Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:24])=[C:4]([N:8]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=[O:16])=[CH:11][N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[C:31]1(=O)[CH2:36][CH2:35][CH2:34][C:33](=[O:37])[CH2:32]1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl.CN(C)C=O>[F:1][C:2]1[C:3]([CH3:24])=[C:4]([N:8]2[C:13](=[O:14])[C:12]([C:15]([O:17][C:31]3[CH2:36][CH2:35][CH2:34][C:33](=[O:37])[CH:32]=3)=[O:16])=[CH:11][N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(F)cccc1-n1c(-c2ccccc2)ncc(C(=O)O)c1=O
Reactant: O=C1CCCC(=O)C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(F)cccc1-n1c(-c2ccccc2)ncc(C(=O)OC2=CC(=O)CCC2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(3-fluoro-2-methylphenyl)-1,6-dihydro-6-oxo-2-phenyl-5-pyrimidinecarboxylic acid (i.e. the product from Example 5, Step B) (41.0 g, 126 mmol) in dichloromethane (400 mL) was added oxalyl chloride (31.05 g, 252.0 mmol) at 0° C. followed by a catalytic amount (7 drops) of N,N-dimethylformamide. The reaction mixture was allowed to warm to room temperature and stir for 1 h. The reaction mixture was then concentrated under reduced pressure. To the resulting residue was added dichloromethane (400 mL), 1,3-cyclohexanedione (17.03 g, 152 mmol), followed by triethylamine (38.30 g, 379 mmol) and the reaction mixture was stirred at room temperature for 30 min. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with dichloromethane. The organic layer was washed once with water. Then the organic layer was dried (MgSO4) and concentrated under reduced pressure. The resulting solid was washed with chlorobutane to afford the title product pure as an off-white solid (37.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[N:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=1)=[O:5]>C(O)C.C(OCC)(=O)C.[Pt]=O>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[N:8]=[CH:9][C:10]([NH2:13])=[CH:11][N:12]=1)=[O:5]
Reactant: O=C(Nc1ncc([N+](=O)[O-])cn1)c1ccccc1Cl
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cnc(NC(=O)c2ccccc2Cl)nc1
Reaction time: 3 h
Yield: 48.7 %

Procedure:
Platinum oxide (60 mg, 0.22 mmol) was added to a solution 2-(N-2-chlorobenzoyl)amino-5-nitropyrimidine (278 mg, 1.0 mmol) in ethanol (1 ml) and ethyl acetate (10 ml) at ambient temperature and the reaction stirred for 3 hours under an atmosphere of hydrogen. The reaction was filtered through a pad of celite and the solvents were evaporated in vacuo. Purification by flash chromatography on silica gel, eluting with 5% methanol in ethyl acetate yielded 2-(N-2-chlorobenzoyl)amino-5-aminopyrimidine (121 mg, 50% yield) as brown solid:
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].Cl[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]I>C1COCC1.CCOCC>[CH2:16]1[C:2]2([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:1]2=[O:8])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCCCCC1
Reactant: ClCCCCCI
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1CCCCCC12CCCCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of cycloheptanone (2.1 mL, 17.83 mmol) and potassium tert-butoxide (2.60 g, 23.18 mmol) in THF (10 mL) was dropwise added a solution of 1-chloro-5-iodopentane (2.74 mL, 19.61 mmol) in THF (10 mL). The mixture was stirred at ambient temperature for 16 hours. It was then diluted with ether (200 mL), washed with saturated NH4Cl and brine, dried with MgSO4, and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel (95:5 hexane-EtOAc, eluant) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 2.50 (t, 2 H), 1.55-1.79 (m, 8 H), 1.30-1.52 (m, 10 H). MS (DCI+) m/z 198 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([C:24]([NH2:26])=[O:25])[C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH3:11])=[C:4]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:3]=1.[H-].[Na+].[CH3:35]I>CN(C)C=O>[CH3:35][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([C:24]([NH2:26])=[O:25])[C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][CH:23]=2)[CH2:9][CH2:10][CH3:11])=[C:4]([N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH:3]=1
Reactant: CI
Reactant: CCCC(c1ccc(O)cc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)OCC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(c1ccc(OC)cc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)OCC)cc1
Reaction time: 0.25 h

Procedure:
A solution of 5.0 gm (11.4 m mol) of ethyl 4-[(1-(4-hydroxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate in 45 ml of absolute dimethylformamide was added dropwise, under stirring, at ambient temperature, to 548 mg (11.4 m mol) of sodium hydride (50% in oil) in 10 ml of absolute dimethylformamide. The mixture was stirred for a further 15 minutes, and then a solution of 0.71 ml (11.4 m mol) of methyliodide in 8 ml of absolute dimethylformamide was slowly added thereto dropwise. The mixture was stirred for a further two and one-half hours at ambient temperature, evaporated in vacuo, and distributed between water and ether. The ether phase was dried, filtered, and concentrated by evaporation in vacuo. The evaporation residue was purified by column chromatography on silica gel [toluene/acetone (20:1)].
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[S:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:27]3[S:26][CH:30]=[CH:29][N:28]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: c1cscn1
Product: COc1ccccc1-c1cccc(-n2cnc(C(=O)c3nccs3)c2)c1

Procedure:
This compound is prepared by method C using compound 12c and thiazole
Reaction SMILES: C([O:4][C:5]1[C:6](OC(=O)C)=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])(=O)C.C(O)(=O)C1C=CC(C(O)=[O:29])=CC=1>C(O)(=O)C>[OH:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:29])=[CH:12][CH:11]=1)=[O:9]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: CC(=O)Oc1cccc(C(=O)c2ccccc2)c1OC(C)=O
Solvent: CC(=O)O
Product: O=C(c1ccc(O)cc1)c1cccc(O)c1
Temperature: 310 °C
Reaction time: 0.8 h

Procedure:
The flask was charged with 9.57 g of diacetoxybenzophenone (0.032 mole) and 4.98 g of terephthalic acid (0.03 mole) and heated, with stirring, under nitrogen at atmospheric pressure from 238° C. to 310° C. in 48 min. Most of the acetic acid by-product was liberated in this time. Heating at 310° C. continued 22 min. more. Then a vacuum of 0.2 torr (0.0266 kPa) was applied, and a temperature was raised to 325° C. in 8 min. and maintained for 17 min. The cooled polymer had an inherent viscosity, ηinh, of 0.78. Its melt was anisotropic above its flow temperature of 296° C. using the TOT test.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[P:14](=[O:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:28]1([C:2]2[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[CH:4][C:3]=2[P:14](=[O:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(P(=O)(c2ccccc2)c2ccccc2)c(I)c(OC)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COc1cc(P(=O)(c2ccccc2)c2ccccc2)c(-c2ccccc2)c(OC)c1OC
Yield: 84.8 %

Procedure:
To a 2 liter Schlenk flask was added (2-iodo-3,4,5-trimethoxyphenyl) diphenylphosphine oxide 21 (30 g, 61 mmol), phenylboronic acid (11.1 g, 91 mmol), and degassed THF (800 ml). A solution of degassed saturated K2CO3 (400 ml) was added afterwards. The whole mixture was degassed with nitrogen for an additional 10 min. Then, Pd(PPh3)4 (1.22 mmol, 1.4 g) was added in the solution through one portion. The mixture was stirred at reflux under nitrogen for 24 hrs. In situ 31PNMR showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove THF and 400 ml of CH2Cl2 was then added. The CH2Cl2 layer was washed with water (200 ml) and brine (200 ml), dried over Na2SO4, and evaporated. The solid residue was recrystallized from EtOAc (100 ml) to give off-white product 22 (23 g). The mother liquid was passed though a silica gel column to give another 4 g of product 22. The total yield was 98%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[Cl-].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C@@H:21]([NH3+:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C@H:21]([NH:28][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([Br:1])[CH:3]=1)[CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Cl:13])[CH3:27]
Reactant: CCOC(=O)C[C@H]([NH3+])Cc1ccccc1Cl
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C[C@@H](Cc1ccccc1Cl)NC(=O)c1ccc(C)c(Br)c1
Reaction time: 1 h

Procedure:
3-Bromo-4-methylbenzoic acid (331 mg, 1.5 mmol, 1.0 eq.) and (R)-2-(2-chloro-phenyl)-1-ethoxycarbonylmethyl-ethyl-ammonium chloride (428 mg, 1.5 mmol, 1.0 eq.) were combined with DIPEA (844 μL, 3.2 eq.) and HATU (585 mg, 1.5 mmol, 1.0 eq.) in DCM (8 mL). The resulting mixture was stirred for 1 hour, then chromatographed (0-80% EtOAc/hexanes gradient) to yield (R)-3-(3-bromo-4-methyl-benzoylamino)-4-(2-chloro-phenyl)-butyric acid ethyl ester.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([NH2:19])[CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([CH3:20])[N:10]=2)[CH2:4][CH2:3]1.[Cl:22][C:23]1[C:28]([C:29](O)=[O:30])=[C:27]([F:32])[C:26]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:25][CH:24]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:22][C:23]1[C:28]([C:29]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[C:11]([CH3:20])[N:10]=[C:9]3[NH:8][CH:5]2[CH2:6][CH2:7][C:2]([F:1])([F:21])[CH2:3][CH2:4]2)=[O:30])=[C:27]([F:32])[C:26]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:25][CH:24]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Cc1nc(NC2CCC(F)(F)CC2)c2cccc(N)c2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(NC2CCC(F)(F)CC2)c2cccc(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)c2n1
Yield: 23.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(4,4-difluorocyclohexyl)-2-methylquinazoline-4,8-diamine (Intermediate-53, 100 mg, 0.342 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 147 mg, 0.513 mmol), oxalyl chloride (97 mg, 0.77 mmol), DMF (1 drop) and DIPEA (132 mg, 1.026 mmol) in CH2Cl2 (3 mL) to afford 46 mg of the title product. 1H NMR (400 MHz, DMSO-d6): δ 10.25 (s, 1H), 8.68 (d, J=7.6 Hz, 1H), 8.18-8.15 (t, J=5.8 Hz, 1H), 8.06-8.04 (d, J=8.4 Hz, 1H), 7.97-7.95 (d, J=7.6 Hz, 1H), 7.48-7.42 (m, 2H), 7.38-7.36 (d, J=8.0 Hz, 1H), 4.44 (m, 1H), 4.30 (d, J=5.6 Hz, 2H), 2.46 (s, 3H), 2.10-1.99 (m, 6H), 1.76-1.73 (m, 2H), 1.14 (s, 9H); MS (m/z): 562.32 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[H-].[Na+].Cl[C:8]1[C:9]2[CH:18]=[CH:17][N:16]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[C:10]=2[C:11](=[O:15])[N:12]([CH3:14])[N:13]=1>CN(C=O)C.O>[CH:2]([O:4][C:8]1[C:9]2[CH:18]=[CH:17][N:16]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[C:10]=2[C:11](=[O:15])[N:12]([CH3:14])[N:13]=1)([CH3:3])[CH3:1]
Reactant: Cc1cc(C)c(-n2ccc3c(Cl)nn(C)c(=O)c32)c(C)c1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-n2ccc3c(OC(C)C)nn(C)c(=O)c32)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 2-propanol (0.026 ml, 0.60 mmol) in DMF (1 ml) was added sodium hydride (60% in oil, 24 mg, 0.60 mmol). The mixture was stirred for 10 min before addition of 4-chloro-1-mesityl-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (45.3 mg, 0.15 mmol). The mixture was stirred at 60° C. for 1 hour, then diluted with water (30 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (5:1) to give 28.3 mg (58%) of the title compound as crystals.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:31][C@@H:32]1[CH2:41][CH2:40][C:39]2[C:34](=[C:35]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)[CH:36]=[CH:37][CH:38]=2)[CH2:33]1>CN(C)C=O>[CH3:48][N:45]1[CH2:46][CH2:47][N:42]([C:35]2[CH:36]=[CH:37][CH:38]=[C:39]3[C:34]=2[CH2:33][C@H:32]([NH:31][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:15][CH:14]=2)[CH2:41][CH2:40]3)[CH2:43][CH2:44]1
Reactant: O=C(O)c1ccc(N2CCCCC2)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCCCC4)cc2)CC3)CC1
Temperature: 75 °C
Reaction time: 17 h
Yield: 42.3 %

Procedure:
To a solution of 4-piperidinobenzoic acid (88 mg, 0.43 mmol; described in: Weringa, W. D.; Janssen, M. J. Recl. Trav. Chim. Pays-Bas 1968, 87 (12), 1372-1380) in anhydrous N,N-dimethylformamide (5 mL) was added 1,1'-carbonyldiimidazole (73 mg, 0.45 mmol) and the reaction was heated at 75° C. When the carbon dioxide evolution had ceased (after 30 min), the reaction was cooled to room temperature and a solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added. The reaction was allowed to stir at ambient temperature for 17 h and the solvent was evaporated in vacuo. Purification on a silica gel column using chloroform/ethanol saturated with NH3 (100:2) as the eluent gave 75 mg (42% yield) of the title compound as white crystals: mp 196-198° C.; [α]21D 63° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 432 (2, M+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7])#[N:2].[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:22]=1)[C:19](Cl)=O.N>>[Br:13][C:14]1[CH:22]=[C:18]([C:19]2[O:9][N:8]=[C:6]([C:5]3[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=3)[C:1]#[N:2])[N:7]=2)[CH:17]=[N:16][CH:15]=1
Reactant: N#Cc1cccc(C(N)=NO)c1
Reactant: O=C(Cl)c1cncc(Br)c1
Agent: N
Product: N#Cc1cccc(-c2noc(-c3cncc(Br)c3)n2)c1

Procedure:
The title compound was prepared according to the procedure of Example 4B using 3-cyano-N′-hydroxybenzimidamide and 5-bromonicotinoyl chloride (Alfa). 1H NMR (300 MHz, DMSO-d6) δ 7.67 (m, 1H), 7.74 (m, 1H), 8.41 (m, 1H), 8.49 (m, 1H), 8.64 (s, 1H), 8.93 (s, 1H), 9.4 (s, 1H) ppm; MS (DCl/NH3) m/z 327 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[CH3:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[SH:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:17][C:13]2[N:12]([CH3:11])[CH:16]=[CH:15][N:14]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: Cn1ccnc1S
Reactant: CC(=O)Nc1ncc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2nccn2C)s1
Temperature: 130 °C
Yield: 91.1 %

Procedure:
A mixture of 2-acetylamino-5-chlorothiazole (5.3 g), 1-methyl-2-mercaptoimidazole (3.6 g) and potassium carbonate (6.2 g) in N,N-dimethylformamide (50 ml) was heated at 130° C. for 5.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitates were collected by filtration washed with water and dried in vacuo to give 2-acetylamino-5-(1-methylimidazol-2-ylthio)thiazole (6.95 g, yield: 91.2%). mp: 155°-160° C. (dec.) IR (Nujol): 3400, 1690, 1565, 1300 cm-1
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=4[O:31][CH3:32])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(OC([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]4[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=4[O:31][CH3:32])[CH2:21][CH2:22]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:14])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(=O)O)c3cc(Cl)ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(=O)N3CCNCC3)c3cc(Cl)ccc23)CC1

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) piperazine-1-carboxylic acid tert-butyl ester gave, after treatment with TFA and neutralisation, the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]2=[O:25])=[C:4]([F:26])[CH:3]=1.S(=O)(=O)(O)O.[N+:32]([O-])([OH:34])=[O:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([F:26])[C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]2=[O:25])=[C:6]([N+:32]([O-:34])=[O:33])[C:7]=1[NH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)Nc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-(4Chloro-5-ethoxycarbonylamino-2-fluorophenyl)-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (XLVII) (1.0 g) was stirred with sulfuric acid (2 ml) at 0° C., then a mixture of nitric acid (1 ml) and sulfuric acid (1 ml) was dropwise added. After stirring at room temperature for 3 hr, it was poured into ice water (50 ml) and yellow crystals formed immediately which was filtered, washed with water and dried in fume hood overnight (0.5 g).
Reaction SMILES: ClC1C=C(N[N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])C=CC=1Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[Cl:24])[NH2:20].C(#N)CC#N.O.[NH2:31][NH2:32]>>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][N:10]=[C:11]2[C:12]([NH2:13])=[N:32][N:31]=[C:14]2[NH2:15])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: N#CC(C#N)=NNc1ccc(Cl)c(Cl)c1
Reactant: NN
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1ccc(Cl)c(Cl)c1

Procedure:
4-[(3,4-dichlorophenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 120 mg (0.5 mmol) of 2-[(3,4-dichlorophenyl)hydrazono]malononitrile, which was derived from 3,4-dichloroaniline (162 mg, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. Precipitate formed in the reaction tube immediately after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, precipitated from an ethyl acetate solution by the addition of hexanes, and dried to yield 53 mg (39%) of the compound as a yellow solid; 1H NMR (ppm, DMSO-d6): 6.30 (br, s, 4H), 7.55-7.79 (m, 2H), 7.95 (s, 1H), 10.80 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8](C=C)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>O>[C:1]([CH:5]1[CH2:12][CH2:11][CH2:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1ccc(C(C)(C)C)cc1
Solvent: O
Product: CC(C)(C)C1CCCCC1

Procedure:
By using the same autoclave as used in Preparation Example 1, 300 g of p-tert-butylstyrene polymer (Mw=20.4×104, Mn=11.2×104, Mw/Mn=1.82) prepared by suspension polymerization in water, was charged instead of 300 g of polystyrene in Preparation Example 1. The hydrogenation reaction and post-treatment were conducted in the same manner as in Preparation Example 1 except that the hydrogenation conditions were changed as identified in Table 1, whereby polyvinyl p-tert-butylcyclohexane was obtained.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH2:7][CH2:8][CH3:9])/[C:3](O)=[O:4].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[Cl-].[Li+].[C:26]1([C@H:32]2[C@@H:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:35][C:34](=[O:43])[NH:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH3:1]/[C:2](=[CH:6]\[CH2:7][CH2:8][CH3:9])/[C:3]([N:33]1[C@@H:32]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[O:35][C:34]1=[O:43])=[O:4]
Reactant: CCC/C=C(\C)C(=O)O
Reactant: O=C1N[C@@H](c2ccccc2)[C@@H](c2ccccc2)O1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC/C=C(\C)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To a solution of (E)-2-methyl-2-hexenoic acid (6.0 g, 47 mmol) in 250 mL of THF at 0° C. was added 16.3 mL (117 mmol) of triethylamine, then 5.8 mL (47 mmol) of pivaloyl chloride resulting in a thick suspension. The mixture was stirred for 1 hour at 0° C. at which time 2.0 g (47 mmol) of lithium chloride was added in one portion, followed by 10.0 g (42 mmol) of (4S,5R)-4,5-diphenyl-2-oxazolidinone in four batches. Stirring was maintained throughout the solid additions. The resulting mixture was stirred for 1 hour at 0° C., then for 1 hour at ambient temperature, and was vacuum filtered through a coarse frit and concentrated. The residue was partitioned between EtOAc/water, and the organics were dried over MgSO4 and concentrated. To the residue was added 100 mL of MTBE and the mixture warmed cautiously with swirling. The warm slurry was filtered to provide 10.5 g (64% yield) of the titled compound as a colorless solid: 1H NMR (CDCl3) δ 7.12 (m, 3H), 7.07 (m, 3H), 6.94 (m, 2H), 6.84 (m, 2H), 6.17 (m, 1H), 5.89 (d, J=7.8 Hz, 1H), 5.68 (d, J=7.8 Hz, 1H), 2.18 (m, 2H), 1.92 (s, 3H), 1.50 (m, 2H), 0.96 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([N:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[N:21][CH2:20]2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:18][CH2:17][CH:16]([N:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[N:21][CH2:20]1)[CH2:15][CH:12]1[CH2:14][CH2:13]1)=[O:6]
Reactant: NCC(CC1CC1)N1C=CC(C(F)(F)F)=NC1
Reactant: O=C(O)c1c(Cl)cccc1Cl
Product: O=C(NCC(CC1CC1)N1C=CC(C(F)(F)F)=NC1)c1c(Cl)cccc1Cl

Procedure:
From 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS (MH+): m/z=418.1, tR (minutes, Method D)=0.79