Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=2)=[CH:5][N:4]=1)=O.[CH3:23][CH:24]([CH3:28])[CH2:25][CH2:26][NH2:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH3:23][CH:24]([CH3:28])[CH2:25][CH2:26][NH:27][CH2:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=2)=[CH:5][N:4]=1
Reactant: CC(C)CCN
Reactant: NC(=O)c1ccc(Oc2cnc(C=O)c3ccccc23)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)CCNCc1ncc(Oc2ccc(C(N)=O)cn2)c2ccccc12
Reaction time: 16 h

Procedure:
To 6-(1-formylisoquinolin-4-yloxy)nicotinamide (Preparation 20) (130 mg, 0.44 mmol) in dichloroethane (8 mL) was added 3-methylbutylamine (154 μL, 1.33 mmol), NaBH(OAc)3 (282 mg, 1.33 mmol) and acetic acid (76 μL, 1.33 mmol). The mixture was stirred for 16 h. NaHCO3 (50 mL) was added and the mixture extracted with EtOAc (3×40 mL). The organic phase was washed with water (30 mL), brine (30 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (0.5 NH3: 5 MeOH: 95 DCM) to give the title compound: RT=2.48 min; m/z (ES+)=365.2 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][C:4]1([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]1=[O:17].[Li+].CC([N-]C(C)C)C.[CH2:35]=[O:36]>C1COCC1>[OH:36][CH2:35][CH:18]([C:4]1([CH2:3][CH:2]([CH3:26])[CH3:1])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]1=[O:17])[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20]
Reactant: C=O
Reactant: CC(C)CC1(CC(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC1(C(CO)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Temperature: -78 °C
Yield: 116.4 %

Procedure:
A cold (-78° C.) solution of tert-butyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (EXAMPLE 1, step 3; 2.00 g, 5.56 mmol) in dry THF (20 mL) is treated with the dropwise addition of LDA (3.20 mL, 6.40 mmol, 2.0N). The solution is maintained at -78° C. for 30 min and then warmed to -30° C. Gaseous formaldehyde (generated by heating 834 mg of paraformaldehyde at 160° C. to provide approximately 28 mmol) is bubbled through the enolate solution. The solution is maintained at -30° C. for 1 hour and then quenched with saturated aqueous NH4Cl (5 mL) and diluted with H2O (20 mL). The product is extracted into EtOAc (3×50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to provide 2.52 g of a yellow solid which is purified by silica gel chromatography (100 g SG; 25% EtOAc/hexane) to give 1.43 g (83%) of the title compound as a golden oil. Another fraction containing 375 mg of a mix of both diastereomers is also recovered. Spectral data for the title compound:
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:10]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.S(Cl)([Cl:32])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:32][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:10]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1nn(-c2ccccc2)c2ccccc12)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: ClC(c1nn(-c2ccccc2)c2ccccc12)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of cyclohexyl(1-phenyl-1H-indazol-3-yl)methanol (716 mg) synthesized above, pyridine (284 μL) and toluene (20 mL) was added thionyl chloride (256 μL), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (767 mg, quantitative) as a pale-yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1.[F:15][C:16]([F:26])([F:25])C1C=CC=CC=1C=O>>[F:15][C:16]([F:26])([F:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(-c2ccccc2Cl)n1
Reactant: O=Cc1ccccc1C(F)(F)F
Product: Cc1cccc(-c2ccccc2C(F)(F)F)n1

Procedure:
6-(2-trifluoromethylphenyl)-2-methylpyridine was prepared substantially according to the procedures of Example 1 for prearing 6-(2-chlorophenyl)-2-methylpyridine except 2-trifluoromethylbenzaldehyde was used to afford 6-(2-trifluoromethylphenyl)-2-methylpyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][O:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C@@H:14]23)[CH:19]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][O:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][NH:26][CH2:27][C@@H:14]23)[CH:19]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Product: Fc1cccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)c1

Procedure:
Using 3-fluorobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 132. LRMS (ES)+: 354.4 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.Cl[P:16]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1>[CH:22]1([P:16]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COc1ccccc1Br
Reactant: ClP(C1CCCC1)C1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccccc1P(C1CCCC1)C1CCCC1
Yield: 88.5 %

Procedure:
Under a nitrogen atmosphere, into a reaction vessel equipped with a dropping funnel were added 0.91 g of 2-bromoanisole and 20 mL of tetrahydrofuran. The resultant solution was cooled down to −78° C., then, 3.4 ml of n-butyllithium (1.62 M/hexane solution) was dropped. The resultant mixture was stirred at the same temperature for 2 hours, then, a solution obtained by dissolving 1.00 g of chlorodicyclopentylphosphine in 13 ml of tetrahydrofuran was dropped at −78° C. The resultant mixture was stirred at room temperature for 3 hours. The resultant reaction mixture was concentrated, and purified by silica gel column chromatography, to obtain 1.19 g of dicyclopentyl(2-methoxyphenyl)phosphine in the form of viscous liquid.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13]1[O:14][C:15]3[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=3[C:17]=1[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:7]2.[H-].[Na+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C=O)C>[Br:1][C:2]1[C:3]2[C:8](=[CH:7][C:6]([C:13]3[O:14][C:15]4[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=4[C:17]=3[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:5][CH:4]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCCCC(=O)c1c(-c2ccc3c(Br)c(O)ccc3c2)oc2ccccc12
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC(=O)OCC)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Method A, Step 5 of Example 1, the title compound was prepared from 1-[2-(5-bromo-6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (1.58 g, 3.73 mmol), sodium hydride (0.194 g, 4.85 mmol), and ethyl bromoacetate (0.51 mL, 4.5 mmol) in DMF (15 mL). Purification by flash chromatography using 10% acetone in hexane as an eluant yielded a yellow gum (0.993 g); 1HNMR (200 MHz, DMSO-d6): δ8.5 (s, 1H), 8.25 (d, 1H, J=8.5 Hz), 8.15 (d, 1H, J=10 Hz), 7.95-8.1 (m, 2H), 7.75 (d, 1H, J=7.5 Hz), 7.2-7.4 (m, 3H), 5.15 (s, 2H), 4.15 (q, 2H, J=6.7 Hz), 2.75 (t, 2H, J=7.5 Hz), 1.5-1.65 (m, 2H), 1.1-1.3 (m, 4H), and 0.7 ppm (t, 3H, J=7.3 Hz).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:34])[CH2:32][C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:31])[C:26]([O:28]CC)=[O:27])[CH:21]=[CH:22][CH:23]=3)=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:11][C:7]=2[C:6](=[O:33])[CH2:5]1>C1COCC1.O>[CH3:3][C:4]1([CH3:34])[CH2:32][C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:31])[C:26]([OH:28])=[O:27])[CH:21]=[CH:22][CH:23]=3)=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:11][C:7]=2[C:6](=[O:33])[CH2:5]1
Reactant: CCOC(=O)C(=O)Nc1cccc(-c2c(N3CCOCC3)sc3c2CC(C)(C)CC3=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3cccc(NC(=O)C(=O)O)c3)c2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.1 %

Procedure:
Sodium hydroxide (53 mg, 1.32 mmol) was added to a mixture of Example 256 (300 mg, 0.66 mmol) in THF (10 mL) and water (10 mL) and the reaction mixture was stirred at room temperature for 3 h. The THF was removed in vacuo and the aqueous phase was diluted with water (10 mL), washed with EtOAc (20 mL) and acidified to pH 2 with 2M aqueous HCl. The aqueous phase was extracted with EtOAc (50 mL) and the organic phase was dried (magnesium sulfate) and the solvent was removed in vacuo to give the title compound (204 mg, 72%) as a yellow solid. δH (CDCl3) 9.04 (1H, br s), 7.77-7.74 (1H, m), 7.59-7.47 (2H, m), 7.28-7.25 (1H, m), 3.72-3.66 (4H, m), 3.04-2.98 (4H, m), 2.51 (2H, s), 2.47 (2H, s), 1.06 (6H, s). LCMS (ES+) 429.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.[CH:16]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][N:18]([CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH2:17]2.[Cl-].[NH4+]>>[CH:20]12[CH2:23][CH2:24][CH:16]([CH2:22][CH2:21]1)[CH2:17][N:18]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:2]1[N:3]=[N:4][C:5]([CH3:15])=[C:6]3[N:14]4[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]4)=[CH:8][C:7]=13)[CH2:19]2
Reactant: Cc1nnc(Cl)c2cc3ccccn3c12
Reactant: NCCCCN1CC2CCC(CC2)C1
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1nnc(NCCCCN2CC3CCC(CC3)C2)c2cc3ccccn3c12

Procedure:
Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine, three equivalents of 4-(3-azabicyclo[3.2.2]non-3-yl)butylamine and one equivalent of ammonium chloride at 145° C. under nitrogen overnight gave the title compound as the free base after flash column chromatography (silica gel, 4:1 methylene chloride:methanol to 100% methanol containing ammonium hydroxide). This was converted to the dihydrochloride salt and recrystallized from ethanol, mp 257°-258° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][NH:27]1>CN(C=O)C>[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][N:27]1[C:16]1[C:17]([F:19])=[C:18]2[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]2[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:14][C:15]=1[F:21]
Reactant: c1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(N3Cc4ccccc4C3)c(F)cc2c1=O
Yield: 33.4 %

Procedure:
178 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 179 mg of isoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 76 mg of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:37])C(=O)C1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:37])[NH:12][C:11]([C:21]2[S:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][N:25]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(C)NC(c2ncc(C(F)(F)F)s2)=NC1c1ccc(F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)C1=C(CBr)NC(c2ncc(C(F)(F)F)s2)=NC1c1ccc(F)cc1Br
Yield: 72.8 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(5-(trifluoromethyl)thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.44 g, 0.89 mmol) was reacted with NBS (0.17 g, 0.94 mmol) in DCM (30 mL) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.37 g, 72%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]#[N:15])[C:8]=2[N:7]=[C:6]1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23].C(N(CC)CC)C.[NH2:36][OH:37]>C(O)C>[OH:37][NH:36][C:14]([C:13]1[C:8]2[N:7]=[C:6]([C:16]3[C:17]([F:23])=[CH:18][CH:19]=[CH:20][C:21]=3[F:22])[N:5]([CH2:4][C:3]3[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:2]=3[F:1])[C:9]=2[CH:10]=[CH:11][CH:12]=1)=[NH:15]
Reactant: NO
Reactant: N#Cc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: CCO
Product: N=C(NO)c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 87.3 %

Procedure:
To 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carbonitrile (Example 105) (0.60 g, 1.57 mmol) dissolved in ethanol (15 mL) and triethylamine (0.5 mL) was added hydroxylamine (0.14 g, 130 M%). After 24 h at reflux, the reaction was concentrated. The residue was redissolved in CH2Cl2 and washed with NaHSO4(10% soln), NaHCO3 (sat. aq) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with 4% methanol/CH2Cl2 and recrystallization from methanol, yielding white crystals of N-hydroxy 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carboxamidine (0.57 g, 1.37 mmol, 87% yield). M.p. 214-216° C. 1H NMR (200 MHz, CD2Cl2): δ7.84 (dd, J=1.1, 7.7 Hz, 1H, H5), 7.57 (m, 1H, H4′), 7.54 (dd, J=1.1, 8.2 Hz, 11H, H7), 7.30 (dd, J=7.7, 8.2 Hz, 1H, H6), 7.28 (m, 1H, H4″), 7.11 (m, 2H, H3′,5′), 6.83 (m, 2H, H3″,5″), 6.61 (br, 2H, NH2), 5.39 (s, 2H, CH2PhF2).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20]([F:32])([F:33])[F:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccccc3C(F)(F)F)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27](OC)=O.Cl>C(O)C.O>[CH:2]1([N:7]2[C:11]3=[N:12][C:27]([CH2:26][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[O:19][CH3:18])=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: COC(=O)Cc1ccccc1OC
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccccc3OC)nc(=O)c1-2
Yield: 52.7 %

Procedure:
Sodium (590 mg) was dissolved in ethanol (45 mL) and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.65 g, 12 mmol), followed by methyl 2-methoxyphenylacetate (4.7 g, 26 mmol) were added. The reaction mixture was refluxed overnight, the solvent was stripped and the residue was treated with water and then 2N HCl. The product was collected by filtration and recrystallized from ethyl acetate to afford 2.23 g of 1-cyclopentyl-3-ethyl-6-(2-methoxyphenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 145°-146° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:16]([F:29])[CH:15]=1)[C:10](=[O:12])[CH3:11].BrC1C=C[C:34]([O:37]C)=[CH:33]C=1N(CC1C=CC(OCCN2CCCCC2)=C(F)C=1)C(=O)C.C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:10]([N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:16]([F:29])[CH:15]=1)[C:3]1[CH:4]=[C:5]([O:8][C:34](=[O:37])[CH3:33])[CH:6]=[CH:7][C:2]=1[Br:1])(=[O:12])[CH3:11]
Reactant: COc1ccc(Br)c(N(Cc2ccc(OCCN3CCCCC3)c(F)c2)C(C)=O)c1
Reactant: CC(=O)N(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(O)ccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(Br)c(N(Cc2ccc(OCCN3CCCCC3)c(F)c2)C(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the total amount of N-(2-bromo-5-hydroxyphenyl)-N-[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]acetamide crude product, which was synthesized from N-(2-bromo-5-methoxyphenyl)-N-[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]acetamide (380 mg) synthesized according to an analogous synthetic method to Example 364 described below, were added pyridine (2 ml) and acetic anhydride (2 ml), and the solution was stirred for 1 hour at room temperature. To the reaction mixture was added a saturated aqueous solution of sodium bicarbonate, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-methanol system) to provide the title compound (350 mg).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].C[O-].[Na+].[Cl:10][C:11]1[CH:30]=[CH:29][C:14]([C:15]([C:17]2[C:26]([Cl:27])=[CH:25][C:20]([CH2:21][N:22]=[N+:23]=[N-:24])=[CH:19][C:18]=2[Cl:28])=[O:16])=[CH:13][CH:12]=1>C(O)C>[NH2:2][C:1]1[N:22]([CH2:21][C:20]2[CH:19]=[C:18]([Cl:28])[C:17]([C:15](=[O:16])[C:14]3[CH:29]=[CH:30][C:11]([Cl:10])=[CH:12][CH:13]=3)=[C:26]([Cl:27])[CH:25]=2)[N:23]=[N:24][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: N#CCC(N)=O
Reactant: [N-]=[N+]=NCc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1nnn(Cc2cc(Cl)c(C(=O)c3ccc(Cl)cc3)c(Cl)c2)c1N
Yield: 41.2 %

Procedure:
A suspension of 2-cyanoacetamide (149 mg, 1.77 mmol) in ethanol (5 ml) was refluxed 20 minutes with sodium methoxide (93 mg, 1.72 mmol), cooled slightly, treated with 4-(4-chlorobenzoyl)-3,5-dichlorobenzyl azide (450 mg, 1.32 mmol), and refluxed 1 hour. The mixture was cooled, evaporated under vacuum, and chromatographed on a column of silica gel (50 g), eluted with 19:1 (v/v) dichloromethane-methanol to provide 231 mg (41%) of 5-amino-1(4-[4-chlorobenzoyl]-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide, m.p. 198.5°-200° C.
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:14](=[O:29])[CH:15](Br)[C:16]1[C:17]([CH:22](Br)[C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:19]=[CH:20][CH:21]=1>C1C=CC=CC=1>[CH3:26][O:25][C:23]([CH:22]1[C:17]2[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]2[C:14](=[O:29])[N:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:9][CH2:10][N:11]12)=[O:24]
Reactant: COC(=O)C(Br)c1ccccc1C(Br)C(=O)OC
Reactant: NCCNCc1ccccc1
Solvent: c1ccccc1
Product: COC(=O)C1c2ccccc2C2C(=O)N(Cc3ccccc3)CCN12

Procedure:
N-(Phenylmethyl)ethylene diamine (10.38 g) is added dropwise to a solution of α,α'-dibromo-1,2-benzenediacetic acid dimethyl ester [24 g, described by G. Cignarella and A. Vigevani, Gazz. Chim. Ital., 98, 1474 (1968)] in benzene (600 ml). The mixture is refluxed for 6 hr, cooled and filtered. The filtrate is evaporated and the residue is chromatographed on silica gel using diethyl ether-methanol (9:1). The appropriate fractions are evaporated to give isomer A (5.7 g) of the title compound, nmr (CDCl3) δ3.3(m), 3.8(s), 4.6(d), 4.92(d), 5.30(d) and 7.3-7.8(m). The eluant for the above chromatography is changed to methanol-diethyl ether (3:7) and the appropriate eluate fractions are evaporated to give isomer B (4.1 g) of the title compound, nmr (CDCl3) δ3.3(m), 3.8(s), 4.6(d), 4.92(d), 5.30(d) and 7.3-7.8(m).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[NH2:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>O1CCOCC1.O>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:26][CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: NCc1cccnc1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: C1COCCO1
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(NCc2cccnc2)nc(N2CCOCC2)n1
Yield: 59.3 %

Procedure:
A stirred mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (0.183 g, 0.5 mmol) and 3-aminomethylpyridine (0.135 g, 1.25 mmol) in 10 mL dioxane was heated under gentle reflux for 5 min. After cooling, the mixture was diluted with water to give an oily solid, which was recrystallized from MeOH to give 0.13 g (59% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(3-pyridinylmethyl)-1,3,5-triazin-2-amine: mp 160-161° C.; 1H NMR (CDCl3) (rotamers) δ 8.61 (d, J=4.4 Hz, 1H), 8.42 and 8.32 (2d, J=7.6 and 8.4 Hz, 1H), 7.89-7.87 (m, 1H), 7.70 (dt, J=7.7, 1.65 Hz, 1H), 7.65 and 7.59 (2t, JHF=53.7 and 53.5 Hz, 1H), 7.43-7.37 (m, 2H), 7.34 (br t, J=8.7 Hz, 1H), 7.24 (br t, J=6.2 Hz, 1H), 6.55 and 6.41 (2 m, exchangeable with D2O, 1H), 4.82 and 4.78 (2 d, J=5.3 and 5.1 Hz, 2H), 3.88 (m, 4H), 3.78 (m, 4H); Anal. Calcd. for C21H20F2N8O: C, 57.5; H, 4.6; N, 25.6. Found: C, 57.7; H, 4.5; N, 25.7%.
Reaction SMILES: C(=O)(O)[O-].[Na+].[OH:6][C@H:7]1[CH2:11][NH:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8]1.[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.C1(C)C=CC=CC=1>[CH2:15]([O:22][C:23]([N:10]1[CH2:11][C@H:7]([OH:6])[CH2:8][C@H:9]1[C:12]([OH:14])=[O:13])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 28 °C
Reaction time: 3 h

Procedure:
Sodium bicarbonate (131.04 g) was dissolved in water (1040 ml), and trans-4-hydroxy-L-proline (78.6 g) was added thereto. To the resultant mixture, a solution of benzyloxycarbonyl chloride (72 ml) in dry toluene (320 ml) was added, and the mixture was stirred at an inner temperature of 28° C. for 3 hours. Sodium bicarbonate (65.52 g) and benzyloxycarbonyl chloride (72 ml) were additionally added thereto, and stirring was continued at the same temperature for 2 hours. The reaction mixture was washed with ether, and the aqueous layer was filtered. The filtrate was washed again with ether. The aqueous layer was adjusted to pH 1 with 6N hydrochloric acid and extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution, dried over sodium sulfate and concentrated to remove the solvent to give trans-1-benzyloxycarbonyl-4-hydroxy-L-proline.