Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.[F:2][C:3]([F:13])([CH2:9][C:10](O)=[O:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5]>O1CCCC1>[F:2][C:3]([F:13])([CH2:9][CH2:10][OH:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(F)(F)CC(=O)O
Agent: B
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CCO
Reaction time: 18 h

Procedure:
A solution of 123.0 mL (0.123 mol) of 1.0 M of borane in tetrahydrofuran was added dropwise at 0° to a mixture of 12.4 g (0.068 mol) of ethyl 2,2-difluoro-3-carboxypropionate in 70 mL of dry tetrahydrofuran. The reaction mixture was stirred at 0° for 18 hr then was quenched by adding 40 mL of water dropwise. The solution was saturated with solid sodium chloride and the product was isolated with ether. The ether layers were washed with saturated aqueous sodium bicarbonate and brine. The solution was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to yield ethyl 2,2-difluoro-4-hydroxybutyrate. NMR (CDCl3) δ4.32 (quartet, 2, 2, J=7 Hz), 3.87 (triplet, 2, J=6 Hz), 2.36 (multiplet, 2) and 1.35 ppm (triplet, 3, J=7 Hz).
Reaction SMILES: [CH2:1]([C:4]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]([O:41]C(C)(C)C)=[O:40])=[CH:29][CH:28]=2)[C:7]2[CH:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:9]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]([OH:41])=[O:40])=[CH:29][CH:28]=2)[C:7]2[CH:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:9]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)N(C(=O)CC(=O)OCC)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)O)cc1)C(C(=O)OCC)N(C(=O)CC(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
The mixture of ethyl 2-n-propyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (657 mg), trifluoroacetic acid (3 ml) and methylene chloride (10 ml) is stirred overnight at room temperature. The reaction mixture is washed with a saturated sodium hydrogen carbonate solution and brine, dried, and evaporated. The crude product is purified by silica gelcolumn chromatography (solvent; chloroform/methanol) to give ethyl 2-n-propyl-3-(2'-carboxybiphenyl-4-yl)methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (516 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:11]=1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[C:16](=[O:29])[C:15]=1[Br:30].C(N(CC)CC)C.C([O:46][CH2:47][C:48](Cl)=[O:49])(=O)C>C1COCC1.O>[Br:30][C:15]1[C:16](=[O:29])[N:17]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])[C:18]([CH3:20])=[CH:19][C:14]=1[O:13][CH2:12][C:11]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:10]=1[CH2:9][NH:8][C:47](=[O:46])[CH2:48][OH:49]
Reactant: Cc1cc(OCc2ccc(F)cc2CN)c(Br)c(=O)n1-c1c(F)cccc1F
Reactant: CC(=O)OCC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCc2ccc(F)cc2CNC(=O)CO)c(Br)c(=O)n1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a suspension of 4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-bromo-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one trifluoroacetate (0.12 g, 0.00021 mol) in THF (2.0 mL) at 5° C., was added triethyl amine (0.036 g, 0.00035 mol) followed by the addition of acetoxyacetyl chloride (0.05 mL). The mixture was stirred at room temperature for 30 min, diluted with cold water (10 mL), and extracted the products with dichloromethane (2×10 mL). The combined organic extracts were washed with water, dried (Na2SO4) and concentrated to dryness. The residue was dissolved in ethanol (0.5 mL), added 1N NaoH (0.5 mL)and stirred at room temperature for 1 h. The resulting solution was diluted with water (15 mL), and extracted with dichloromethane (2×10 mL). The combined dichloromethane extracts were washed with water, dried (Na2SO4) and concentrated to dryness. The residue was purified by flash chromatography (1% MeOH in EtOAc) to afford the title compound (0.032 g, 30%) as a white amorphous powder: 1H NMR (CDCl3/400 Hz) δ 7.45 (m, 2H), 7.18 (m, 1H), 7.05 (m, 3H), 6.23 (s, 1H), 5.24 (s, 2H), 4.56 (d, 2H, J=6.4 Hz), 4.08 (d, 2H, J=5.2 Hz), 2.79 (t, 1H), and 2.08 (s, 3H;) 19F NMR (CDCl3/400 MHz) δ−111.88 (m), and −118.62 (m); ES-HRMS m/z 511.0482 (M+H C22H19N2O4F3Br requires 511.0475).
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C1C=CC=CC=1>[C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCC(=O)OC(C)(C)C
Solvent: c1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCC(=O)O

Procedure:
A solution of the ester (35) (0.15 g, 0.222 mmol) in dry benzene (3 ml) under nitrogen was treated with a catalytic amount of toluenesuphonic acid and the resulting solution heated at reflux for 5 hours, after which time no starting material remained on tlc. The volatile components were removed in vacuo and the residue chromatographed on silica (5 g). Elution with 10% ether in petrol gave the title compound (42) as a white wax (0.1 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[C:19]([CH3:20])=[N:18][C:11]3[N:12]=[C:13]([NH:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=2)[CH:7]=1.Cl[C:24]([O:26][C:27]([CH3:29])=[CH2:28])=[O:25]>N1C=CC=CC=1>[F:22][C:3]1[CH:4]=[C:5]([CH3:21])[C:6]([C:8]2[C:19]([CH3:20])=[N:18][C:11]3[N:12]=[C:13]([NH:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:7][C:2]=1[NH:1][C:24](=[O:25])[O:26][C:27]([CH3:29])=[CH2:28]
Reactant: C=C(C)OC(=O)Cl
Reactant: CNc1ncc2cc(-c3cc(N)c(F)cc3C)c(C)nc2n1
Solvent: c1ccncc1
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(NC)nc3nc2C)c(C)cc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
Treat a cooled solution (0° C.) of 6-(5-amino-4-fluoro-2-methylphenyl)-N,7-dimethylpyrido[2,3-d]pyrimidin-2-amine (0.85 g, 2.86 mmol) in pyridine (10 mL) dropwise with isopropenyl chloroformate (0.281 ml, 2.57 mmol) and stir the mixture for 20 min. at 0° C. Concentrate the mixture to dryness, dissolve the residue in DCM, wash with brine, dry over Na2SO4 and concentrate to dryness to afford the title compound. Use it without purification (assuming 100% yield). MS (m/z): 382.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[C:23]([CH2:25]Cl)[CH:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:18][C:19]1[CH:24]=[C:23]([CH2:25][N:15]2[CH2:14][CH2:13][N:12]([C:10](=[O:11])[CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:17][CH2:16]2)[CH:22]=[CH:21][N:20]=1
Reactant: O=C(COCc1ccccc1)N1CCNCC1
Reactant: ClCc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(COCc1ccccc1)N1CCN(Cc2ccnc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Benzyloxyacetyl-piperazine (1.0 equiv) was mixed with the compound 2-chloro-4-(chloro-methyl)pyridine (1.0 equiv) and K2CO3 (4 equiv) in DMF. The mixture was stirred for 1 h at rt. After removing most of the solvent, the residue was partitioned in water and EtOAc. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography to give the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[N:28]1([S:34]([C:37]2[CH:38]=[C:39]([NH2:43])[CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[N:28]1([S:34]([C:37]2[CH:38]=[C:39]([NH:43][C:25]([C:24]3[CH:23]=[N:22][N:15]4[C:16]([C:18]([F:19])([F:21])[F:20])=[CH:17][C:12]([C:4]5[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:11])[F:10])=[C:2]([CH3:1])[CH:3]=5)=[N:13][C:14]=34)=[O:27])[CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)N5CCOCC5)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II. Yellow solid. MS (ISP) 614.4 [(M+H)+]; mp 272° C.
Reaction SMILES: [Na].[N+]([C:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[N:7](COCC[Si](C)(C)C)[N:6]=1)([O-])=O.[CH3:21][OH:22]>>[CH3:21][O:22][C:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[NH:7][N:6]=1
Reactant: CO
Reactant: C[Si](C)(C)CCOCn1nc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Na]
Product: COc1cc([N+](=O)[O-])[nH]n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a stirred solution of anhydrous MeOH (25 mL) was added sodium (300 mg, 13.04 mmol) portionwise. To the clear solution was added SEM-protected 3,5-dinitropyrazole from Step D (1 g, 3.47 mmol) and the mixture was stirred at 60° C. for 2 h. The mixture was allowed to cool to rt and was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0-30% EtOAc/hexane to afford a single regioisomer of SEM-protected 3-methoxy-5-nitropyrazole (SEM=((2-(trimethylsilyl)ethoxy)methyl)) as a clear oil (723 mg, 76%). 1H NMR (300 MHz, CDCl3) δ 6.23 (s, 1H), 5.41 (s, 2H), 4.02 (s, 3H), 3.70-3.65 (m, 2H), 0.96-0.91 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: FC(F)(F)C1C=CC(CN)=CC=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][NH2:23])[CH:18]=[CH:19][CH:20]=1.[C:24]([NH:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][N:41]=1)[C:36](O)=[O:37])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([NH:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][N:41]=1)[C:36]([NH:23][CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=1)=[O:37])(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Reactant: COc1cccc(CCN)c1
Agent: NCc1ccc(C(F)(F)F)cc1
Product: COc1cccc(CCNC(=O)c2ccnc(NC(=O)c3ccccc3)c2)c1
Yield: 45 %

Procedure:
Following the procedure as described in Example 1, making variations as required to replace (4-(trifluoromethyl)phenyl)methanamine with 2-(3-methoxyphenyl)ethanamine to react with 2-benzamidoisonicotinic acid, 2-benzamido-N-[2-(3-methoxyphenyl)ethyl]isonicotinamide was obtained as a colorless solid in 45% yield: 1H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.88 (t, J=5.5 Hz, 1H), 8.57 (s, 1H), 8.52-8.49 (m, 1H), 8.07-8.04 (m, 2H), 7.63-7.48 (m, 4H), 7.24-7.17 (m, 1H), 6.84-6.76 (m, 3H), 3.73 (s, 3H), 3.55-3.48 (m, 2H), 2.85 (t, J=7.3 Hz, 2H); MS (ES+) m/z 376.5 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:17])[CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:18][C:19]1([CH3:28])[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21](=O)[CH2:20]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:21]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH2:24][C:19]([CH3:28])([CH3:18])[CH2:20]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:17])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(O)c(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(Br)cc2)c2ccc(O)c(F)c2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a stirred suspension of zinc powder (0.54 g, 8.13 mmol) in THF (20 mL) was slowly added TiCl4 (0.45 mL, 4.07 mmol) via syringe at room temperature under a nitrogen atmosphere. The mixture was heated at reflux for 2 h. A solution of (4-bromophenyl)(3-fluoro-4-hydroxyphenyl)methanone (82) (0.30 g, 1.02 mmol) and 3,3,5,5-tetramethyl cyclohexanone (0.48 g, 3.05 mmol) in THF (6 mL) was added to the mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 1 h. The reaction mixture was allowed to cool to room temperature. To the reaction mixture was slowly added 10% aqueous K2CO3 (20 mL). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc (100 mL). The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was further extracted with EtOAc (25 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as yellow oil. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 30:1) to give 0.33 g (78%) of compound 139 as a light yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 0.91 (s, 6H), 0.93 (s, 6H), 1.29 (s, 2H), 1.92 (s, 2H), 1.97 (s, 2H), 4.99 (d, J=3.8 Hz, 1H), 6.78-6.87 (m, 2H), 6.90 (t, J=8.6 Hz, 1H), 7.01 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H). LCMS (ES): m/z 415 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH2:18])=[CH:16][N:15]=[CH:14]1.[F:19][C:20]([F:24])([F:23])[S:21]Cl.O>C(Cl)Cl>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:17]([NH2:18])=[C:16]([S:21][C:20]([F:24])([F:23])[F:19])[N:15]=[CH:14]1
Reactant: Nc1cncn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: FC(F)(F)SCl
Solvent: O
Solvent: ClCCl
Product: Nc1c(SC(F)(F)F)ncn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
To a solution of 4.8 g (14.91 mmole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-aminoimidazole in 400 ml of methylene chloride was added 1.3 ml (14.91 mmole) of trifluoromethanesulfenyl chloride at 0° C. The mixture was stirred at 0° C. for 4 h and then at RT for 15 h. Water was added and the mixture was partitioned between water and methylene chloride. The organic layer was dried over anhydrous sodium sulfate and the solvent removed. The residue was recrystallized from methylene chloride to give 3.36 g (52.51% yield) of the desired product., mp 134° C.
Reaction SMILES: [P:1]([O:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:32][CH:33]2[CH2:36][CH2:35][CH2:34]2)[C:24]([C:26]2[NH:30][N:29]=[C:28]([Cl:31])[CH:27]=2)=[O:25])=[C:18]([F:37])[CH:17]=1)([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(#N)C>[P:1]([OH:8])([OH:3])([O:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:32][CH:33]2[CH2:34][CH2:35][CH2:36]2)[C:24]([C:26]2[NH:30][N:29]=[C:28]([Cl:31])[CH:27]=2)=[O:25])=[C:18]([F:37])[CH:17]=1)=[O:2]
Reactant: CC(C)(C)OP(=O)(OCOc1ccc(CN(CC2CCC2)C(=O)c2cc(Cl)n[nH]2)c(F)c1)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(Cl)n[nH]1)N(Cc1ccc(OCOP(=O)(O)O)cc1F)CC1CCC1
Reaction time: 24 h
Yield: 40.7 %

Procedure:
To a solution of di-tert-butyl ((4-((3-chloro-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamido)methyl)-3-fluorophenoxy)methyl) phosphate (0.030 g, 0.054 mmol) in 1 mL ACN was added TFA 0.5 mL and Et3SiH 0.5 mL. After 24 h, the reaction mixture was concentrated. The solvent was removed by evaporation under reduced pressure. Preparative HPLC purification (Water/ACN, 10-100%, 15 min; 100%, 5 min.) provide pure product (4-((3-chloro-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamido)methyl)-3-fluorophenoxy)methyl dihydrogen phosphate (0.010 g, 0.022 mmol, 42% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][C:11](=O)[NH:10][C:9]=2[CH:15]=1)=[O:4]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][CH2:11][NH:10][C:9]=2[CH:15]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)NC(=O)CS2
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)NCCS2
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
Borane-tetrahydrofuran complex solution (1 M in tetrahydrofuran, 45 mL, 45 mmol) was added at 0° C. to a suspension of methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (2.00 g, 8.96 mmol) in tetrahydrofuran (20 mL). The ice bath was removed, the homogenous solution stirred at room temperature for 2 h, then excess reagent was destroyed by careful addition of methanol (42 mL) at 0° C. After evaporation of volatile material, the residue was taken up in 5% methanolic sulfuric acid solution (25 mL) and the solution was heated at reflux over 80 min. After cooling, the reaction mixture was partitioned between ethyl acetate and water, the organic layer was dried (MgSO4) and evaporated to produce 3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid methyl ester (1.79 g, 96%). Light yellow solid, MS (ISP)=210.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:37][C:38]1([C:44]2[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[CH:46][CH:45]=2)[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([N:41]1[CH2:42][CH2:43][C:38]([C:44]2[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[CH:46][CH:45]=2)([F:37])[CH2:39][CH2:40]1)=[O:9]
Reactant: Cc1cc(C)c(C(=O)O)cc1N
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C(=O)N2CCC(F)(c3ccc(C#N)cc3)CC2)cc1N
Reaction time: 1 h
Yield: 72.9 %

Procedure:
A mixture of 5-amino-2,4-dimethylbenzoic acid (compound 42.1, 2.264 g, 13.71 mmol, 1.00 equiv), HBTU (7.803 g, 20.59 mmol, 1.50 equiv), 4-(4-fluoropiperidin-4-yl)benzonitrile (compound 11.2, 2.8 g, 13.71 mmol, 1.00 equiv), and DIEA (3.541 g, 27.45 mmol, 2.00 equiv) in DMF (50 mL) was stiffed at room temperature. After 1 h, the mixture was diluted with 100 mL of EtOAc and washed with 1×100 mL of water followed by 1×100 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 3.51 g (73%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O)[CH2:2][CH3:3].[C:13]([N:17]1[C:21]([NH2:22])=[C:20]([C:23]([NH2:25])=[O:24])[CH:19]=[N:18]1)([CH3:16])([CH3:15])[CH3:14].CS(O)(=O)=O>C(O)C>[C:13]([N:17]1[C:21]2=[N:22][C:7]([C:6]3[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=3[O:4][CH2:1][CH2:2][CH3:3])=[N:25][C:23](=[O:24])[C:20]2=[CH:19][NH:18]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CCCOc1ccccc1C=O
Reactant: CC(C)(C)n1ncc(C(N)=O)c1N
Agent: CS(=O)(=O)O
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2n(C(C)(C)C)[nH]cc-2c(=O)n1
Yield: 21.9 %

Procedure:
A mixture of 2-propoxybenzaldehyde (3.0 g, 18.27 mmol), 1-tert-butyl-5-amino-1H-pyrazole-4-carboxamide (2.5 g, 13.7 mmol), methanesulfonic acid (0.2 ml) and xylenes (50 ml) was refluxed overnight. The reaction mixture was stripped to dryness, treated with ethanol and again stripped to dryness. The residue was partitioned between chloroform and 10% KHCO3, the layers were separated, and the aqueous layer was extracted with chloroform (2×100 ml). The organic layers were combined, and concentrated in vacuo and the residue was dissolved in CH2Cl2 (30 ml) and combined with silica gel (20 g). The preloaded silica gel was placed on a silica gel column and eluted with 70% ether/hexanes, followed by ether (100%) to afford 0.98 g (22%) of 1-tert-butyl-6-(2-propoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-one 1/100 hydrate, m.p. 130°-131° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][N:16]2[CH3:21])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[CH3:21][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20][C@H:15]1[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: CN1CCCC[C@H]1CN1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CN1CCCC[C@H]1CN1CCNCC1
Yield: 50 %

Procedure:
To a solution of (S)-1-benzyl-4-[(1-methylpiperidin-2-yl)methyl]piperazine 0.87 g (3.03 mmol) in THF (40 ml) was added 10% Pd/C 0.4 g and exposed to 1 atm hydrogen overnight. The reaction mixture was filtered. The filtrate was concentrated 0.3 g of desired product in 50% yield.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7]>O>[C:4]([C:3]1[N:7]=[N:6][N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=2[F:12])[CH:2]=1)#[N:5]
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Solvent: O
Product: N#Cc1cn(Cc2c(F)cccc2F)nn1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-difluorobenzyl azide (34.2 9), 2-chloroacrylonftrile (26.6 g) and water (125 ml) is stirred at about 70° C. for 24 hours. Excess 2-chloroacrylonitrile is distilled off by raising the external temperature to about 130° C. The mixture is cooled to about 95° C. and the product is crystallized by seeding. After cooling to about 40° C., the suspension is treated with cyclohexane (50 ml) and brought to about 20° C., and the product is isolated by filtration, washed with cyclohexane (75 ml) and then with water and dried in vacuo at about 60° C. Yield: 36.38 g=82.6%.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[C:14](Cl)=[N:13][N:12]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>CCOC(C)=O.O.[Cl-].[Na+].O.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:10][C:11]1[C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=2[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:13][N:12]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1nnc(Cl)c2c1CCCC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1nnc(-c2ccccc2)c2c1CCCC2
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.270 g, 0.369 mmol), phenylboronic acid (0.900 g, 7.38 mmol) and 1,4-dichloro-5,6,7,8-tetrahydrophthalazine (2.25 g, 11.1 mmol) were combined in a 150 mL sealable vessel under argon. 15 mL dioxane and 2.0 M Sodium carbonate, aqueous (7.38 ml, 14.8 mmol) were added. The vessel was sealed and heated to 80° C. to give a homogenous brown reaction. After 30 min, the reaction was cooled to ambient temperature and was diluted with EtOAc, water, and brine. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a red solid. This was taken up in dichloromethane and purified by silica gel chromatography (0-60% EtOAc in hexanes) to give 1-chloro-4-phenyl-5,6,7,8-tetrahydrophthalazine as an off-white solid. MS m/z=245 [M+H]+. Calc'd for C14H13ClN2: 244.7.