Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([F:12])[C:4]=1[F:13])#[N:2].C(Cl)(=O)C(Cl)=O.C(C1C=CC(C(Cl)=O)=C(F)C=1F)#N.[Br:33][C:34]1[CH:40]=[C:39]([C:41]([F:50])([C:46]([F:49])([F:48])[F:47])[C:42]([F:45])([F:44])[F:43])[CH:38]=[C:37]([C:51]([F:54])([F:53])[F:52])[C:35]=1[NH2:36]>ClCCl.CN(C=O)C.CN1C(=O)N(C)CC1.C(OCC)(=O)C.O>[Br:33][C:34]1[CH:40]=[C:39]([C:41]([F:50])([C:42]([F:44])([F:45])[F:43])[C:46]([F:47])([F:49])[F:48])[CH:38]=[C:37]([C:51]([F:52])([F:53])[F:54])[C:35]=1[NH:36][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[C:4]([F:13])[C:5]=1[F:12]
Reactant: N#Cc1ccc(C(=O)O)c(F)c1F
Reactant: Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F
Agent: N#Cc1ccc(C(=O)Cl)c(F)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Product: N#Cc1ccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2C(F)(F)F)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
To a solution of 0.840 g (4.59 mmol) of 4-cyano-2,3-difluorobenzoic acid in 10 ml of dichloromethane were added one drop of DMF and 0.470 ml (5.51 mmol) of oxalyl chloride, followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the obtained 4-cyano-2,3-difluorobenzoyl chloride was added to a solution of 1.56 g (3.83 mmol) of 2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)aniline obtained in 1-2 of Example 1 in 5 ml of DMI, followed by stirring at 130° C. for 5 hours. To the reaction liquid were added water and ethyl acetate, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=1:0→10:1) to prepare 0.58 g (yield 27%) of a target compound.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:38]1[N:43]=[CH:42][N:41]=[C:40]2[N:44]([C:47]3[C:52]([Cl:53])=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:54])[N:45]=[CH:46][C:39]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:36][C:38]1[N:43]=[CH:42][N:41]=[C:40]2[N:44]([C:47]3[C:52]([Cl:53])=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:54])[N:45]=[CH:46][C:39]=12)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:17])([CH3:18])[CH3:19])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Clc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Reactant: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccc(F)cn1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1c(Cl)cccc1Cl)C(=O)Nc1ccc(F)cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (83 mg, 2.07 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-fluoropyridin-2-yl)-2-hydroxypropanamide (Intermediate BA2) (500 mg, 1.04 mmol) in anhydrous THF (20 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate BA3) (310 mg, 1.04 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was adjusted to pH 7 by addition of 1M citric acid and the reaction mixture diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 25 to 100% EtOAc in isohexane to afford the product (637 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 0.99 (9H, t), 3.69-3.72 (2H, m), 3.82 (2H, t), 4.16-4.24 (2H, m), 6.06 (1H, t), 7.31-7.47 (8H, m), 7.52-7.55 (2H, m), 7.63-7.66 (4H, m), 8.12 (1H, d), 8.26-8.29 (1H, m), 8.42 (1H, s), 8.58 (1H, s), 8.79 (1H, s).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)([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:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:28][C:29]([CH3:38])([CH:36]=[CH2:37])[CH2:30][C:31]1[N:32]=[CH:33][NH:34][CH:35]=1.[Cl-].[NH4+]>C(Cl)Cl>[CH3:28][C:29]([CH3:38])([CH:36]=[CH2:37])[CH2:30][C:31]1[N:32]=[CH:33][N:34]([C:8]([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)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:35]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CC(C)(C)Cc1c[nH]cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (1.5 mL, 53 mmol) followed by of trityl chloride (9 g, 32 mmol) were added to a 0° C. solution of 4-(2,2-dimethylbut-3-en-1-yl)-1H-imidazole (4 g, 27 mmol) in methylene chloride (40 mL). After stirring at ambient temperature for 3 h, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted with methylene chloride. The combined organic extracts were washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography over silica eluting with 10-40% ethyl acetate/hexane afforded the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([C:16]([NH2:18])=O)[S:14][CH:15]=2)[N:9]=[C:8]([C:19]([F:22])([F:21])[F:20])[CH:7]=1.Cl>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH2:16][NH2:18])[S:14][CH:15]=2)[N:9]=[C:8]([C:19]([F:21])([F:22])[F:20])[CH:7]=1
Reactant: NC(=O)c1cc(-n2nc(C(F)(F)F)cc2-c2ccco2)cs1
Agent: Cl
Solvent: C1CCOC1
Product: NCc1cc(-n2nc(C(F)(F)F)cc2-c2ccco2)cs1
Temperature: 70 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A one molar solution of BH3 in THF (1.2 mL, 1.2 mmol) was added to amide 4 (128 mg, 0.39 mmol) in THF (1.5 mL) and the mixture was heated in a sealed tube at 70° C. for 5 h, then it was stirred at room temperature for 16 h. The mixture was cooled in ice and few drops of conc HCl were added, then most of the solvent was removed and H2O was added and the mixture was heated to reflux for 20 min. EtOAc was added and the PH adjusted to 8 with saturated NaHCO3 and extracted with EtOAc (2×). The organic extracts were dried over MgSO4, filtered and concentrated leaving crude 5 (110 mg) as a clear oil. LRMS (ESI): calc. 313.3; found 314.0 (MH)+. The material was used as is for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:11]=[C:10]([C:19]3[S:20][CH:21]=[CH:22][C:23]=3[Cl:24])[CH2:9]2)=[CH:4][CH:3]=1.N(C1C=CC=CN=1)N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:11]=[C:10]([C:19]3[S:20][CH:21]=[CH:22][C:23]=3[Cl:24])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2CC(c3sccc3Cl)=NN2c2ccccn2)cc1
Agent: NNc1ccccn1
Product: Clc1ccc(-c2cc(-c3sccc3Cl)nn2-c2ccccn2)cc1

Procedure:
5-(4-Chloro-phenyl)-3-(3-chloro-thiophen-2-yl)-1-(pyridin-2-yl)-4,5-dihydro-1H-pyrazole: The title compound was prepared from 3-(4-chloro-phenyl)-1-(3-chloro-thiophen-2-yl)-propenone and 2-hydrazinopyridine by a procedure similar to that of Example 105a as a yellowish oil (141 mg, 73.8%). 1H NMR (CDCl3): 8.04 (m, 1H), 7.59 (t, 1H), 7.46 (d, J=9.0 Hz, 1H), 7.27 (m, 6H), 6.92 (d, J=5.4 Hz, 1H), 6.68 (t, 1H), 4.01 (t, 1H), 3.41 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([S:17][CH3:18])[C:14]([F:19])=[CH:13][N:12]=3)=[N:9][N:8]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:5]2=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:47])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([S:17]([CH3:18])=[O:47])[C:14]([F:19])=[CH:13][N:12]=3)=[N:9][N:8]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CSc1nc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(Cl)cc23)ncc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(Cl)cc23)ncc1F
Reaction time: 2 h

Procedure:
To a stirred solution of 5-chloro-3-(5-fluoro-4-(methylthio)pyrimidin-2-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridine, 50, (0.078 g, 0.150 mmol) in CH2Cl2 at 0° C. was added mCPBA (0.036 g, 0.160 mmol). The mixture was kept at 0° C. for 2 hr. Then, the mixture was diluted with CH2Cl2, washed with K2CO3 (2×), dried over Na2SO4, filtered and concentrated in vacuo to provide 78 mg of the desired crude which was carried forward without further purification: LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, RT=1.62 min (M+H) 554.47.
Reaction SMILES: C(=O)([O-])O.[Na+].[CH2:6]([O:11][C:12]1[C@@H:17]([C@H:18]([CH2:20][OH:21])[OH:19])[O:16][C:14](=[O:15])[C:13]=1[OH:22])[CH:7]([CH2:9][OH:10])[OH:8].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH2:6]([O:11][C:12]1[C@@H:17]([C@H:18]([CH2:20][OH:21])[OH:19])[O:16][C:14](=[O:15])[C:13]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:7]([CH2:9][OH:10])[OH:8]
Reactant: BrCc1ccccc1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(OCC(O)CO)=C1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C(OCC(O)CO)=C1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 127.9 %

Procedure:
Under an argon atmosphere, water and sodium hydrogen carbonate (1.42 g) were added to 3-O-glyceryl ascorbic acid (1.42 g) obtained in Example 1, and the mixture was stirred at room temperature for 30 minutes. To the mixture, benzyl bromide (2.61 g) was added, and the resultant mixture was heated up to 50° C. and stirred for 2 hours. Thereafter, the mixture was concentrated under reduced pressure, then, dissolved in methanol. Then, the resultant solution was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and 6.13 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:10/3/0.4), and concentration was performed under reduced pressure to obtain to obtain 3-O-glyceryl-2-O-benzyl ascorbic acid (2.47 g).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[C:12]([OH:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](Cl)(=[O:23])[CH3:22]>C1(C)C=CC=CC=1>[C:21]([O:14][C:12]1[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=[C:9]([S:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:13]=1)(=[O:23])[CH3:22]
Reactant: Oc1nc(SCc2ccccc2)nn1-c1ccccc1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(=O)Oc1nc(SCc2ccccc2)nn1-c1ccccc1

Procedure:
A mixture of the product of stage (c) (20 g), toluene (150 ml) and acetyl chloride (12.2 ml) was heated under reflux for 5 hours. The volatile materials were removed in vacuo, and the residue was triturated with ether and filtered off. Recrystallisation from ethanol gave 19.8 g of desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[C:31]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:43]2[CH:44]=[CH:45][C:40]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:41][CH:42]=2)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccc(-c3ccccc3)cc2)sc1C(=O)OCC

Procedure:
Prepared from 2-bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethy ester, example 81(b), and 1,1′-biphenyl-4-yl-boronic acid under conditions analogous to experimental example 81(c). MS: (+) m/z 575.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([Cl:11])=[C:4](Cl)[C:3]=1[Cl:13].[OH-].[Na+].[NH2:16][NH2:17].Cl>O>[Cl:11][C:5]1[C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]([Cl:1])=[C:3]([Cl:13])[C:4]=1[NH:16][NH2:17]
Reactant: O=C(O)c1nc(Cl)c(Cl)c(Cl)c1Cl
Reactant: NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NNc1c(Cl)c(Cl)nc(C(=O)O)c1Cl
Temperature: 25 °C

Procedure:
To a reaction flask containing 200 milliliters of water at the boiling point was added 26.1 grams (0.1 mole) of tetrachloropicolinic acid, 4.1 grams (0.103 mole) of sodium hydroxide in 25 milliliters of water and 3.47 grams (0.105 mole) of hydrazine. The reaction mixture was stirred under reflux for 30 minutes. An additional 4.1 grams (0.103 mole) of sodium hydroxide in 25 milliliters of water was slowly added to the reaction mixture over a 25 minute period and the mixture refluxed for 45 minutes. The reaction mixture was cooled to room temperature and 25 milliliters of 5 Normal hydrochloric acid was added thereto. The solid 3,5,6-trichloro-4-hydrazinopicolinic acid (as the mono-hydrate) which precipitated was recovered by filtration in a yield of 22.9 grams (83.5 percent of theoretical) and melted at 166°-168°C.
Reaction SMILES: CS/[C:3](=[N:9]\[C:10](=O)[CH:11]=[C:12]([CH3:14])[CH3:13])/[N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[NH2:16][NH2:17]>>[CH3:13][C:12]([CH3:14])=[CH:11][C:10]1[NH:17][N:16]=[C:3]([N:4]2[CH2:8][CH2:7][CH2:6][CH2:5]2)[N:9]=1
Reactant: NN
Reactant: CS/C(=N\C(=O)C=C(C)C)N1CCCC1
Product: CC(C)=Cc1nc(N2CCCC2)n[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 29.39 %

Procedure:
A mixture of 3-methyl-but-2-enoic acid 1-methylsulfanyl-1-pyrrolidin-1-yl-meth-(Z)-ylidene amide (1.2 g, 5.3 mmol) and hydrazine solution was stirred for 2 hours at 100° C. in a sealed tube. The mixture was cooled and concentrated. The crude material was purified by combiflash column chromatography using 50% ethyl acetate in hexane to give 5-(2-methyl-propenyl)-3-pyrrolidin-1-yl-1H-[1,2,4]triazole (300 mg, 29.39%) as a white solid. MS: m/z=193 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27](F)[CH:26]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:46][NH2:47]>O.CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:26]=[C:27]3[C:28]([C:31]([NH2:32])=[N:46][NH:47]3)=[CH:29][CH:30]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)NCC2CCCCC2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: CO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](C(=O)NCC2CCCCC2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 110 °C
Yield: 59.9 %

Procedure:
Into a microwave tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(cyclohexylmethyl)-6-methyl-3-piperidinecarboxamide (187 mg, 0.415 mmol), 5 mL of EtOH, Hunig's base (0.290 ml, 1.66 mmol), and hydrazine anhydrous (0.078 ml, 2.49 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid and the yellow solution were carefully separated due to the black solid being heavier than yellow solution. Water (20 mL) was added to the yellow solution, and a solid formed. The solid was filtered and washed by water, dried in vacuum, and then treated with EtOAc and CH3OH. The solid in the solvent was filtered, washed by EtOAc, and dried in vacuum to afford the title compound (115 mg) as a light yellow solid. LC-MS (ES) m/z=463 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.88 (m, 2H), 1.05-1.26 (m, 6H), 1.32-1.46 (m, 1H), 1.54-1.74 (m, 8H), 1.75-1.88 (m, 1H), 2.21-2.38 (m, 1H), 2.76-3.08 (m, 3H), 5.38 (s, 2H), 6.07 (s, 2H), 6.57 (s, 1H), 7.54-7.59 (m, 1H), 7.66-7.72 (m, 1H), 7.87-7.92 (m, 1H), 7.94 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([NH:9][NH2:10])=[O:8].[C:15](=S)=[S:16]>O.C(O)C>[SH:16][C:15]1[O:8][C:7]([C:6]2[CH:11]=[CH:12][C:13]([OH:14])=[C:4]([OH:3])[CH:5]=2)=[N:9][N:10]=1
Reactant: NNC(=O)c1ccc(O)c(O)c1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Oc1ccc(-c2nnc(S)o2)cc1O
Reaction time: 1.5 h
Yield: 86.3 %

Procedure:
19.8 g (0.353 mol) of potassium hydroxide was dissolved in 5.1 ml of water and 830 ml of ethanol, and 39.6 g (0.236 mol) of 3,4-dihydroxybenzohydrazide and 99 ml (1.65 mol) of carbon disulfide was added thereto. The mixture was heated for 24 hours under reflux. The reaction solution was stirred for 1.5 hours under cooling with ice. The precipitated crystals were collected by filtration and washed with 200 ml of ethanol. The crystals were dissolved in 3 liter of water and adjusted to pH1.5 with 6N hydrochloric acid under cooling with ice. The solution was extracted with 1 liter of ethyl acetate and 400 ml of ethyl acetate. The organic layers were put together, washed twice with 300 ml of a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 42.8 g (yield: 86.5%) of 2-mercapto-5-(3,4-dihydroxyphenyl)-1,3,4-oxadiazole.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[CH:34]=[CH:33][C:26]([CH2:27][N:28]2[N:32]=[CH:31][CH:30]=[N:29]2)=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:34]=[CH:33][C:26]([CH2:27][N:28]3[N:29]=[CH:30][CH:31]=[N:32]3)=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Brc1ccc(Cn2nccn2)cc1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(Cn4nccn4)cc3)s2)c(F)c1

Procedure:
5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-{[4-(2H-1,2,3-triazole-2-ylmethyl)phenyl]amino}thiophene-3-carboxamide was prepared according to the general procedure in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (100 mg, 0.320 mmol) and 2-(4-bromobenzyl)-2H-1,2,3-triazole (76 mg, 0.320 mmol) as the starting materials.
Reaction SMILES: [Br-:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][P+:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([N+:29]([O-])=O)[CH:4]=1>CCO.Br.[Zn]>[Br-:1].[NH2:29][C:5]1[CH:4]=[C:3]([F:2])[CH:8]=[CH:7][C:6]=1[CH2:9][P+:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: [Br-]
Agent: [Zn]
Solvent: CCO
Product: Nc1cc(F)ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 54.5 %

Procedure:
A solution of 175 g (0.35 mol) of [(4-fluoro-2-nitrophenyl)methyl]-triphenylphosphonium bromide in 760 mL of EtOH and 380 mL of 48% HBr was brought to reflux and 138 g (2.1 mol) of zinc dust was added in portions over 4 h and refluxed further for 2 h. The mixture was cooled and the EtOH evaporated. The residue was partitioned between CH2Cl2 and H2O. The CH2Cl2 solution was washed with 7M NH4OH. The aqueous phase was decanted and the precipitate dissolved in CH2Cl2 /EtOH. The organic phase was washed with brine, dried (Na2SO4) and concentrated. There was obtained 89 g (54%) of [(2-amino-4-fluorophenyl)methyl]triphenylphosphonium bromide as a solid: 1H NMR (Me2SO-d6) δ 8.0-7.6 (m, 15H); 6.6 (m, 1H); 6.4 (m, 1H); 6.15 (m, 1H); 5.5 (br s, 2H); 4.95 (d, 2H). ##STR17##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[O:39][CH3:40])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:23][CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[O:39][CH3:40])[CH2:29][CH2:28]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: COc1ccccc1N1CCN(CCCN)CC1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Product: COc1ccccc1N1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)CC1

Procedure:
This compound was prepared by a procedure similar to that described in Example 49 starting with 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37 and 1.00 g (4.00 mmol) of 1-(3-aminopropyl)-4-(2-methoxyphenyl)piperazine yielding 0.103 g of pure product; mp 187°-188° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([CH2:34][CH3:35])([OH:33])[CH2:31][CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])=[CH:9][C:8]=1[F:40].[Cl-].[NH4+]>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:41])=[O:4])=[C:8]([F:40])[CH:9]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([CH2:31][CH3:32])([OH:33])[CH2:34][CH3:35])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)OC)c(F)c3)c(C)c2)cc1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)O)c(F)c3)c(C)c2)cc1C
Reaction time: 4 h
Yield: 104.5 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.21 mL) was added to a solution of (4′-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-3-fluoro-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 109-(1); 37.5 mg, 0.0703 mmol) in methanol (0.7 mL), and the mixture was stirred for four hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (38.1 mg, 99%).
Reaction SMILES: [SH:1][C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+].CN(C=O)C.[Cl:21][C:22]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:23]=1[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)=[O:25]>C(O)C.O>[Cl:21][C:22]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:23]=1[C:24]([C:26]1[CH:27]=[CH:28][C:29]([CH2:30][S:1][C:2]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:32][CH:33]=1)=[O:25]
Reactant: Cn1c(S)nc2ccccc2c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: Cn1c(SCc2ccc(C(=O)c3ccc(Cl)cc3Cl)cc2)nc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a solution of 2-mercapto-3-methyl-4(3H)-quinazolinone (1.0 g) and sodium hydroxide (250 mg) in 50% ethanol (15 ml)-DMF (15 ml) was added 4-(2,4-dichlorobenzoyl)benzyl bromide (1.88 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixtrue was poured in water and the resulting crystals were collected by filtration, rinsed with water and methanol, and recrystallized from methanol to provide the title compound as colorless solid (2.16 g). IH-NMR (CDCl3) δ: 3.59(3H,s), 4.59(2H,s), 7.25-7.80(10H,m), 8.22(1H,dd,J=8.2,1.4Hz).