.94 g (27.6 mmol) thiocabonyl di-imidazole in methylene chloride (150 ml). The resulting mixture is stirred at room temperature overnight. An additional 400 mg thiocarbonyl di-imidazole (TCDI) is added and the reaction is continued for 2 hours more. The reaction is diluted with hexane and filtered through silica. Concentration provides 5.1 g of the desired 3-benzyloxyphenyl isothiocyanate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:37][CH:38]([CH3:43])[CH2:39][CH2:40][CH2:41]O>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:41][CH2:40][CH2:39][CH:38]([CH3:43])[CH3:37])=[C:12]([C:27]3[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Reactant: CC(C)CCCO
Product: CC(C)CCCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 178, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 4-methyl-1-pentanol in place of 2-ethyl-1-hexanol (yield: 120 mg, 52%). mp 98–99° C. 1H NMR (300 MHz, DMSO-d6) δ 0.73 (d, J=7 Hz, 6H), 1.02 (m, 2H), 1.29 (m, 1H), 1.54 (m, 2H), 3.30 (s, 3H), 4.40 (t, J=7 Hz, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 463 (M+H)+; (APCI−) m/z 497 (M+Cl)−. Anal. calc. for C23H24F2N2O4S: C, 59.72; H, 5.23; N, 6.05. Found: C, 59.57; H, 5.28; N, 6.01.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].NC(N)=[S:13]>C(O)CCC>[SH:13][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1ccc(C#N)c(Cl)n1
Reactant: NC(N)=S
Solvent: CCCCO
Product: Cc1ccc(C#N)c(S)n1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A mixture of 2-chloro-6-methylnicotinonitrile (220 mg, 1.45 mmol) and thiourea (348 mg, 4.57 mmol) was heated at reflux (118° C.) in n-butanol for 4 h. After cooling to room temperature, the yellow solution turned to a suspension containing light yellow solids. The solids were collected by filtration, rinsed with n-butanol, and dried in vacuo to give 2-mercapto-6-methylnicotinonitrile (218 mg, 100% yield). C7H6N2S; yellow powder; 1H NMR (400 MHz, CDCl3) δ 7.97 (1H, dt, J=8, 0.8 Hz), 7.79 (1H, dt, J=8, 0.8 Hz), 7.70 (1H, td, J=8, 1.2 Hz), 7.46 (1H, td, J=8, 1.2 Hz), 4.64 (2H, s); 13C NMR (100 MHz, CDCl3) δ 177.39, 154.77, 144.83, 117.1, 113.3, 112.7, 19.2; ESI-HRMS (negative mode) calcd for C7H5N2S: 149.0173. found: m/z 149.0172 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:30])=[C:6]([C@:8]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])([CH3:17])[CH2:9][S:10][C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])[CH:7]=1.C(N(C(C)C)CC)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:30])=[C:6]([C@@:8]2([CH3:17])[N:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH3:29])[C:12](=[O:13])[C:11]([CH3:16])([CH3:15])[S:10][CH2:9]2)[CH:7]=1
Reactant: COc1ccc(CN[C@@](C)(CSC(C)(C)C(=O)O)c2cc(Br)ccc2F)c(OC)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)C(C)(C)SC[C@@]2(C)c2cc(Br)ccc2F)c(OC)c1
Temperature: 23 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a solution of (R)-2-(2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino) propylthio)-2-methylpropanoic acid (2.6 g, 5.2 mmol, Eq: 1.00) and diisopropylethylamine (2.01 g, 2.72 ml, 15.6 mmol, Eq: 3.0) in ethyl acetate (104 ml) was added at 23° C. 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate) (4.96 g, 4.63 ml, 7.79 mmol, Eq: 1.5). The colourless reaction solution was stirred at 23° C. for 2 hours. The reaction mixture was washed with sat NaHCO3-sol., water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the crude and nearly pure (R)-5-(5-bromo-2-fluorophenyl)-4-(2,4-dimethoxybenzyl)-2,2,5-trimethylthiomorpholin-3-one (2.45 g, 5.08 mmol, 97.7% yield) as a colourless oil which crystallized in the fridge. MS (ISP): m/z=482.0 [M+H]+ and 484.3 [M+2+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(OCc2ccc(-c3cc(C(N)=O)on3)cc2)c1
Temperature: 85 °C
Yield: 57.6 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 3-methoxyphenol (21 μL, 0.19 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 85° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(3-methoxy-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (20 mg, 58%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (br. s., 1H), 8.00 (br. s., 1H), 7.91 (d, J=8.1 Hz, 2H), 7.54-7.62 (m, 3H), 7.18 (t, J=7.9 Hz, 1H), 6.47-6.64 (m, 3H), 5.16 (s, 2H), 3.26-3.33 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([Li])(C)(C)C.[B:17](OC)([O:20]C)[O:18]C>C1COCC1>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([B:17]([OH:20])[OH:18])[CH:3]=1
Reactant: COB(OC)OC
Reactant: Brc1cnc2ccccc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: OB(O)c1cnc2ccccc2c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
3-Bromoquinoline (0.4 mL, 3 mmol) was dissolved in THF, and the solution was cooled to -78° C. To this solution was added t-butyllithium (4.1 mL, 7 mmol), and the reaction mixture was stirred for 20 minutes. Trimethyl borate (0.81 mL, 7.1 mmol) was added at -78° C., and the mixture was stirred and allowed to warm to room temperature. The reaction was quenched with water, and the solvents were removed under vacuum. The residue 180 mg was taken directly to the next step.