Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[NH2:17][C:18]1([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(#N)C>[Br:1][C:2]1[C:3]([NH:17][C:18]2([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: NC1(CO)CCCC1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OCC1(Nc2nc(Cl)ncc2Br)CCCC1
Temperature: 0 °C

Procedure:
An ice-cooled solution of 2.28 g (10.0 mmol) of 5-Bromo-2,4-dichloropyrimidine and 1.7 ml (12.0 mmol) of triethylamine in 10 ml of acetonitrile is mixed with 1.38 g (12.0 mmol) (1-amino-cyclopentyl)-methanol. After 16 hours at room temperature the batch is filtrated to remove the solid precipitate. The precipitate is dried. 1.48 g (4.8 mmol, corresponding to 48% of theory) of the product is obtained.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=[CH:32][CH2:33][C:34](O)=[O:35])=[CH:27][CH:26]=1.C1(N(C2CCN(C(=O)C=CCCC)CC2)S(C2C=CC=C(C(F)(F)F)C=2)(=O)=O)CC1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:34](=[O:35])[CH2:33][CH:32]=[C:31]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Reactant: O=C(O)CC=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CCCC=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Product: O=C(CC=C(c1ccc(F)cc1)c1ccc(F)cc1)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1

Procedure:
N-Cyclopropyl-N-{1-[4,4-bis(4-fluorophenyl)-but-3-enoyl]piperidin-4-yl}-3-trifluoromethylbenzenesulfonamide (33) was prepared by reacting N-cyclopropyl-N-piperidin-4-yl-3-trifluoromethylbenzenesulfonamide with 4,4-bis(4-fluorophenyl)-but-3-enoic acid following the procedure described for the synthesis of N-cyclopropyl-N-(2-hexenoyl)piperin-4-yl-3-trifluoromethyl-benzenesulfonamide (30) in Example 19, step a. 1H NMR (CDCl3): δ 8.12 (s, 1H), 8.03 (d, 1H), 7.86 (d, 1H), 7.71 (t, 1H), 7.15 (m, 6H), 6.96 (m, 2H), 6.21 (t, 1H), 4.68 (m, 1H), 4.02 (m, 1H), 3.61 (m, 1H), 3.15 (d, 2H), 2.93 (m, 1H), 2.51 (m, 1H), 1.93 (m, 1H), 1.69 (m, 2H), 1.25 (m, 1H), 0.90 (m, 5H). LC: 100%. MS (M+H+): 605.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2([C:10]([O:12]C(C)(C)C)=[O:11])[CH2:9][CH2:8]2)=[C:4]([F:19])[C:3]=1[NH:20][C:21](=[O:36])[C@H:22]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C@@H:23]([CH3:28])[C:24]([F:27])([F:26])[F:25].C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)=[C:4]([F:19])[C:3]=1[NH:20][C:21](=[O:36])[C@H:22]([C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C@@H:23]([CH3:28])[C:24]([F:27])([F:26])[F:25]
Reactant: C[C@H]([C@H](C(=O)Nc1c(Cl)ccc(CC2(C(=O)OC(C)(C)C)CC2)c1F)c1ccc(Cl)cc1)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]([C@H](C(=O)Nc1c(Cl)ccc(CC2(C(=O)O)CC2)c1F)c1ccc(Cl)cc1)C(F)(F)F
Reaction time: 1 h

Procedure:
22.0 mg (0.040 mmol) of tert-butyl 1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-2-fluorobenzyl)cyclopropanecarboxylate were dissolved in 0.19 ml of dichloromethane, and 0.5 ml of TFA was added at RT. After 1 h at RT, the reaction mixture was concentrated under reduced pressure and the residue was dried under high vacuum overnight. This gave 17.8 mg (82.2% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:47]=[CH:46][C:18]2[C:19]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:20]([CH2:22][O:23][C:24]3[C:28]([C:29]([O:31]CC)=[O:30])=[CH:27][N:26]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:25]=3)[O:21][C:17]=2[CH:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:47]=[CH:46][C:18]2[C:19]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[C:20]([CH2:22][O:23][C:24]3[C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:25]=3)[O:21][C:17]=2[CH:16]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1OCc1oc2cc(OCc3nc(-c4ccccc4)oc3C)ccc2c1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2c(-c3ccccc3)c(COc3nn(-c4ccccc4)cc3C(=O)O)oc2c1
Yield: 91.6 %

Procedure:
To a mixture of ethyl 3-({6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-phenyl-1-benzofuran-2-yl}methoxy)-1-phenyl-1H-pyrazole-4-carboxylate (0.40 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was heated under reflux for 1 hr. The reaction mixture was neutralized by adding 1N hydrochloric acid and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-({6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-phenyl-1-benzofuran-2-yl}methoxy)-1-phenyl-1H-pyrazole-4-carboxylic acid as colorless crystals (0.35 g, yield 92%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 200-201° C.
Reaction SMILES: CN(C(O[N:9]1[N:17]=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[OH:23][C:24]([CH3:51])([CH3:50])[CH2:25][C@@:26]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[O:31][C:30](=[O:32])[N:29]([C@H:33]([C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=2)[CH3:34])[CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C.O.NN>CN(C)C=O.O>[OH:23][C:24]([CH3:51])([CH3:50])[CH2:25][C@@:26]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[O:31][C:30](=[O:32])[N:29]([C@H:33]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([NH:9][NH2:17])=[O:40])=[CH:37][CH:36]=2)[CH3:34])[CH2:28][CH2:27]1
Reactant: C[C@@H](c1ccc(C(=O)O)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccc(C(=O)NN)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
TBTU [2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 0.33 g] was added to 4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-benzoic acid (0.37 g) and EtNiPr2 (0.41 mL) dissolved in dimethylformamide (5 mL). After stirring the solution at room temperature for 10 min, hydrazine hydrate (0.23 mL) was added. The solution was stirred at room temperature overnight and then diluted with water. The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with brine and dried (MgSO4). The solvent was removed and the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 98:2→90:10) to afford the title compound as a colorless foam-like solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]=12.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:18][C:19]1[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([CH3:28])=[C:21]([CH2:29]Cl)[N:20]=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[N:9]([CH2:29][C:21]3[C:22]([CH3:28])=[C:23]([O:26][CH3:27])[C:24]([CH3:25])=[C:19]([Cl:18])[N:20]=3)[N:10]=[CH:11][C:3]=12
Reactant: COc1c(C)c(Cl)nc(CCl)c1C
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(C)c(Cl)nc(Cn2ncc3c(Cl)nc(N)nc32)c1C
Temperature: 80 °C

Procedure:
A mixture of 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (124 mg), Cs2CO3 (392 mg) and crude 2-chloro-6-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (200 mg) in DMF (2 ml) was heated to 80° C. for 1 h, diluted with EtOAc and washed with water. Concentration and purification by preparative TLC (EtOAc) gave the title compound. R.t. 6.43 min. 1H-NMR (CDCl3) δ 7.86 (s, 1H), 5.48 (s, 2H), 5.37 (s, 2H), 3.71 (s, 3H), 2.27 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:20]=O)[C:8]([OH:19])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>>[ClH:18].[C:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:19])=[C:7]([CH2:20][NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(F)c(Cl)c2)c1
Product: CC(C)(C)NCc1cc(C(C)(C)C)cc(-c2ccc(F)c(Cl)c2)c1O
Product: Cl

Procedure:
5-(tert-Butyl)-3-((tert-butylamino)methyl)-3′-chloro-4′-fluoro-[1,1′-biphenyl]-2-ol hydrochloride was prepared as a white solid using the procedure described in Example 9 from 5-(tert-Butyl)-3′-chloro-4′-fluoro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde and tert-butylamine.
Reaction SMILES: [F:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[F:1][CH:2]1[CH:7]([O:8][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(F)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C(F)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate, 2.4 (63 g, 0.287 mol) in anhydrous methylene chloride (630 mL) was treated with triethylamine (60 mL, 0.43 μmol) followed by methane sulfonyl chloride (26.7 mL, 0.345 mol) at 0° C. under N2 atmosphere. The solution was allowed to warm slowly to ambient temperature and stirred for 14 hours. The mixture was partitioned between saturated NaHCO3 (400 mL) and methylene chloride (400 mL). The aqueous layer was extracted with methylene chloride (2×500 mL). The combined organic phases were washed with 1N HCl, brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with 20-30% EtOAc/Hexane to provide the tert-butyl 3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate, 2.5 (78 g, 91%). 1HNMR (CDCl3, 400 MHz): δ 4.98-4.86 (m, 1H), 4.80-4.74 (m, 0.5H), 4.67-4.63 (m, 0.5H), 3.92-3.45 (m, 3H), 3.44-3.25 (m, 1H), 3.08 (s, 3H), 2.20-2.07 (m, 1H), 1.93-1.80 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:12][NH:11][C:10](=[O:13])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.I[CH3:15].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[C:7]([CH:8]2[CH2:12][N:11]([CH3:15])[C:10](=[O:13])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1CC(c2cccnc2F)CN1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CC(c2cccnc2F)CC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-fluoropyridin-3-yl)pyrrolidin-2-one (0.254 g, 1.41 mmol) in DMF (5 mL) at 0° C. was added iodomethane (0.090 mL, 1.4 mmol) and sodium hydride (60% weight dispersion in mineral oil, 0.056 g, 1.4 mmol). The reaction mixture was stirred at 0° C. for 30 min, warmed to room temperature, and stirred for 30 min. The reaction mixture was diluted with EtOAc, quenched with water, and diluted with brine and water. The aqueous phase was extracted with EtOAc (6×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (50% to 100% EtOAc (10% MeOH) in hexanes) gave 4-(2-fluoropyridin-3-yl)-1-methylpyrrolidin-2-one as a pale yellow oil. MS (ESI, pos. ion) m/z: 195.1 (M+1).
Reaction SMILES: [C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17]I)[C:10]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CN(C)C=O>[C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[C:10]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1CCNCC1
Reactant: O=C1N(CCCCI)CCN1N=Cc1ccccc1
Solvent: CN(C)C=O
Product: CN1CCN(CCCCN2CCN(N=Cc3ccccc3)C2=O)CC1
Yield: 86.6 %

Procedure:
A stirred solution of 1-phenylmethyleneamino-3-(4-iodobutyl)-2-imidazolidinone (10.0 g, 0.0269 mole), dimethylformamide (150 ml) and 1-methylpiperazine (6.0 ml, 3.4 g, 0.0539 mole) is heated to reflux. Reflux is maintained for 2.5 hours. The solution is concentrated under reduced pressure to a semi-solid residue. This residue is dissolved in CHCl3 (300 ml), then washed with saturated NaHC3 solution. (3×400 ml), H2O (2×100 ml) and dried over MgSO4. The filtered solution is concentrated under reduced pressure to an oily residue. This residue is triturated in hexane (300 ml) by stirring. The solid is collected and air-dried to give 8.0 g (0.0233 mole) of 1-phenylmethyleneamino-3-[4-(4-methyl-1-piperazinyl)butyl]-2-imidazolidinone.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[C:9]1([NH:15]N)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH2:6]1[C:1]2[NH:15][C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:2]=2[C:3](=[O:7])[CH2:4][CH2:5]1
Reactant: O=C1CCCC(=O)C1
Reactant: NNc1ccccc1
Solvent: O
Product: O=C1CCCc2[nH]c3ccccc3c21
Yield: 91.5 %

Procedure:
To a solution of 1,3-cyclohexane dione (1.99 g, 17.7 mmol) in water (55 mL) is added phenylhydrazine (1.92 g, 17.7 mmol) in 10 mL of water. A gummy solid quickly formed, which after completion of the addition is scrapped with a spatula to give a solid. The solid is collected, washed with water, and dried in a vacuum oven to give 3.0 g of a tan solid. After drying, the tan solid is stirred at reflux in TFA (25 mL) overnight. Upon cooling, TFA is removed in vacuo and water is added to the residue. The resulting solid is collected, washed with water, and dried to give 1.82 g (55%) of the title compound; mp 218-220° C.; IR (drift) 3150, 3130, 3104, 3093, 3056, 2976, 2954, 2944, 1607, 1577, 1466, 1413, 1251, 1178, 755 cm−1; 1H NMR (CDCl3) δ2.26, 2.64, 3.00, 7.26, 7.35, 8.21, 8.74. Anal. Calcd for C12H11NO: C, 77.81; H, 5.99; N, 7.56. Found: C, 77.82; H, 6.15; N, 7.54.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[O:32]1[C:36]2[CH:37]=[CH:38][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:40][C:35]=2[CH:34]=[CH:33]1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([C:2]3[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:3]=3)=[CH:40][C:35]=2[CH:34]=[CH:33]1
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2occc2c1
Yield: 85.4 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol), tetrakis(triphenylphosphine) palladium(0) (0.058 mg; 0.05 mmol), N,N-diisopropylethylamine (0.345 mL; 2 mmol) and 2-(benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.366 g; 1.5 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.171 g (85%) of the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[C:12]([CH3:16])[C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([CH3:17])[CH:6]=2)[CH2:3][CH2:2]1.[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24].N1CCCCC1>CN(C=O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[C:12]([CH3:16])[C:13]([CH:14]=[C:22]4[S:18][C:19](=[O:24])[NH:20][C:21]4=[O:23])=[C:9]3[N:8]=[C:7]([CH3:17])[CH:6]=2)[CH2:3][CH2:2]1
Reactant: O=C1CSC(=O)N1
Reactant: Cc1cc(NC2CC2)n2nc(C)c(C=O)c2n1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: Cc1cc(NC2CC2)n2nc(C)c(C=C3SC(=O)NC3=O)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 7-(cyclopropylamino)-2,5-dimethylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde (0.25 mmol) in DMF was added thiazolidine-2,4-dione (88 mg, 0.75 mmol) and piperidine (25 μl, 0.25 mmol). The mixture was stirred at room temperature overnight. Mixture was prepared by HPLC to yield 5-((7-(cyclopropylamino)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione. LCMS (M+1=330)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:32])[CH:12]2[CH2:31][N:16]3[C:17]4[C:22]([C:23](/[CH:24]=[CH:25]/[C:26]([O:28]CC)=[O:27])=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].CC(O)=O>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:32])[CH:12]2[CH2:31][N:16]3[C:17]4[C:22]([C:23](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1c2n(c3ccccc13)CC(N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C1CCc2c(/C=C/C(=O)O)c3ccccc3n2C1)S(=O)(=O)c1ccc(F)cc1
Temperature: 50 °C
Yield: 11.3 %

Procedure:
A solution of 85 mg of the product from Step 2 in 2 mL of THF and 3 mL of MeOH was added 0.5 mL of 2N NaOH. The mixture was heated at 50° C. for 8 h and 1 mL of AcOH was then added, and concentrated. The residue was suspended in 5 mL of water and the solid was collected by filtration, and then purified by Combiflash eluted with a gradient up to 70% EtOAc/hexane containing 5% of AcOH to give 9 mg of the title compound (eluted first). 1H NMR (500 MHz, acetone-d6) d 8.12 (m, 2H), 7.87 (d, 1H), 7.87 (m, 1H), 7.48 (t, 1H), 7.42 (m, 1H), 7.28 (m, 2H), 6.28 (d, 1H), 4.65 (m, 1H), 4.27 (m, 1H), 4.04 (t, 1H), 3.49 (m, 1H), 3.10 (m, 1H), 3.02 (s, 3H), 2.10 (m, 1H), 1.78 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:22][CH:21]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)n1c(C(=O)c2ccc(OC(F)(F)F)cc2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-4′-trifluoromethoxyacetophenone.
Reaction SMILES: [CH:1]([S:4]([C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=1)=[O:5])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CCO>[CH:1]([S:4]([C:6]1[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(S(=O)C(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)S(=O)c1ccc(C(=O)O)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of ethyl 4-isopropylsulfinylbenzoate (245 mg, 1.02 mmol) in EtOH (1 mL) at room temperature was added NaOH (300 μL of 5.0 M, 1.50 mmol) dropwise and the mixture stirred for 30 min. The pH of the mixture was adjusted to 2 with 1N HCl before it was evaporated to dryness. The solids were taken up in water, filtered, washed with water (2×), and dessicated to give 4-isopropylsulfinylbenzoic acid (80%) as a white solid. 1H NMR (400 MHz, DMSO) δ 13.30 (s, 1H), 8.11 (d, J=8.2 Hz, 2H), 7.73 (d, J=8.2 Hz, 2H), 3.07-2.97 (m, 1H), 1.22 (d, J=6.9 Hz, 3H), 0.90 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C@@H:9]([OH:15])[CH2:10][CH2:11]C(N)=O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:16]([OH:19])(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C(#[N:33])C>>[CH3:8][C:6]1[CH:5]=[C:4]([C@H:9]2[O:15][C:16](=[O:19])[NH:33][CH2:11][CH2:10]2)[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: CC#N
Reactant: Cc1cc(C)cc([C@@H](O)CCC(N)=O)c1
Reactant: CC(=O)O
Solvent: Ic1ccccc1
Product: Cc1cc(C)cc([C@@H]2CCNC(=O)O2)c1

Procedure:
A stirred solution of (4S)-4-(3,5-dimethylphenyl)-4-hydroxybutanamide (Step B; 204 mg; 0.99 mmol) and iodobenzene diacetate (317 mg; 0.99 mmol) in acetonitrile (8 mL) was heated at 40° C. for 16 h. The reaction was concentrated in vacuo and the residue purified by flash silica gel chromatography (0-100% EtOAc/hexanes gradient) to afford (6S)-6-(3,5-dimethylphenyl)-1,3-oxazinan-2-one as a white solid. LCMS=206.3 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.01 (s, 2H), 7.00 (s, 1H), 5.73 (s, 1H), 5.30 (dd, J=9.8, 2.8 Hz, 1H), 3.50 (dt, J=11, 4.8 Hz, 1H), 3.43-3.38 (m, 1H), 2.35 (s, 6H), 2.26-2.21 (m, 1H), 2.14-2.06 (m, 1H).
Reaction SMILES: C(OO)(=[O:3])C.[NH2:6][C:7]1[N:12]=[C:11]([NH:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=[C:9]([Cl:18])[N:8]=1.CCCCCC>C(Cl)(Cl)Cl>[NH2:6][C:7]1[N+:12]([O-:3])=[C:11]([NH:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=[C:9]([Cl:18])[N:8]=1
Reactant: CC(=O)OO
Reactant: COC(=O)Nc1cc(Cl)nc(N)n1
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1cc(Cl)nc(N)[n+]1[O-]
Temperature: 25 °C

Procedure:
32 ml (0.20 mol) of 40% peracetic acid are added slowly to a solution of 20.2 g (0.10 mol) of methyl 2-amino-6-chloro-4-pyrimidinecarbamate in 500 ml of chloroform. The suspension obtained is warmed to 50° for 4 hours, whereby a clear solution gradually results. After cooling to room temperature, there is obtained by the slow addition of hexane a crystalline precipitate which is recrystallized from chloroform/methanol. There is obtained methyl 2-amino-6-chloro-4-pyrimidinecarbamate-3-oxide of melting point 220°-221°.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[C:31]([C:38]([F:41])([F:40])[F:39])[CH:30]=4)[CH2:24][CH2:23]3)=O)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:51])=CC=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[C:31]([C:38]([F:41])([F:40])[F:39])[CH:30]=4)[CH2:24][CH2:23]3)=[S:51])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)c1ccc(N2CCN(CCCC(=O)N3CCC(Nc4ccc([N+](=O)[O-])c(C(F)(F)F)c4)CC3)CC2)cc1
Product: CC(C)(C)c1ccc(N2CCN(CCCC(=S)N3CCC(Nc4ccc([N+](=O)[O-])c(C(F)(F)F)c4)CC3)CC2)cc1

Procedure:
4-[4-(4-tert-Butyl-phenyl)-piperazin-1-yl]-1-[4-(4-nitro-3-trifluoromethyl-phenylamino)-piperidin-1-yl]-butan-1-one (28 mg; 0.049 mmol, prepared in accordance with Example 90) is reacted with Lawesson's reagent (10 mg; 0.024 mmol) according to the general conditions described in Example 109. The desired product is obtained following purification by preparative HPLC (13 mg; 0.023 mmol). The structure was confirmed using Protocol I-B. Calculated mass=592; observed mass=592; HPLC retention time=4.811 min.