Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35]([N:39]=[C:40]=[O:41])[CH:36]=[CH:37][CH:38]=1>C(Cl)Cl>[F:31][C:32]([F:42])([F:43])[C:33]1[CH:34]=[C:35]([NH:39][C:40]([N:26]2[CH2:25][CH2:24][N:23]([S:20]([C:17]3[CH:16]=[CH:15][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:29])([F:1])[F:30])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:19][CH:18]=3)(=[O:22])=[O:21])[CH2:28][CH2:27]2)=[O:41])[CH:36]=[CH:37][CH:38]=1
Reactant: O=S(=O)(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)N1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1
Reaction time: 3 h

Procedure:
To [[4-[(7-trifluoromethyl-4-quinolinyl)amino]-phenyl]sulfonyl]piperazine (prepared in Example 9, part D) in methylene chloride is added dropwise, at room temperature, m-trifluoromethylphenyl isocyanate in methylene chloride solution. The reaction is conducted in an atmosphere of nitrogen at room temperature for 1-5 hours. 1[[(m-Trifluoromethylphenyl)amino]carbonyl]-4-[[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]phenyl]sulfonyl]piperazine is isolated by conventional methods, e.g., filtration, chromatography.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][N:28](C=O)[CH3:29].CNC>O.C1COCC1>[CH3:27][N:28]([CH3:29])[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: CN(C)C=O
Agent: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 60 °C

Procedure:
To a mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.14 g of potassium carbonate and 3 ml of DMF, 3 ml of a THF solution of dimethylamine was added and stirred while heating at 60° C. for 3.3 hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the resultant crystals were washed with diethyl ether to give 0.27 g of dimethyl-{4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-yl}amine (hereinafter, referred to as “active compound 131”).
Reaction SMILES: C(=O)=[N:2][S:3](Cl)(=[O:5])=[O:4].[CH3:8][O:9][C:10](=[O:24])[C:11]1[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:20])=[C:13]([CH:21]([CH3:23])[CH3:22])[CH:12]=1>C1(C)C=CC=CC=1>[CH3:8][O:9][C:10](=[O:24])[C:11]1[CH:12]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:14]([O:20][S:3](=[O:4])(=[O:5])[NH2:2])=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:16]=1
Reactant: COC(=O)c1cc(C(C)C)c(O)c(C(C)C)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(C)C)c(OS(N)(=O)=O)c(C(C)C)c1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
N-Chlorosulfonyl isocyanate (2.12 mL, 24.3 mmol) was added slowly to a warm solution of 3,5-diisopropyl-4-hydroxy-benzoic acid methyl ester (5.47 g, 23.1 mmol) in 300 mL toluene. The resulting solution was heated to reflux for 6 hours and then cooled to room temperature and concentrated to give a brown oil. Quenched with 200 g ice and extracted with ethyl acetate. The organic solution was dried over magnesium sulfate, filtered, and concentrated to give a tan solid. Chromatography on silica gel (20% ethyl acetate/hexanes) gave 3.58 g of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([O:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:16]=[CH:15][N:14]=1
Reactant: Cc1cccc(C)c1O
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1cccc(C)c1Oc1ccnc(Cl)c1
Yield: 96.3 %

Procedure:
Using the method of Example 3, Step A, 2,6-dimethylphenol (0.771 g, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to provide 2-chloro-4-(2,6-dimethylphenoxy)pyridine (1.42 g, 96% yield) as a white solid. 1H NMR (CDCl3) δ 8.20 (d, 1H), 7.12 (s, 4H), 6.65-6.68 (m, 2H), 2.11 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[Cl:9][CH2:10][CH2:11][N:12]=[C:13]=[O:14]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:13]([NH:12][CH2:11][CH2:10][Cl:9])=[O:14])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCCCl
Reactant: Nc1cccc(Br)n1
Solvent: C1CCOC1
Product: O=C(NCCCl)Nc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
To a solution of 6-bromo-2-pyridinamine (1 g, 5.78 mmol) in anh. THF (25 mL), at r.t., under N2, was added 1-chloro-2-isocyanatoethane (1.2 mL, 2.5 eq) and the reaction mixture was stirred at r.t. for 18 hr. The crude mixture was partitioned between CH2Cl2 and water. The phases were separated and the organic layer was dried over anh. Na2SO4. The solids were filtered and the solvent evaporated to give the title compound (1.06 g, 66%) which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([Cl:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[Cu][C:14]#[N:15].CN(C=O)C>CCOC(C)=O>[Cl:12][C:7]1[N:8]=[CH:9][C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([C:14]#[N:15])[CH:11]=2
Reactant: Clc1cc2ccc(Br)cc2cn1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc2cc(Cl)ncc2c1
Temperature: 150 °C

Procedure:
To a flask charged with 7-bromo-3-chloroisoquinoline (1.0 g, 4.1 mmol) and a stir bar was added copper(I) cyanide (550 mg, 6.2 mmol) and DMF (50 mL). The mixture was heated to 150° C. for 24 hours under an atmosphere of nitrogen. The reaction was diluted with EtOAc, washed with sat. NH4OAc and brine, dried over sodium sulfate, concentrated and purified by silica gel chromatography (Hexanes:DCM) and the solvent removed to afford the title compound. LC-MS (IE, m/z): 189 [M+1]+.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:3][CH2:2]1.[C:22]1(=O)[CH2:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:22]1([N:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][CH2:6][CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:25][CH2:24][CH2:23]1
Reactant: NS(=O)(=O)c1ccc(NCCCNC2CC2)c([N+](=O)[O-])c1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(NCCCN(C2CCC2)C2CC2)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 308A (314 mg) in dichloromethane (5 mL) was added cyclobutanone (70 mg) followed by sodium triacetoxyborohydride (318 mg). The mixture was stirred overnight. The mixture was diluted with dichloromethane (300 mL) and washed with aqueous NaHCO3, water and brine and dried over Na2SO4. After filtration, evaporation of solvent gave the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:6](=[O:22])[N:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[S:8](=[O:17])(=[O:16])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[C:24]1[C:29]([Cl:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1>CN(C=O)C>[C:18]([N:7]1[C:6](=[O:22])[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:24]2[C:29]([Cl:30])=[CH:28][C:27]([C:31]([F:34])([F:32])[F:33])=[CH:26][N:25]=2)=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8]1(=[O:17])=[O:16])([CH3:19])([CH3:21])[CH3:20]
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)N1C(=O)C(NCCN)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NCCNc2ncc(C(F)(F)F)cc2Cl)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 38.3 %

Procedure:
4-[(2-Aminoethyl)amino]-2-tert-butyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.088 g, 0.27 mmol), 2,3-dichloro-5-(trifluoromethyl)pyridine (0.065 g, 0.30 mmol) and TEA (0.055 g, 0.54 mmol) was dissolved in dry DMF (3 ml) and heated in a microwave reactor at 120° C. for 25 mins. The reaction mixture was extracted with EtOAc (75 ml) and the organic phases were washed with water (3×50 ml), dried over MgSO4, filtered and evaporated. The residue was purified by silica gel column chromatography using petroleum ether and EtOAc (85:15) as eluant, to give the title compound (0.052 g, 38%). 1H NMR (500 MHz, CDCl3): δ 8.3-8.25 (m, 1H), 7.67-7.62 (m, 2H), 7.49-7.43 (m, 2H), 7.43-7.35 (m, 3H), 6.47-6.41 (m, 1H), 5.47-5.41 (m, 1H), 3.52 (q, 2H), 3.09 (q, 2H), 1.7 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 159.4, 155.7, 143.7, 143.6, 135.5, 133.2, 133.1, 131.5, 129.4, 128.5, 125, 124.6, 122.4, 116.8, 116.6, 115, 107.1, 61.4, 45.4, 40.9, 27.5; Mass Spectrum: M−H+ 503.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1.[CH3:23]S(C)=O.[H-].[Na+].CI>O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH:14]([CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOC(=O)C(C)c1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Reaction time: 0.5 h

Procedure:
6.4 Grams (0.02 mole) of ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate is dissolved in 100 ml. of dimethyl sulfoxide (DMSO) and added to a slurry of 0.48 g. (0.02 mole) of sodium hydride in approximately 30 ml. of DMSO. The mixture is stirred for 30 mins. before 2.84 g. (0.02 mole) of methyl iodide is added. Stirring is continued for 15 mins. The reaction mixture is then poured into water and the precipitate filtered off and recrystallized from 2-propanol to yield ethyl 5-(p-chlorobenzoyl)-1,4,α-trimethylpyrrole-2-acetate, m.p. 88°-90° C.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C@H:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:8][O:9][S:26]([CH3:25])(=[O:28])=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(CO)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](COS(C)(=O)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-(tert-butyl-dimethyl-silanyloxy)-2-phenyl-ethanol (85 mg, 0.337 mmol) in dichloromethane (2 mL) were added triethylamine (61 μl, 0.44 mmol) and methanesulfonyl chloride (27 μl, 0.35 mmol) in the order, followed by stirring at room temperature for 20 min. The solution was washed with an aqueous saturated sodium bicarbonate solution to separate an organic layer. The organic layer was dried over sodium sulfate and filtrated. The filtrate was concentrated and dried for 30 min in a vacuum to give methanesulfonic acid (R)-2-(tert-butyl-dimethyl-silanyloxy)-2-phenyl-ethyl ester. Methanesulfonic acid (R)-2-(tert-butyl-dimethyl-silanyloxy)-2-phenyl-ethyl ester, 1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-5-[4-(5-trifluoromethyl-furan-2-ylmethyl)-piperazin-1-yl]-1H-pyrimidine-2,4-dione (5-3) (60 mg, 0.112 mmol) and potassium carbonate (77 mg, 0.560 mmol) were dissolved at 70° C. for 12 hrs in DMF (1 ml) in a nitrogen atmosphere with stirring. The solution was cooled to room temperature, washed with an aqueous saturated sodium bicarbonate solution and concentrated. The residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate, 5/1) and dried in a vacuum to afford 83 mg of the compound as a white solid (yield 97%). 1H NMR (300 MHz, CDCl3) δ −0.23 (3H, s), −0.11 (3H, s), 0.80 (9H, s), 2.25 (2H, m), 2.33 (3H, s), 2.47 (2H, m), 2.80 (2H, m), 3.50-3.70 (2H, m), 3.62 (2H, s), 3.83 (1H, dd), 4.36 (1H, dd), 5.13 (1H, dd), 5.26-5.50 (2H, m), 6.30 (1H, d), 6.73 (1H, m), 7.16-7.43 (7H, m), 7.53 (1H, d)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9](=[O:21])[CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]([CH3:20])[CH:13]=2)[S:5][C:6]=1[CH2:7][CH3:8].[CH2:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)[CH3:23]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:7]([C:6]1[S:5][C:4]([C:9](=[O:21])[CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]([CH3:20])[CH:13]=2)=[CH:3][C:2]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:22][CH3:23])[CH3:8]
Reactant: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1Br
Reactant: CCc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CCc1ccccc1-c1cc(C(=O)CCc2cc(C)c(O)c(C)c2)sc1CC
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1-(4-Bronno-5-ethyl-thiophen-2-yl)-3-(4-hydroxy-3,5-dimethyl-phenyl)-propan-1-one (45 mg, 123 μmol) and 2-ethylphenylboronic acid (22 mg, 148 μmol) are dissolved in degassed dioxane (0.8 mL) and degassed 2 M aq. Na2CO3 solution. To this solution PdCl2(dppf) (5 mg, 7 μmol) is added under a stream of argon. The mixture is stirred at 80° C. for 8 h. The mixture is cooled to rt and an aliquot is purified by prep. HPLC to give 1-[5-ethyl-4-(2-ethyl-phenyl)-thiophen-2-yl]-3-(4-hydroxy-3,5-dimethyl-phenyl)-propan-1-one as a colourless resin; LC-MS: tR=1.10 min, [M+1]+=383.25.
Reaction SMILES: C([NH:4][CH2:5][C:6]1[S:10][C:9]([SH:11])=[N:8][N:7]=1)(=O)C.[ClH:12]>>[ClH:12].[NH2:4][CH2:5][C:6]1[S:10][C:9]([SH:11])=[N:8][N:7]=1
Reactant: CC(=O)NCc1nnc(S)s1
Agent: Cl
Product: NCc1nnc(S)s1

Procedure:
Thus obtained 5-acetamidomethyl-1,3,4-thiadiazole-2-thiol (44 g) was suspended in 6N hydrochloric acid (400 ml) and the mixture was heated to reflux for 2 hours. The reaction mixture was allowed to cool, and the precipitates were collected by filtration and washed with ethanol to give 5-aminomethyl-1,3,4-thiadiazole-2-thiol hydrochloride (28.3 g). m.p. 213° to 217° C. The mother liquid obtained above was concentrated under reduced pressure and the residue was washed with ether to give the same objective product (12.6 g). Total yield is 40.9 g.
Reaction SMILES: [N:1]1[N:2]([C:10]2[N:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]([NH:14][CH:15]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]([OH:20])[C:17]([OH:19])=O)=[O:13])[CH:3]=[C:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2.Cl.[CH:33]1([NH2:36])[CH2:35][CH2:34]1>>[CH:33]1([NH:36][C:17](=[O:19])[CH:16]([OH:20])[CH:15]([NH:14][C:12](=[O:13])[C:11]2[CH:28]=[CH:29][CH:30]=[N:31][C:10]=2[N:2]2[CH:3]=[C:4]3[C:9]([CH2:8][CH2:7][CH2:6][CH2:5]3)=[N:1]2)[CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:35][CH2:34]1
Reactant: NC1CC1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1cc2c(n1)CCCC2
Agent: Cl
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NC1CC1)c1cccnc1-n1cc2c(n1)CCCC2

Procedure:
The reaction was carried out in analogy to reaction step 3.1 by reacting 3-[2-(4,5,6,7-tetrahydro-2H-indazol-2-yl)nicotinamido]-2-hydroxy-4-phenylbutanoic acid and cyclopropylamine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13]>C(O)(=O)C>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][CH2:13][CH2:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: C=CC(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)CCNc1ccc(C(=O)O)cc1
Yield: 63.2 %

Procedure:
A solution of 4-aminobenzoic acid (6.85 g, 0.05 mol) and ethyl acrylate (15 g, 0.15 mol) in acetic acid (40 mL) was heated to 100° C. for 15 h. The solid which formed was filtered, washed with hexane and dried to give the title compound (7.5 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16](SC)[N:15]=[C:14]([C:20]2[CH:21]=[CH:22][C:23](=[O:26])[NH:24][CH:25]=2)[CH:13]=1.ClC1C=C(C=CC=1)[C:31](OO)=[O:32].C[O-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:32][CH3:31])[N:15]=[C:14]([C:20]2[CH:21]=[CH:22][C:23](=[O:26])[NH:24][CH:25]=2)[CH:13]=1
Reactant: CSc1nc(NCCc2c(F)cccc2Cl)cc(-c2ccc(=O)[nH]c2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1nc(NCCc2c(F)cccc2Cl)cc(-c2ccc(=O)[nH]c2)n1
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a mixture of above 5-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methylsulfanyl-pyrimidin-4-yl}-1H-pyridin-2-one [1 g, 2.56 mmol, Example 31] in a mixture of MeOH (30 mL) and DCM (20 mL), is added 3-chloro-peroxybenzoic acid (70%, 1.32 g, 7.68 mmol) at room temperature. After 3 hours at 20° C., a 25% solution of sodium methoxide in MeOH (12 mL) is added at 0° C. After additional 1 hour, the mixture is concentrated, diluted with water, and neutralized with 3 M hydrochloric acid (pH 7). The resulting solid is filtered, and re-dissolved in a basic solution (pH 12). After acidifying into pH 3, the precipitate is filtered, and dried to give 5-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-1H-pyridin-2-one [0.92 g, 96%, Example 32] as a solid. LCMS: RT=2.23 minutes, MS: 375 (M+H).
Reaction SMILES: [C:1]([C@H:4]1[C@@H:9]([NH2:10])[CH2:8][CH2:7][C@@H:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:5]1)(=[O:3])[CH3:2].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:1]([C@H:4]1[C@@H:9]([NH:10][C:28](=[O:29])[CH2:27][NH:26][C:24](=[O:25])[C:23]2[CH:31]=[CH:32][CH:33]=[C:21]([C:20]([F:19])([F:35])[F:34])[CH:22]=2)[CH2:8][CH2:7][C@@H:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: CC(=O)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(=O)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.4 %

Procedure:
Tert-butyl (1R,3R,4S)-3-acetyl-4-aminocyclohexylcarbamate (500 mg) dissolved in DMF (2 mL) prior to the addition of 2-(3-(trifluoromethyl)benzamido)acetic acid (626 mg), 4-methylmorpholine (1.1 mL), and BOP (1.3 g). The reaction was stirred for 12 h at rt and then partitioned between EtOAc and 1N HCl solution. The organic phases were combined, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford tert-butyl (1R,3R,4S)-3-acetyl-4-(2-(3-(trifluoromethyl)benzamido)acetamido)cyclohexylcarbamate (430 mg). MS found: (M+H)+=486.2.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(N2CCNCC2)cc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (3 mL) was added dropwise with stirring at 0° C. to a solution of t-butyl 4-(4-chlorophenyl)piperazine-1-carboxylate (360.6 mg, 1.21 mmol, 1.00 equiv) in dichloromethane (12 mL). The resulting solution was stirred for 3 h at 20° C. in an oil bath. The pH value of the solution was adjusted to 7-8 with a saturated solution of sodium bicarbonate. The resulting solution was extracted with 6×20 mL of dichloromethane, the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 264.5 mg (102%) of 1-(4-chlorophenyl)piperazine as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13]O>OS(O)(=O)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:13])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: CO
Reactant: COc1cc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)cc1OC
Yield: 96 %

Procedure:
A suspension of 4-chloro-2-methoxybenzoic acid (5 g, 27 mmol) in MeOH (18 mL) and conc. H2SO4 (1.5 mL) was refluxed overnight. MeOH was evaporated and the residue was extracted to EtOAc and successively washed with water and brine, dried over MgSO4, filtered and evaporated to give methyl 4-chloro-2-methoxybenzoate as a white solid (5.17 g, 96%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Br:11])[N:3]=1.O.[OH-].[Na+]>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Br:11])[N:3]=1
Reactant: O=[N+]([O-])c1cc(Br)nc(Br)c1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(Br)nc(Br)c1
Temperature: 90 °C

Procedure:
To a solution of 2,6-dibromo-4-nitro-pyridine (1.0 g, 3.54 mmol) in glacial acetic acid (20 mL) was added Fe-powder (1.0 g, 17.74 mmol) at room temperature. The reaction mixture was refluxed for 90° C. for 30 min. After completion of reaction (TLC monitoring), water was added (100 mL), basified with 2N NaOH (pH 12-14). The resulting mixture was filtered through celite-bed and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, dried (Na2SO4), filtered and evaporated to dryness to get the desired product as an off white solid (0.80 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:15]3[CH2:16][CH2:17][O:18][CH:14]3[O:13][N:12]=2)=[C:9]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:24]1(=O)[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH2:25]1>ClCCl>[Cl:1][C:2]1[C:10]([C:11]2[CH:15]3[CH2:16][CH2:17][O:18][CH:14]3[O:13][N:12]=2)=[C:9]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:24]1[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH:25]=1)=[O:5]
Reactant: O=C1CCCC(=O)C1
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1C1=NOC2OCCC12
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(C(=O)OC2=CC(=O)CCC2)c(Cl)c1C1=NOC2OCCC12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.9 g (2.5 mmol) of 2-chloro-4-ethylsulfonyl-3-(3a,4,5,6a-tetrahydrofuro[3,2-d]-isoxazol-3yl)benzoic acid together with 0.31 g (2.8 mmol) of 1,3-cyclohexandione in 50 ml of dichloromethane are treated with 0.53 g (2.8 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimi hydrochloride and 0.1 g of N,N-dimethylaminopyridine. After the mixture has been stirred for 16 hours at room temperature, it is washed with 1 N hydrochloric acid and sodium chloride solution and dried over magnesium sulfate. It is filtered with suction and the filtrate is concentrated. This gives 0.66 g (58% of theory) of crude 3-oxocyclohex-1-enyl 2-chloro-4-ethylsulfonyl-3-(3a ,4,5,6a-tetrahydrofurro[3,2-d]isoxazol-3-yl)benzoate.