Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1)[NH2:5].Cl[C:19]1[C:24]([C:25]#[N:26])=[CH:23][N:22]=[C:21]2[S:27][C:28]3[CH2:29][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:32][C:33]=3[C:20]=12>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:19]2[C:24]([C:25]#[N:26])=[CH:23][N:22]=[C:21]3[S:27][C:28]4[CH2:29][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:32][C:33]=4[C:20]=23)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Cl)c23)C1
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)C1

Procedure:
In analogy to Example 54A, the title compound was synthesized from 3-chloro-4-[(3-fluorobenzyl)oxy]aniline from Example 4A (180 mg, 0.72 mmol) and tert-butyl 4-chloro-3-cyano-5,8-dihydrothieno[2,3-b:5,4-c′]dipyridine-7(6H)-carboxylate (250 mg, 0.72 mmol) from Example 53A to yield 258 mg (64%).
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[F:1][C:2]1[C:10]2[S:9][C:8]([C:11]3[N:31]([C:28]4[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=4)[N:32]=[C:13]([C:14]([F:17])([F:16])[F:15])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1nc2cccc(F)c2s1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: Cl
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2nc3cccc(F)c3s2)cc1
Yield: 38 %

Procedure:
The procedure of Example 9 was repeated using 1-(7-fluorobenzothiazol-2-yl)-4,4,4-trifluorobutane-1,3-dione and 4-methylsulfonylphenylhydrazine hydrochloride as the starting materials to obtain 7-fluoro-2-[1-(4-methylsulfonylphenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]benzothiazole (yield, 38%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14](=[O:19])C(F)(F)F)=[C:4]1[CH3:20])[CH3:2].[OH-:21].[K+].Cl>C(O)C.O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]([OH:19])=[O:21])=[C:4]1[CH3:20])[CH3:2]
Reactant: [OH-]
Reactant: CCn1c(C)c(C(=O)C(F)(F)F)c2ccc(OC)cc21
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCn1c(C)c(C(=O)O)c2ccc(OC)cc21
Temperature: 25 °C
Yield: 73.9 %

Procedure:
To a solution of 1-(1-ethyl-6-methoxy-2-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone 71b (580 mg, 2.03 mmole) in 10 ml ethanol was added a solution of KOH (1.1 g, 20 mmole) in 10 ml water. The mixture was heated to reflux for 1 hour and cooled to room temperature. Concentrated HCl was added to adjust pH to 1. The mixture was extracted with EtOAc and the combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was further purified by column chromatography (eluting with 1–2% MeOH in CH2Cl2) to give 350 mg product as brown solid (74% yield). 1H NMR (400 MHz, CDCl3) δ 8.07 (1H, d, J=8.7 Hz), 6.90 (1H, dd, J=2.2, 8.7 Hz), 6.80 (1H, d, J=2.2 Hz), 4.14 (2H, q, J=7.2 Hz), 3.88 (3H, s), 2.77 (3H, s), 1.37 (3H, t, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][N:7]1[C:11]([NH2:12])=[C:10]([C:13]#[N:14])[C:9]([S:15][CH3:16])=[N:8]1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][N:7]1[C:11]([NH2:12])=[C:10]([C:13]#[N:14])[C:9]([S:15]([CH3:16])=[O:30])=[N:8]1
Reactant: CSc1nn(Cc2cccc(C(F)(F)F)c2)c(N)c1C#N
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nn(Cc2cccc(C(F)(F)F)c2)c(N)c1C#N
Reaction time: 15 h
Yield: 77.5 %

Procedure:
2.7 g of 1-(3-trifluoromethylbenzyl)-3-methylmercapto-4-cyano-5-amino-pyrazole are dissolved in 30 ml of chloroform. A mixture of 1.8 g of 3-chloroperbenzoic acid and 20 ml of chloroform are added dropwise to this solution at 20° C. and stirred for 15 hours. The mixture is subsequently washed with saturated sodium bicarbonate solution, 2% strength sodium thiosulphate solution, and again with saturated aqueous sodium bicarbonate solution. The organic phase is dried using anhydrous sodium sulphate, concentrated, and triturated in petroleum ether. 2.2 g (75% of theory) of 1-(3-trifluoromethylbenzyl)-3-methylsulphinyl-4-cyano-5-amino-pyrazole of melting point 143° C. are obtained.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][OH:7].[S:10](Cl)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].O>N1C=CC=CC=1>[CH3:17][C:16]1[CH:18]=[CH:19][C:13]([S:10]([O:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([F:9])([F:8])[F:1])(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCC(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCOCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(2,2,2-trifluoroethoxy)ethanol (intermediate BR) (12.7 g) was dissolved in anhydrous pyridine, then TsCl (1.3 eq) was added, and the mixture was stirred at room temperature for 16 h, after which TLC showed the reaction was complete. Then the mixture was poured into water, extracted with EA, washed with water and brine, and dried with anhydrous Na2SO4. The solvent was removed and the residue purified by column chromatography to obtain intermediate BS (0.3 g).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[F:11][C:12]1[CH:28]=[CH:27][C:15]([CH2:16][C:17]2[O:21][C:20]([CH2:22][C:23](Cl)=[N:24][OH:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[F:11][C:12]1[CH:28]=[CH:27][C:15]([CH2:16][C:17]2[O:21][C:20]([CH2:22][C:23]3[CH:2]=[C:1]([C:3]4[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=4)[O:25][N:24]=3)=[CH:19][CH:18]=2)=[CH:14][CH:13]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(Cc2ccc(F)cc2)o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(Cc4ccc(F)cc4)o3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 32.8 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynyl-pyridin-2,6-diamine (50 mg, 0.376 mmol) described in Manufacturing Example 13-1-3 and (5-(4-fluorobenzyl)-furan-2-yl)acetohydroximoyl chloride (161 mg, 0.602 mmol) described in Manufacturing Example 208-1-5 was added triethylamine (131 μL, 0.94 mmol), which was stirred for 19 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1, then ethyl acetate) to obtain the title compound (45 mg, 33%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([O:15][P:16]([O:20]CC)[O:17][CH2:18][CH3:19])[CH3:14]>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=1[CH2:2][P:16]([O:17][CH2:18][CH3:19])([O:15][CH2:13][CH3:14])=[O:20]
Reactant: COC(=O)c1ccccc1CBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccccc1C(=O)OC)OCC
Temperature: 25 °C
Yield: 92.5 %

Procedure:
step 1—A solution of methyl 2-bromomethyl-benzoate (9.99 g, 43.6 mmol) and triethylphosphite (7.25 g, 43.6 mmol) was heated to 150° C. for 5 h. The reaction mixture as cooled to RT then purified by SiO2 chromatography to afford 11.55 g of 2-(diethoxy-phosphorylmethyl)-benzoic acid methyl ester (72)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:29][C:30]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][C:33]([NH2:34])=[C:32]([O:40][CH3:41])[CH:31]=1>CC(O)CCC>[Br:29][C:30]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][C:33]([NH:34][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[N:10][N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)=[C:32]([O:40][CH3:41])[CH:31]=1
Reactant: COc1cc(Br)c([N+](=O)[O-])cc1N
Reactant: Clc1nccc(-c2cnn3c2CCCC3)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCC(C)O
Solvent: O
Product: COc1cc(Br)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Yield: 58.7 %

Procedure:
A solution of 3-(2-chloropyrimidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (Intermediate 128, 0.893 g, 3.80 mmol), p-toluene sulphonic acid monohydrate (1.034 g, 5.43 mmol) and 4-bromo-2-methoxy-5-nitroaniline (Intermediate 4, 0.895 g, 3.62 mmol) in 2-pentanol (35 mL) was heated at reflux for 16 h under an atmosphere of N2. The mixture was then allowed to cool, and was concentrated in vacuo. The resulting residue was triturated in CH3CN until a yellow precipitate formed. The solid was collected by filtration and was washed with diethyl ether. The solid then was dissolved in 10% CH3OH in CH2Cl2 and the resulting solution was washed twice with sat. NaHCO3, then with water. The solution was then dried (MgSO4) and concentrated in vacuo. The resulting residue was triturated with CH3CN, the resulting solid collected by filtration, washed with diethyl ether, and then air dried to give the title compound (0.946 g, 59%) as a yellow solid; 1H NMR: 1.80-1.87 (2H, m), 1.96-2.03 (2H, m), 3.11 (2H, t), 4.04 (3H, s), 4.13 (2H, t), 7.17 (1H, d), 7.50 (1H, s), 8.13 (1H, s), 8.21 (1H, s), 8.45 (1H, d), 9.10 (1H, s); m/z: ES+ MH+ 445/447.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]2[CH:8]=[CH:9][N:10]3[CH:16]=[CH:15][CH:14]=[C:11]3[C:12](=[O:13])[C:6]=2[CH:5]=1)(=[O:3])N.S(=O)(=O)(O)[OH:20].N([O-])=O.[Na+]>O>[C:1]([C:4]1[CH:18]=[CH:17][C:7]2[CH:8]=[CH:9][N:10]3[CH:16]=[CH:15][CH:14]=[C:11]3[C:12](=[O:13])[C:6]=2[CH:5]=1)([OH:20])=[O:3]
Reactant: NC(=O)c1ccc2ccn3cccc3c(=O)c2c1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc2ccn3cccc3c(=O)c2c1

Procedure:
To 9-carbamoyl-11H-pyrrolo[2,1-b][3]benzazepin-11-one (27 g., 0.112 moles) in 300 ml. of 50% sulfuric acid maintained at 50° C. is added slowly 25 g. of sodium nitrite in 75 ml. of water. At the end of the addition, the solid is filtered, washed with water and air-dried to yield 9-carboxy-11H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: [NH2:1][N:2]1[C:11]([OH:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:20])[CH:9]=2)[N:4]=[CH:3]1.[C:21]1(=[O:35])[N:25]([CH2:26][C:27](Cl)=[O:28])[C:24](=[O:30])[C:23]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:22]12>N1C=CC=CC=1>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]([C:10]1[CH:9]=[C:8]([Cl:20])[CH:7]=[CH:6][C:5]=1[N:4]([CH:3]=[N:2][NH:1][C:27](=[O:28])[CH2:26][N:25]1[C:21](=[O:35])[C:22]2[C:23](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:24]1=[O:30])[C:27](=[O:28])[CH2:26][N:25]1[C:24](=[O:30])[C:23]2[C:22](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:21]1=[O:35])=[O:19]
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: NN1C=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Solvent: c1ccncc1
Product: O=C(CN1C(=O)c2ccccc2C1=O)NN=CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1, 3-amino-6-chloro-3,4-dihydro-4-hydroxy-4-(o-chlorophenyl)quinazoline with pyridine is reacted with α-phthalimidoacetyl chloride to give 1,3-dioxo-2-isoindolineacetic acid [[N-[2-(o-chlorobenzoyl)-4-chlorophenyl]-1,3-dioxo-2-isoindolineacetamido]-methylene]hydrazide.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].[Si:9]([O:16][C@H:17]1[CH2:26][C@H:25](O)[C@H:24]2[C:19]([CH:20]=[CH:21][C@H:22]([CH3:45])[C@@H:23]2[CH2:28][CH2:29][C@H:30]2[O:35][C:34](=[O:36])[CH2:33][C@H:32]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:31]2)=[CH:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>>[Si:9]([O:16][C@H:17]1[CH2:26][C@H:25]([O:5][C:4](=[O:6])[C:3]([O:2][CH3:1])([CH3:8])[CH3:7])[C@H:24]2[C:19]([CH:20]=[CH:21][C@H:22]([CH3:45])[C@@H:23]2[CH2:28][CH2:29][C@H:30]2[O:35][C:34](=[O:36])[CH2:33][C@H:32]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40])[CH2:31]2)=[CH:18]1)([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:11])[CH3:10]
Reactant: COC(C)(C)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: COC(C)(C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 70.7 %

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 860 mg of 2-methoxy-2-methylpropionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 836 mg of the title compound as a colorless foam.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[C:12]2=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1(C)C=CC=CC=1.P(Br)(Br)[Br:32]>C1COCC1>[Br:32][C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:21][CH3:22])=[CH:15][CH:14]=2)[CH2:19][CH2:20][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)CCC(c1ccc(S(C)(=O)=O)cc1)C2=O
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCC(c1ccc(S(C)(=O)=O)cc1)=C2Br
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
Combine 2-(4-methanesulfonylphenyl)-6-methoxytetralone (1.0 eq.), hyflo (20%/weight), and toluene (7.5 volumes). Add PBr3 (1.5˜1.75 eq.) in one portion while stirring at room temperature. Heat contents to reflux (˜110° C.) overnight. Upon reaction completion, as judged by HPLC analysis (usually 15 hours), cool solution to 45° C. and slowly add 20 volumes THF. Stir for 30 minutes at 45° and filter warm over a pad of hyflo. The pad is washed with 2×2 volumes THF at 45° C. Concentrate filtrate to approximately 7 volumes. Add 7.5 volumes water to the remaining mixture keeping the temperature below 40° C. (NOTE: initial addition of water is very exothermic with large evolution of HBr). Cool slurry to room temperature and stir for 2 to 3 hours. Filter over a polypropylene pad and wash with 2×2 volumes water. Dry filter cake overnight at 60° C. under vacuum to give 1-bromo-2-(4-methanesulfonylphenyl)-3,4-dihydro-6-methoxynaphthalene.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])=[C:6]2[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=1.[CH3:29][O-:30].[Na+]>CO>[CH3:29][O:30][C:2]1[N:7]2[N:8]=[CH:9][C:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])=[C:6]2[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=1
Reactant: C[O-]
Reactant: Cc1c(Cc2cnn3c(Cl)cc(N4CCOCC4)nc23)cccc1C(F)(F)F
Agent: [Na+]
Solvent: CO
Product: COc1cc(N2CCOCC2)nc2c(Cc3cccc(C(F)(F)F)c3C)cnn12
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(7-chloro-3-(2-methyl-3-(trifluoromethyl)benzyl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine (181 mg, 0.44 mmol) in methanol (5 mL) stirred under nitrogen at 0° C. was added a 33% solution of sodium methoxide in dropwise. The reaction mixture was stirred at 40° C. for 1 hour. Solvent was removed in vacuo. The residue was dissolved with ethyl acetate (30 mL) and water (10 mL). Two layers were separated. Organic layer was dried and concentrated. The crude product was purified by reverse-phase HPLC to provide the titled compound. (15 mg, 8.4%); LC/MS: MS (ES+) m/e 407 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.39-2.47 (m, 3H) 3.60 (br. s., 2H) 3.61 (d, J=4.55 Hz, 2H) 3.65-3.73 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=O)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32]3[CH2:31][CH2:30][CH:29]([CH3:33])[NH:28][C:27]=3[CH:26]=[N:25]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:32]3[CH2:31][CH2:30][CH:29]([CH3:33])[N:28]([C:8](=[O:10])[CH:7]([N:6]4[C:2]([CH3:1])=[CH:3][C:4]([C:13]([F:16])([F:15])[F:14])=[N:5]4)[CH2:11][CH3:12])[C:27]=3[CH:26]=[N:25]2)=[CH:22][CH:23]=1
Reactant: CCC(C(=O)O)n1nc(C(F)(F)F)cc1C
Reactant: CC1CCc2c(cnn2-c2ccc(F)cc2)N1
Product: CCC(C(=O)N1c2cnn(-c3ccc(F)cc3)c2CCC1C)n1nc(C(F)(F)F)cc1C
Yield: 46 %

Procedure:
The title compound was prepared from 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)butanoic acid and 1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method A. The reaction slurry was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to provide 13 mg (46%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.47 (m, 2H), 7.16 (m, 2H), 6.35 (s, 1H), 5.37 (dd, J=6.7, 8.6 Hz, 1H), 4.63 (m, 1H), 2.86 (m, 1H), 2.73 (ddd, J=1.9, 5.1, 11.3 Hz, 1H), 2.37 (s, 3H), 2.27 (m, 2H), 1.92-1.97 (m, 2H), 0.93 (t, J=6.5 Hz, 3H), 0.57 (t, J=6.7 Hz, 3H); MS: (ES) m/z calculated for C22H24F4N5O [M+H]+ 450.2, found 450.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[S:17])[NH2:16])=[CH:11][C:10]=1[CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][C:23](=O)[CH2:24][CH3:25]>CCO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:17][CH:22]=[C:23]([CH2:24][CH3:25])[N:16]=2)=[CH:11][C:10]=1[CH2:18][CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)CBr
Reactant: CCCc1cc(C(N)=S)ccc1OCc1ccccc1
Solvent: CCO
Product: CCCc1cc(-c2nc(CC)cs2)ccc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(benzyloxy)-3-propylbenzenecarbothioamide (0.53 g, 1.86 mmol) (Example 31) in EtOH (70 mL) was added 1-bromo-2-butanone (0.47 g, 2.79 mmol), and the reaction was stirred for 3 h at 70° C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was saved. This procedure was repeated on a 1.1 g scale (based on thioamide). The two crude residues were combined and purified by silica gel chromatography (EtOAc/hexane (v/v)=1:9, then 100% EtOAc) to give 0.87 g (67% overall) of the title compound. 1H NMR (400 MHz, CDCl3):δ 7.72 (s, 1H), 7.67 (d, 1H), 7.45-7.28 (m, 5H), 6.88 (d, 1H), 6.76 (s, 1H), 5.12 (s, 2H), 4.09 (q, 2H), 2.84 (q, 2H), 2.75-2.66 (m, 2H), 1.30 (t, 3H), 0.93 (t, 3H).
Reaction SMILES: [NH2:1][OH:2].[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([Br:13])[C:11]=1[OH:12])[C:7]#[N:8]>O.C(O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([Br:13])[C:11]=1[OH:12])[C:7](=[N:1][OH:2])[NH2:8]
Reactant: NO
Reactant: N#Cc1cc(Br)c(O)c(Br)c1
Solvent: CCO
Solvent: O
Product: NC(=NO)c1cc(Br)c(O)c(Br)c1
Temperature: 25 °C
Yield: 75 %

Procedure:
Hydroxylamine (10 mL of a 50% solution in water) was added in one portion to a stirred suspension of 3,5-dibromo-4-hydroxybenzonitrile (30 g, 110 mmol) in ethanol (100 mL) at room temperature and the mixture was heated to reflux for 3 hours before cooling back down to room temperature. The solid was filtered, washed with cold ethanol and dried to yield the title compound (25.5 g, 75%) as a colourless powder. 1H NMR δ (ppm) (DMSO-d6): 5.92 (2 H, br s), 7.87 (2 H, s), 9.69 (1 H, br s), 10.19 (1 H, br s).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:20])=[N+]=[N-].[H][H]>O.CO.[Pd]>[NH2:1][CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:20]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O

Procedure:
5'-Azido-5-ethyl-2',5'-dideoxyuridine (300 mg) is dissolved in a mixture of water-methanol (1:1, 25 ml) and then hydrogen gas is introduced with 10% Pd/C at room temperature under 1 atmosphere for 2 hr, after which the mixture is filtered and the filtrate is evaporated to a foam (160 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[N-:13]=[C:14]=[O:15].[K+]>O.C(O)(=O)C>[NH:1]([C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)[C:14]([NH2:13])=[O:15]
Reactant: [N-]=C=O
Reactant: Nc1ccc(/C=C/C(=O)O)cc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccc(/C=C/C(=O)O)cc1
Temperature: 100 °C
Yield: 79.5 %

Procedure:
A stirred solution of (E)-3-(4-aminophenyl)acrylic acid (1.0 g, 5.0 mmol) and potassium isocyanate (2.0 g, 5 equiv.) in a mixture of water and acetic acid (50 mL) was heated at 100° C. for 12 hours. After cooling, a white solid precipitated out. Filtration, washing of the filter cake with a mixture of water and MeOH, and drying it in vacuo gave the title compound (0.82 g, 80%) as a white solid. MP>350° C.
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5][N:6]([CH2:8]Cl)[CH:7]=1.[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:2][C:3]1[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5][N:6]([CH2:8][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])[CH:7]=1
Reactant: CC(C)(C)c1nn(CCl)cc1Br
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1nn(CC(C#N)(C#N)CCC(F)(F)F)cc1Br
Yield: 78.8 %

Procedure:
1.85 g of 4-bromo-3-t-butyl-1-(chloromethyl)-1H-pyrazole hydrochloride and 1.18 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 21 ml of N,N-dimethylformamide. 2.02 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.91 g of [(4-bromo-3-t-butyl-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (12), hereinafter) shown by below formula.
Reaction SMILES: Cl[C:2]([Cl:12])=[CH:3][C:4]([CH2:10][CH3:11])([CH3:9])[CH2:5][CH2:6][CH2:7][CH3:8].[C:13]1([O-:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+]>CN(C)C=O.C(Cl)Cl>[Cl:12][CH:2]=[C:3]([O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]([CH2:10][CH3:11])([CH3:9])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: [O-]c1ccccc1
Reactant: CCCCC(C)(C=C(Cl)Cl)CC
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCC(C)(CC)C(=CCl)Oc1ccccc1
Yield: 65.3 %

Procedure:
626 g (3 moles) of 1,1-dichloro-3-ethyl-3-methyl-1-heptene and 676 g (6 moles) of sodium phenolate are heated under relfux in 3 l of dimethylformamide for 16 hours. The mixture is diluted with methylene chloride and extracted by shaking several times with 2N aqueous sodium hydroxide solution. After drying and evaporating on a rotary evaporator, 666 g of crude product remain. Distillation at boiling point0.1 100°-110° C. gives 523 g (65% of theory) of 1-chloro-3-ethyl-3-methyl-2-phenoxy-hept-1-ene.