Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][CH:24]=1.C([O-])(=O)C.[Na+]>C(O)C>[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][C:15]2[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)(=[O:11])=[O:10])=[CH:13][C:14]=2[N+:19]([O-:21])=[O:20])=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Nc2ccc(Br)cc2)ccc1Cl
Reactant: Nc1ccc(S)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(Sc2ccc(S(=O)(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A mixture of the product of Example 149A (500 mg, 1.277 mmol), 4-aminothiophenol (240 mg, 1.915 mmol) and anhydrous sodium acetate (524 mg, 6.384 mmol) in anhydrous ethanol (9 mL) was heated at reflux under a nitrogen atmosphere for 1 hour. The reaction was cooled to room temperature and the ethanol removed by rotary evaporation under vacuum. The residue was taken up in ethyl acetate (100 mL) and washed with water (2×50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum, co-evaporating the oil with methylene chloride/hexanes to obtain the title compound as an orange foam (613 mg, 100%).
Reaction SMILES: N[C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[C:23]([Cu])#[N:24].N(OC(C)(C)C)=O.O>CS(C)=O>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:6]1[C:5]2[C:17]([C:19]([F:21])([F:22])[F:20])=[CH:18][C:2]([C:23]#[N:24])=[CH:3][C:4]=2[NH:8][C:7]1=[O:9]
Reactant: N#C[Cu]
Reactant: Nc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccccc1Cl
Agent: CC(C)(C)ON=O
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccccc1Cl
Temperature: 55 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
5-Amino-1-(2-chlorophenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-benzimidazole-2-one (46.2 mg) was dissolved in dimethyl sulfoxide (1 ml), and to the solution was added CuCN (16.4 mg). The mixture was heated at 55° C. At the same temperature, a solution of t-butyl nitrite (43.6 mg) in dimethyl sulfoxide (0.5 ml) was added dropwise during about 1.5 hours. After the addition was completed, the mixture was stirred at about 60° C. for 1 hour. After allowing to cool, to the reaction mixture was added water, and the mixture was extracted 2 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (20 g, CHCl3-methanol=20:1) to give the title compound (17.6 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1.CN(C)CC(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[CH:18][CH:19]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(O)cc2)COC1(C)C
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(Oc2ccc(C[C@H]3COC(C)(C)N3C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
To a solution of (S)-4-(4-Hydroxy-benzyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol, 1 eq.)), 4-iodoanisole (180 mg, 0.75 mmol, 1.5 eq.) in dioxane (4 ml) was added CuI(I) (20 mg, 0.05 mmol, 0.1 eq.), N,N-dimethylglycine (30 mg, 0.15 mmol, 0.3 eq.) and cesium carbonate (500 mg, 1.5 mmol, 3 eq.). The resulting mixture was stirred under Ar at reflux overnight. After cooling to room temperature, the volatile material was removed under reduced pressure to give a residue, which was partitioned between water (10 ml) and ethyl acetate (10 ml). The ethyl acetate layer was separated and dried over anhydrous MgSO4. Evaporation of solvent under reduced pressure gave a residue, which was passed through a plug of silica gel using dichloromethane (50 ml) as eluent to give 106 mg of desired product (51% yield).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:34])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][NH2:36]>>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:36][CH3:35])[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:34])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cnn(C(C)(C)C)c4)c3)c(=O)n(C)c2n1
Product: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cnn(C(C)(C)C)c4)c3)c(=O)n(C)c2n1
Yield: 46.1 %

Procedure:
Using a procedure analogous to Example A1, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.3 g, 0.63 mmol) and methyl amine (1.3 ml of 1M solution, 1.3 mmol) were combined to afford 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea as a white solid (0.135 g, 66% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.73-8.70 (m, 1H), 8.65 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.41-8.39 (m, 1H), 7.85 (s, 1H), 7.81 (brs, 2H), 7.38 (s, 1H), 7.24-7.22 (m, 2H), 3.61-3.57 (m, 3H), 2.90 (d, J=4.0 Hz, 1H), 2.60 (s, 3H), 1.46 (s, 9H); (ESI) m/z: 465.2 (M+H*).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH2:17][CH2:18][OH:19]>O1CCCC1.C(OCC)(=O)C>[F:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: NCCCO
Reactant: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1NCCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
To a stirred solution of 2-chloro-5-fluoro-1,3-dinitrobenzene (3.24 g, 14.7 mmol) in tetrahydrofuran (50 mL) was added 3-amino-1-propanol (2.80 mL, 36.8 mmol) at 0° C. After being stirred for 3 h at room temperature, the mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo to give the title compound as a yellow solid (3.59 g, 13.8 mmol, 94%).
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][CH2:23]Cl)[CH3:21]>CN(C=O)C>[Br:1][C:2]1[N:10]([CH2:23][O:22][CH2:20][CH3:21])[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1
Reactant: CCOCCl
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a stirring suspension of 8-bromo-3-methylxanthine (7.06 g, 28.8 mmol) and potassium carbonate (3.98 g, 28.8 mmol) in DMF (150 ml) was added chloromethyl ethyl ether (2.72 g, 28.8 mmol). After stirring overnight at room temperature, the reaction mixture was poured into ice-cold water (650 ml). After stirring at 0-5° C. for 1 hour, the cloudy mixture was filtered, washed with water (3×15 ml) and dried under vacuum to provide 8-bromo-7-ethoxymethyl-3-methylxanthine (6.15 g, 70% yield) as a white solid.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([C:17]#[N:18])[CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[NH2:26][C@@H:27]([CH2:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[C:44]([F:49])[CH:43]=1)[C@H:28]([OH:40])[CH2:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH3:39])[CH:33]=1>C(Cl)Cl>[CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([C:17]#[N:18])[CH:10]=[C:11]([C:14]([NH:26][C@@H:27]([CH2:41][C:42]3[CH:43]=[C:44]([F:49])[CH:45]=[C:46]([F:48])[CH:47]=3)[C@H:28]([OH:40])[CH2:29][NH:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH3:39])[CH:33]=3)=[O:16])[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ccc2c(C#N)cc(C(=O)O)cc21
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCn1ccc2c(C#N)cc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.3 %

Procedure:
To a mixture of 1-butyl-4-cyano-1H-indole-6-carboxylic acid (0.29 g) in methylene chloride (10 mL) was added 1,1-carbonyldiimidazole (0.194 g) and triethylamine (0.267 g). The mixture was stirred at room temperature for 45 minutes at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.5 g) dissolved in methylene chloride (10 mL) was added. The mixture was stirred at room temperature for 18 h then poured into methylene chloride (50 mL), washed with water followed by brine, dried over anhydrous magnesium sulfate and concentrated under vacuum. Column chromatography on silica gel (100 mL) using 5% methanol in methylene chloride as eluent to give 0.47 g of the title compound: MS (ESI+) for C33H36F2N4O2 m/z 559.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[Br:7][C:8]1[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1.Cl>O1CCOCC1.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[C:10]([S:14]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CC(C)(N)CO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
To a solution of commercially available 2-amino-2-methyl-1-propanol (8.91 g, 100 mmol) in dioxane (20 mL) at 5° C. was added commercially available 3-bromobenzenesulfonyl chloride (2.88 mL, 20 mmol) and the mixture was vigorously stirred at 23° C. for 1 h. Poured into 1 N HCl, diluted with EtOAc, separated phases, washed organic layer with brine, dried over Na2SO4. Removal of the solvent in vacuum left the title compound as a white solid (5.47 g, 89%). MS (ISN) 306.1 [(M−H)−] and 308.2 [(M+2−H)−]; mp 138° C.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:15])[CH:10]([NH2:14])[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C1COCC1>[CH2:1]([NH:8][C:9](=[O:15])[CH:10]([NH:14][C:22](=[O:24])[CH3:23])[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC(N)C(=O)NCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COCC(NC(C)=O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 13 (0.20 g, 0.98 mmol) in dry THF (2.0 mL) is added pyridine (0.086 g, 1.08 mmol), and then acetic anhydride (0.2 g, 1.96 mmol) is added dropwise. The reaction is stirred at room temperature for 18 hours. The solvent is evaporated in vacuo and the residue purified by flash column chromatography to obtain the above compound as the R isomer.
Reaction SMILES: O1CCCC1.[CH:6]1([CH2:9][OH:10])[CH2:8][CH2:7]1.[H-].[Na+].[Br:13][C:14]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]2[CH:18]=[N:19][NH:20][C:21](=[O:22])[C:16]=2[C:15]=1[CH2:32]Br>O>[Br:13][C:14]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]2[CH:18]=[N:19][NH:20][C:21](=[O:22])[C:16]=2[C:15]=1[CH2:32][O:10][CH2:9][CH:6]1[CH2:8][CH2:7]1
Reactant: OCC1CC1
Reactant: C[Si](C)(C)CCOCn1c(Br)c(CBr)c2c(=O)[nH]ncc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1c(Br)c(COCC2CC2)c2c(=O)[nH]ncc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.2 %

Procedure:
To 10 ml of dehydrated tetrahydrofuran solution containing 0.92 g (13 mmol) of cyclopropylmethanol was added 0.25 g (6.2 mmol) of sodium hydride (60% dispersed material in mineral oil) under ice-cooling, the mixture was stirred at room temperature for 30 minutes, then, 10 ml of dehydrated tetrahydrofuran solution containing 0.56 g (1.3 mmol) of 2-bromo-3-bromomethyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 24-(f) was further added to the mixture, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=2:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 157 mg of the title compound as a pale yellowish solid. (Yield: 29%)
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH:9]([CH2:14][CH:15]=[CH2:16])[C:10]([O:12]C)=[O:11].Cl>O.C1COCC1>[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH:9]([CH2:14][CH:15]=[CH2:16])[C:10]([OH:12])=[O:11]
Reactant: C=CCC(C(=O)OC)N1CCCC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC(C(=O)O)N1CCCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.1 %

Procedure:
Step A (2): A solution of LiOH (2 M, 0.73 g, 30.4 mmol) in 15 mL H2O was added to a solution of methyl 2-(2-oxopyrrolidin-1-yl)pent-4-enoate (2.0 g, 10.1 mmol) from step A(1) in THF (15 mL) at room temperature. The mixture was stirred at room temperature for 16 h. Poured into 1 N HCl. Extracted with EtOAc (3×250 mL). Washed combined organics with brine, dried with Na2SO4 After concentration in vacuo, dried on high-vacuum for ˜3 h to give 1.5 g (81%) of 2-(2-oxopyrrolidin-1-yl)pent-4-enoic acid as a beige solid: LC-MS (M+H)+=184.1; 1H NMR (300 MHz, CDCl3) δ 11.85 (s, 1H), 5.47-5.81 (m, 1H), 4.91-5.25 (m, 2H), 4.81 (dd, J=11.14, 4.73 Hz, 1H), 3.45-3.59 (m, 1H), 3.25-3.40 (m, 1H), 2.59-2.83 (m, 1H), 2.30-2.52 (m, 3H), 1.80-2.12 (m, 2H).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([OH:11])=[O:10].[CH3:16]N(C)C=O>CO>[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([O:11][CH3:16])=[O:10]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(=O)O)cc1C
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)c(C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Thionyl chloride (80 ml; 2 equiv.) was added at room temperature to a solution of 3,4-dimethylbenzoic acid (35 g; 1 equiv.) and dimethylformamide (1 ml) in 227 ml of methanol. The resulting reaction mixture was stirred for 12 h at room temperature and then concentrated under reduced pressure. The resulting residue was taken up in dichloromethane and washed with 5% sodium carbonate solution. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The methyl 3,4-dimethylbenzoate so obtained (38.2 g) was used in the next stage without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17](=[O:20])[NH:18][CH3:19])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:25][CH2:26][CH:27]4[CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]4)[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:29]1[CH2:30][CH:27]([CH2:26][CH2:25][N:24]([S:38]([CH3:41])(=[O:40])=[O:39])[C:12]2[C:13]([CH:21]3[CH2:22][CH2:23]3)=[CH:14][C:15]3[C:10]([CH:11]=2)=[N:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:16]=3[C:17]([NH:18][CH3:19])=[O:20])[CH2:28]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCC3CN(C(=O)OC(C)(C)C)C3)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCC3CNC3)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a solution of tert-butyl 3-(2-{[2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)-2H-indazol-6-yl](methylsulfonyl)amino}ethyl)azetidine-1-carboxylate (prepared by reacting 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide with tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate), (25 mg, 0.04 mmol) in DCM (3 mL) was added TFA (1 mL) and the reaction stirred at ambient temperature. After 1 h, the reaction was concentrated in vacuo and the residue partitioned between EtOAc (25 mL) and aq. saturated sodium bicarbonate (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (3×15 mL). The combined organics were washed with brine (15 mL), dried (MgSO4), concentrated in vacuo and purified by preparative HPLC eluting with acetonitrile:0.1% formic acid in water to afford Compound (6) (8.8 mg, 42%). ESI-MS m/z calculated for [M+H]+: 502.2. found: 502.1 1H NMR (400 MHz, CD3CN) δ 8.40 (s, 1H), 7.83 (s, 1H), 7.64-7.54 (m, 4H), 7.39 (s, 1H), 7.37 (br d, J=3.9 Hz, 1H), 3.94-3.81 (m, 2H), 3.76-3.59 (m, 2H), 3.59-3.50 (m, 2H), 3.09 (d, J=10.3 Hz, 3H), 2.97-2.86 (m, 4H), 2.43-2.33 (m, 1H), 1.95-1.86 (m, 2H), 1.14-1.00 (m, 3H), 0.71-0.59 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:14]=[C:15]([CH:22]=[CH:23][CH:24]=1)[O:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21])[C:5]2=O.O.[NH2:27][NH2:28]>>[Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]([OH:8])=[C:4]([C:5]2[C:6]([C:13]3[CH:14]=[C:15]([CH:22]=[CH:23][CH:24]=3)[O:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21])=[CH:7][NH:28][N:27]=2)[CH:3]=1
Reactant: NN
Reactant: N#CCCCOc1cccc(-c2coc3cc(O)c(Cl)cc3c2=O)c1
Solvent: O
Product: N#CCCCOc1cccc(-c2c[nH]nc2-c2cc(Cl)c(O)cc2O)c1

Procedure:
This compounds was synthesised in the same manner as described above. 4-[3-(6-Chloro-7-hydroxy-4-oxo-4H-chromen-3-yl)-phenoxy]-butyronitrile (0.3 g, 0.84 mmol), Hydrazine hydrate (6 ml). The quenched reaction was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give a clear oil which was purified by column chromatograpy to give 4-{3-[3-(5-chloro-2,4-dihydroxy-phenyl)-1H-pyrazol-4-yl]-phenoxy}-butyronitrile as a white soild Rf 0.6 ethyl acetate/hexane (70/30).
Reaction SMILES: [SH2:1].[C:2]([N:4]=[C:5]1[NH:10][CH2:9][CH2:8][CH2:7][NH:6]1)#[N:3].[OH-].[Na+]>O>[C:2]([N:4]=[C:5]1[NH:10][CH2:9][CH2:8][CH2:7][NH:6]1)(=[S:1])[NH2:3]
Reactant: N#CN=C1NCCCN1
Reactant: S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=S)N=C1NCCCN1
Temperature: 45 °C
Reaction time: 27.5 h
Yield: 94 %

Procedure:
Hydrogen sulphide is first passed into a solution of 190 g (1.53 mols) of 2-(N-cyanimino)-hexahydropyrimidine (a) in 760 ml of water at 75° C. for 12 hours; and then at 65°-70° C. for another 25-30 hours. (On the second day, some of the precipitate no longer dissolves). The suspension is then warmed to 45° C. and 46 ml of 40% strength NaOH are added. Stirring is continued for 30 minutes and the residue is ground and filtered off with suction. After drying, 228 g (94%) of product are obtained. Melting point=187°-189° C. (decomposition).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[NH2:20][C:21]1[C:25]([C:26]#[N:27])=[C:24]([CH3:28])[NH:23][N:22]=1>>[CH3:28][C:24]1[C:25]([C:26]#[N:27])=[C:21]2[N:20]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]2[N:23]=1
Reactant: Cc1[nH]nc(N)c1C#N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Product: Cc1nn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc2c1C#N
Yield: 63.2 %

Procedure:
Reaction of 1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (284 mg, 1.0 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and commercially available 3-amino-4-cyano-5-methyl -pyrazole (122 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (234 mg, 63%). MS (ISP) 371.1 [(M+H)+]; mp 184° C.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[CH:13]=[CH:12][C:11]([C@H:14]([NH2:17])[CH2:15][OH:16])=[CH:10][CH:9]=1.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[Cl-].[NH4+]>O1CCCC1>[OH:16][CH2:15][C@@H:14]([NH:17][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:11]1[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN[C@H](CO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.7 %

Procedure:
Following the literature procedure (Panek, J., J. Org. Chem., 1998, 63, 2382), triethylamine (6.2 ml, 44.5 mmole) was added to a solution of (S)-phenylglycinol (5 g, 36.45 mmole) in anhydrous tetrahydrofuran (150 ml) under argon at 0° C. After stirring for 15 min, tert-butyl bromoacetate (5.9 ml, 39.96 mmole) was added slowly to this cooled solution. The resulting mixture was warmed to room temperature, and stirred for 15 h. Saturated ammonium chloride aqueous solution was added, and the aqueous layer was extracted with diethyl ether (3 times). The combined extracts were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness in vacuo. The resulting solid was recrystallized from a diethyl ether/n-hexane mixture to give tert-butyl (S)-(2-Hydroxy-1-phenyl-ethylamino)-acetate as a white solid (3 g, 33%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9](O)=[O:10])([O-:3])=[O:2].CN(C=O)C.C(Cl)(=O)C([Cl:23])=O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([Cl:23])=[O:10])([O-:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1cccc([N+](=O)[O-])c1

Procedure:
To a solution of 3-nitrocinnamic acid (5.0 g) in dry Toluene (100 ml), oxalyl chloride (11.33 ml) was carefully added, followed by dry DMF (0.1 mL). The resulting yellow solution was refluxed for 3 hrs and then evaporated to dryness, to get the 3-nitro cinnamoyl chloride as a solid residue, This solid residue was dissolved in THF, the resulting solution was cooled at 0° C., and 2M methylamine (13 ml) was added to the reaction mixture, the reaction mixture was stirred for 30 min. Solvents were evaporated under vacuum, the crude material was re-crystallised from diethylether to afford the title compound (4 gm).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1.C(=O)([O-])[O-:30].[K+].[K+].OO>CS(C)=O>[Cl:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([NH2:10])=[O:30])=[CH:7][N:6]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Oc2ccc(CN3CCC(c4ccccc4)C3)cc2Cl)nc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(CN3CCC(c4ccccc4)C3)cc2Cl)nc1
Yield: 126.6 %

Procedure:
Using a similar method to Example 371, and using (±)-6-[2-chloro-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinonitrile (step 2 above) (0.198 g, 0.508 mmol), potassium carbonate (0.0337 g, 0.244 mmol), and 30% hydrogen peroxide solution (aq) (0.180 mL, 1.59 mmol) in dimethylsulfoxide (5.0 mL) provides 0.126 g (61%) of the title compound as a yellowish syrup: high resolution mass spectrum (electrospray): m/z calc for C23H23ClN3O, 408.1479, found 408.1449; 1H NMR (methanol-d4): 8.61 (d, 1H, J=2.4 Hz), 8.32 (d, 1H, J=2.4, 8.8 Hz), 7.61 (d, 1H, J=2.0 Hz), 7.44 (dd, 1H, J=2.0, 8.3 Hz), 7.35-7.29 (m, 4H), 7.27 (d, 1H, J=8.3 Hz), 7.24-7.18 (m, 1H), 7.11 (d, 1H, J=8.8 Hz), 3.80 (d, 1H, J=13.2 Hz), 3.76 (d, 1H, J=13.2 Hz), 3.50-3.39 (m, 1H), 3.15 (dd, 1H, J=7.8, 9.3 Hz), 2.99-2.91 (m, 1H), 2.82 (td, 1H, J=6.3, 8.8 Hz), 2.60 (t, 1H, J=8.8 Hz), 2.45-2.34 (m, 1H), 2.03-1.92 (m, 1H).