Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[C:14](Cl)(Cl)=[S:15]>O>[N:1]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1)=[C:14]=[S:15]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: S=C(Cl)Cl
Solvent: O
Product: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reaction time: 1 h

Procedure:
4-Amino-2-trifluoromethylbenzonitrile, (2.23 g, 12 mmol) was added portionwise over 15 minutes into the well-stirred heterogeneous mixture of thiophosgene (1 ml, 13 mmol) in water (22 ml) at room temperature. Stirring was continued for an additional 1 h. The reaction medium was extracted with chloroform (3×15 ml). The combined organic phase was dried over MgSO4 and evaporated to dryness under reduced pressure to yield desired product, 4-isothiocyanato-2-trifluoromethylbenzonitrile, (1a), as brownish solid and was used as such for the next step (232 g, 11.9 mmol, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[CH2:12][C:11](=O)[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:15]([NH:22][CH:11]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:13]=2[CH2:12]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: COc1cccc2c1CC(=O)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1CC(NCc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (500 mg) and benzylamine (0.29 ml) in the presence of catalytic amounts of p-toluenesulfonic acid monohydrate in toluene (5 ml) was refluxed for 2 hours to remove water as the toluene azeotrope, and then the mixture was evaporated in vacuo. To the solution of the residue in methanol (5 ml) was added sodium borohydride (99 mg) under nitrogen at 5° C., and the mixture was stirred at room temperature for 12 hours. After the resulting mixture was evaporated in vacuo, the residue was dissolved into ice-cold water and ethyl acetate. After separation, the organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1 to 1:1) to give N-benzyl-(4-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (660 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH3:19])[C:9]=2[C:10]=1[CH3:11])=[O:5])C.[Li+].[OH-]>C1COCC1>[CH2:17]([O:16][C:12]1[C:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[O:7][C:8]=2[CH:15]=[CH:14][CH:13]=1)[CH2:18][CH3:19]
Reactant: CCCOc1cccc2oc(C(=O)OCC)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCOc1cccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a solution of 160 mg of 4-propoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester dissolved in 1 mL of THF was added 3 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature overnight. The solvents were removed under vacuum and the residue was dissolved in 5 mL of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried under vacuum to give 124 mg (87% yield) of 4-propoxy-3-methyl-benzofuran-2-carboxylic acid, obtained as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:13]([F:16])([F:15])[F:14])=[N:8][C:9](Cl)=[N:10][CH:11]=1)=[O:5])[CH3:2].[Cl:17][C:18]1[N:19]=[N:20][C:21]([N:26]2[CH2:31][CH2:30][NH:29][C@H:28]([CH3:32])[CH2:27]2)=[C:22]([CH3:25])[C:23]=1[CH3:24]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:13]([F:16])([F:15])[F:14])=[N:8][C:9]([N:29]2[CH2:30][CH2:31][N:26]([C:21]3[N:20]=[N:19][C:18]([Cl:17])=[C:23]([CH3:24])[C:22]=3[CH3:25])[CH2:27][C@H:28]2[CH3:32])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: Cc1c(Cl)nnc(N2CCN[C@H](C)C2)c1C
Product: CCOC(=O)c1cnc(N2CCN(c3nnc(Cl)c(C)c3C)C[C@H]2C)nc1C(F)(F)F
Yield: 97.2 %

Procedure:
Following the protocol above with 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid ethyl ester (400 mg, 1.57 mmol, 1 eq) and 3-chloro-4,5-dimethyl-6-((R)-3-methyl-piperazin-1-yl)-pyridazine (400 mg, 1.66 mmol, 1 eq) affords 700 mg of desired product as a white solid (97%).
Reaction SMILES: N(C(OCC)=O)=N[C:3](OCC)=[O:4].[OH:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@@H:16]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=3)=[O:44])[CH2:36][CH2:35]2)=[O:33])[CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)=O>O1CCCC1>[CH:3]([O:13][C@@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[O:20])[C@@H:16]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=3)=[O:44])[CH2:36][CH2:35]2)=[O:33])[CH2:15]1)=[O:4]
Reactant: O=C(OCCN1CCN(C(=O)[C@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CO[C@H]1C[C@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.17 h
Yield: 45.2 %

Procedure:
A solution of 1.31 g of diethyl azodicarboxylate in 5 ml of tetrahydrofuran was added dropwise, whilst ice-cooling, to a solution of 3.0 g of (2R,4R)-4-hydroxy-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)-pyrrolidine [prepared as described in Preparation 57(i)] and 1.97 g of triphenylphosphine in 25 ml of tetrahydrofuran, and the resulting mixture was stirred at the same temperature for 10 minutes. 283 μl of formic acid were then added dropwise to the mixture, and the mixture was stirred at the same temperature for 5 minutes and at room temperature for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 1.42 g of the title compound, as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[CH2:20]Br>CN(C=O)C>[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[CH2:20][O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(O)cc1
Reactant: Fc1cccc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1ccc(OCc2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-Hydroxybenzyl cyanide (5 g, 37.5 mmol) and K2CO3 (6.74 g, 48.8 mmol) in dry DMF (20 ml) was added 2,6-Difluorobenzyl bromide (7.77 g, 37.5 mmol). The reaction mixture was stirred for 4 hour at room temperature and concentrated in vacuo. The crude residue was taken in EtOAc and washed with water and brine. The aqueous layer was washed one more time with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated to provide the title compound as a white solid.
Reaction SMILES: C1([O:7][S:8](=O)(=[O:10])[NH2:9])C=CC=CC=1.[F:12][C:13]([F:20])([F:19])[CH2:14][C:15]1([OH:18])[CH2:17][CH2:16]1>>[F:12][C:13]([F:20])([F:19])[CH2:14][C:15]1([O:18][S:8](=[O:10])(=[O:7])[NH2:9])[CH2:17][CH2:16]1
Reactant: OC1(CC(F)(F)F)CC1
Reactant: NS(=O)(=O)Oc1ccccc1
Product: NS(=O)(=O)OC1(CC(F)(F)F)CC1

Procedure:
Sulfamic acid 1-trifluoroethyl-cyclopropyl ester was synthesized according to the method presented in the synthesis of sulfamic acid phenyl ester in Example 1 with the exception of utilizing 1-trifluoroethylcyclopropanol (synthesized by methods reported in Synthesis 1991, 234) to obtain sulfamic acid 1-trifluoroethyl-cyclopropyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][CH:4]([SH:8])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)#[N:17]>C(#N)C.O>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][CH:4]([S:8][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([C:16]#[N:17])=[CH:19][CH:20]=2)[CH2:3]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC1(C)CCCC(S)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1(C)CCCC(SCc2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.1 %

Procedure:
To a solution of 3,3-dimethylcyclohexanethiol (0.6 g, 4.16 mmol) in acetonitrile (50 mL) add potassium carbonate (1.72 g, 12.48 mmol) and stir at room temperature for 10 min. Add 4-cyanobenzyl bromide (816 mg, 4.16 mmol) and stir the suspension for 18 h. Dilute with water (50 mL) and extract with EtOAc (50 mL). Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1) to obtain the desired intermediate as a clear oil (0.4 g, 37%).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([OH:15])[C:5]1=[O:16])[CH:2]=[CH2:3].[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20]Cl.Cl>C(OCC)(=O)C>[CH2:1]([N:4]1[CH2:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([O:15][CH2:20][CH2:19][N:18]([CH3:22])[CH3:17])[C:5]1=[O:16])[CH:2]=[CH2:3]
Reactant: CN(C)CCCl
Reactant: C=CCN1CC(c2ccccc2)=C(O)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: C=CCN1CC(c2ccccc2)=C(OCCN(C)C)C1=O

Procedure:
In a manner analogous to that described in Example 1, 30.6 g. 1-allyl-3-hydroxy-4-phenyl-3-pyrrolin-2-one are reacted with 23.0 g. β-dimethylaminoethyl chloride. The base obtained is reacted with gaseous hydrogen chloride in ethyl acetate. There is obtained 15.0 g. (45.5% of theory) 1-allyl-3-(β-dimethylaminoethoxy)-4-phenyl-3-pyrrolin-2-one hydrochloride: m.p. 115°-117° C., after recrystallization from methyl ethyl ketone.
Reaction SMILES: [N+]([O-])(O)=O.Cl.[C:6]12([NH2:16])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.[OH-:17].[Na+]>S(=O)(=O)(O)O>[OH:17][C:8]12[CH2:9][CH:10]3[CH2:11][CH:12]([CH2:13][C:6]([NH2:16])([CH2:15]3)[CH2:7]1)[CH2:14]2
Reactant: [OH-]
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: NC12CC3CC(C1)CC(O)(C3)C2
Temperature: 10 °C
Reaction time: 4 h

Procedure:
To a mixture of 150 ml of concentrated sulfuric acid and 15 ml of concentrated nitric acid, cooled to 10° C. is added 10 g (0.053 moles) of 1-adamantanamine hydrochloride over 5 minutes. This mixture is stirred in an ice bath for 4 hours. The reaction is then poured over ice and the pH adjusted to pH 10 using 50% NaOH. The product is extracted into chloroform which is dried over MgSO4 and then evaporated to dryness. The residue is recrystallized from ethyl acetate to give 3-hydroxytricyclo[3.3.1.13,7 ]decan-1-amine (m.p. 260°-264° C.) which is used directly in step B.
Reaction SMILES: [CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([C:20]([F:23])([F:22])[F:21])=[C:14]([N+:17]([O-])=O)[CH:15]=3)[NH:10][C:9](=[O:24])[C:8]2=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>O1CCCC1.[Pd]>[CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([C:20]([F:21])([F:22])[F:23])=[C:14]([NH2:17])[CH:15]=3)[NH:10][C:9](=[O:24])[C:8]2=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: O=c1[nH]c2cc(C(F)(F)F)c([N+](=O)[O-])cc2n(C2CCCCC2)c1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2C1CCCCC1
Yield: 100 %

Procedure:
8 g (22.4 mmol) of 1-cyclohexyl-6-trifluoromethyl-7-nitro-2,3(1H,4H)-quinoxalinedione dissolved in 200 ml of tetrahydrofuran were hydrogenated under a pressure of about 1 bar of hydrogen in the presence of 1 g of palladium/active carbon (10% by weight Pd) at room temperature. The reaction mixture was filtered. Conventional workup of the filtrate gave a 100% yield of the abovementioned compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.[CH3:10][C:11]([S:14]([NH2:16])=[O:15])([CH3:13])[CH3:12]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[N:16][S:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])=[N:6][CH:7]=1
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1ccc(Br)cn1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)S(=O)N=Cc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a stirred solution of 5-Bromo-pyridine-2-carbaldehyde (2.0 g, 10.753 mmol) in CH2Cl2 (20 mL) and 2-Methyl-propane-2-sulfinic acid amide (2.602 g, 21.505 mmol) is added CuSO4 (5.589 g, 21.505 mmol) at room temperature. Resulting reaction mixture is stirred at room temperature for 3 hours. Reaction mixture is filter through celite. Diluted with water and extracted with CH2Cl2. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combi-flash chromatography using 5% ethyl acetate in hexane to afford the title compound (2.5 g): 1H-NMR (400 MHz, DMSO-d6) δ: 1.19 (s, 9H), 8.03 (d, J=8.52 Hz, 1H), 8.25-8.27 (dd, J=2.32 Hz, J=8.32 Hz, 1H), 8.44 (s, 1H), 8.90 (d, J=1.84 Hz, 1H). LC-MS (m/z): [M+H]=291.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([OH:25])=O)=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][NH2:27]>>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([NH:27][CH3:26])=[O:25])=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: O=C(O)c1cnn2ccc(N3C[C@H](O)C[C@@H]3c3cccc(F)c3)nc12
Product: CNC(=O)c1cnn2ccc(N3C[C@H](O)C[C@@H]3c3cccc(F)c3)nc12
Yield: 45 %

Procedure:
Prepared by the method described in Example 1 using 5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and methylamine to provide the final product as a white solid (9.4 mg, 45% yield). MS (apci) m/z=356.1 (M+H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCC(=O)Cl
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(=O)NCCCSc1ccncc1
Yield: 93.1 %

Procedure:
To a solution of 1.21 g (5.00 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.79 ml (20.0 mmol) of triethylamine in 50 ml of methylene chloride was added 1.02 ml (6.00 mmol) of caproyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with hexane and dried to obtain 1.24 g of the desired compound (84.2%, colorless powder), mp: 48.0°-49.0° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([NH2:12])=O)[CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:22]2)=CC=1>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10](=[S:22])[NH2:12])[CH:3]=1
Reactant: NC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=S)c1cc(Cl)c(Cl)c(Cl)n1
Yield: 58.7 %

Procedure:
A mixture of 4, 5, 6-trichloropyridine-2-carboxamide (10.4 g, 46 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent, 22.0 g, 54 mmol) in toluene (150 mL) was heated under reflux for two hours. The reaction mixture was cooled, diluted with water (250 mL) and extracted with ethyl acetate (2×150 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (20% ethyl acetate in hexanes) to give 4, 5, 6-trichloropyridine-2-carbothioamide (6.5 g, 27 mmol): mp 168-169° C.
Reaction SMILES: C(=O)([O-])OCC[C:5](=[O:18])[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[CH:7]=1.[S].N1C2C(=CC=CC=2)C=CC=1.[H][H]>[Pd]>[CH3:17][O:16][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([O:12][CH3:13])[C:9]=1[O:14][CH3:15])[CH:5]=[O:18]
Reactant: COc1cc(C(=O)CCOC(=O)[O-])cc(OC)c1OC
Reactant: [H][H]
Agent: [Pd]
Agent: [S]
Solvent: c1ccc2ncccc2c1
Product: COc1cc(C=O)cc(OC)c1OC
Reaction time: 12 h
Yield: 0.9 %

Procedure:
To a solution of 28.4 g (10.1 moles) of 3,4,5-trimethoxy-benzoylethyl carbonate in ml 300, prepared as described in step (a), 14.2 g of Pd supported on BaSO4 (10%) and 0.1 ml of a solution of sulfur and quinoline prepared following Rosemund and Zetzsche and diluted 1:3000 are added. The mixture is hydrogenated in a PARR apparatus in an hydrogen atmosphere at ordinary pressure and 25° C. under efficient shaking during 12 hours. The catalyst is removed by filtration and recovered, whereas the organic solution is washed with a 5% NaOH solution and finally evaporated in a vacuum. 17.64 g of 3,4,5-trimethoxybenzaldehyde are obtained, with the same characteristics generally described in the literature.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13](=[O:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[CH:10][S:11][CH:12]=1.[F:16][C:17]([F:24])([F:23])[C:18](OCC)=[O:19].C[O-].[Na+].Cl>C(OC)(C)(C)C>[F:16][C:17]([F:24])([F:23])[C:18](=[O:19])[CH2:14][C:13]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[N:9]=[CH:10][S:11][CH:12]=2)=[C:2]([F:1])[CH:3]=1)=[O:15]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(-c2cscn2)c(F)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Product: O=C(CC(=O)C(F)(F)F)c1ccc(-c2cscn2)c(F)c1
Reaction time: 20 h
Yield: 99 %

Procedure:
To a stirred solution of 1-[3-fluoro-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone (666 mg, 3.01 mmol), ethyl trifluoroacetate (470 mg, 3.31 mmol) in t-butylmethylether (40 ml) was added sodium methoxide (28 wt. % solution in methanol; 0.8 ml, 3.6 mmol) over 5 minutes, and the mixture was stirred for 20 hours. The mixture was made neutral by addition of 2N HCl aqueous solution, and the whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was used for next reaction without purification. (1.06 g, 99% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]([NH:26][C:27](OCC)=[O:28])=[N:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])=[CH:15][CH:14]=2)[CH:10]=1)=[O:5])[CH3:2].ClCCCl>[Ti](Cl)(Cl)(Cl)Cl.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:26][C:27](=[O:28])[C:14]3[C:13](=[CH:18][CH:17]=[C:16]([C:19]([N:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)=[O:20])[CH:15]=3)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)NC(=Nc1ccc(C(=O)N2CCCC2)cc1)n1cc(C(=O)OCC)cn1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCO
Solvent: ClCCCl
Product: CCOC(=O)c1cnn(-c2nc3ccc(C(=O)N4CCCC4)cc3c(=O)[nH]2)c1
Temperature: 100 °C
Yield: 2.1 %

Procedure:
Titanium (IV) chloride (0.377 mL, 3.43 mmol) was carefully added to a solution of 1-{ethoxycarbonylamino-[4-(pyrrolidine-1-carbonyl)-phenylimino]-methyl}-1H-pyrazole-4-carboxylic acid ethyl ester (0.977 g, 2.29 mmol) and DCE (5.5 mL). The reaction mixture was heated to 100° C. for 2.5 h and was then cooled to room temperature and quenched with ethanol (10 mL). The resulting solution was concentrated and the residue was partitioned between DCM (30 mL) and water (30 mL). The two layers were filtered to remove a solid byproduct and then separated. The aqueous layer was washed with DCM (30 mL) and the combined organic layers were washed with brine (30 mL), dried (MgSO4), and concentrated. The residue was triturated with diethyl ether and then with ethanol to yield the titled compound (18 mg, 2.0% yield). MS (ESI/Cl): mass calcd. for C19H19N5O4, 381.1; m/z found, 382.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:12])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([CH:8]=1)[NH2:7].[NH4+].[Cl-]>CCO.O.[Fe]>[Cl:1][C:2]1[CH:8]=[C:6]([NH2:7])[C:5]([NH2:9])=[CH:4][C:3]=1[I:12]
Reactant: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)c(I)cc1N
Temperature: 50 °C
Reaction time: 45 h

Procedure:
To a suspension of 5-chloro-4-iodo-2-nitroaniline (36.5 g, 122 mmol) in EtOH (800 mL) and water (150 mL) was added iron powder (38 g, 673 mmol) and NH4Cl (16 g, 306 mmol). The mixture was heated under nitrogen at 50° C. overnight. Additional iron powder (38 g, 673 mmol) and NH4Cl (16 g, 306 mmol) were added and heating was continued for 45 h. The reaction mixture was cooled, filtered and concentrated. The residue was re-dissolved in ethyl acetate and washed with sodium bicarbonate solution. The organic phase was concentrated to afford the desired product as a gray solid, which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.Br.[NH2:14][C@@:15]1([CH3:23])[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[C:6](=[O:8])[N:14]([C@@:15]1([CH3:23])[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:9]2=[O:10]
Reactant: C[C@]1(N)CCC(=O)NC1=O
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@]1(N2C(=O)c3ccc(Br)cc3C2=O)CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
A mixture of 4-bromophthalic anhydride (7.53 g, 33.2 mmol), (3S)-3-amino-3-methyl-piperidine-2,6-dione hydrobromide (8.00 g, 44.1 mmol) and sodium acetate (2.72 g, 33.2 mmol) in acetic acid (150 mL) was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under vacuum. The residue was stirred in water (170 mL) for 3 hours, and the resulting solid was filtered, washed with additional water (80 mL), and dried, to afford 6.3 g of 5-bromo-2-[(3S)-3-methyl-2,6-dioxo-piperidin-3-yl]-isoindole-1,3-dione, in 54% yield; 1H NMR (DMSO-d6) δ 1.89 (s, 3H), 2.01-2.09 (m, 1H), 2.53-2.73 (m, 3H), 7.79 (dd, J=5.7 Hz, J=2.7 Hz, 1H), 8.06 (m, 2H), 11.04 (s, 1H); 13C NMR (DMSO-d6) δ 21.0, 28.5, 29.0, 58.9, 124.9, 125.9, 128.3, 130.0, 133.0, 137.4, 166.6, 167.2, 172.0, 172.1.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[C:10](OS(C(F)(F)F)(=O)=O)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][S:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[C:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)=[C:10]([C:34]3[CH:35]=[CH:36][C:31]([S:30][CH3:29])=[CH:32][CH:33]=3)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: O=c1c(-c2ccc(F)cc2)c(OS(=O)(=O)C(F)(F)F)cnn1-c1ccccc1
Product: CSc1ccc(-c2cnn(-c3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Yield: 92 %

Procedure:
The 2-phenyl-4-(4-fluorophenyl)-5-trifluoromethanesulfonyloxy-3(2H)-pyridazinone was coupled with 4-(methylthio)phenylboronic acid as in Example 9 to provide 2-phenyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 915 mg, 92%) which was immediately oxidized with peracetic acid as in Example 9 to provide the title compound after column chromatography (silica gel, 1:1 hexanes-ethyl acetate) and crystallization from diethyl ether-hexanes (yield: 288 mg, 69%). mp 219-220° C. 1H NMR (300 MHz, DMSO-d6) δ 3.25 (s, 3H), 7.15 (t, J=9 Hz, 2H), 7.30 (m, 2H), 7.46 (m, 1H), 7.56 (m, 4H), 7.64 (m, 2H), 7.90 (d, J=9 Hz, 2H), 8.24 (s, 1H). MS (DCI/NH3) m/z 421 (M+H)+, 438 (M+NH4)+.