Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[N:2]1.[C:11](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:11]([N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[N:2]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1c[nH]nn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nn1
Yield: 88.8 %

Procedure:
3.47 g of ethyl 1,2,3-triazole-4-carboxylate and 7.55 g of trityl chloride were dissolved in 100 ml of chloroform and 3.77 ml of triethylamine was added dropwise thereto under stirring and cooling in an ice-bath. The resulting mixture was stirred for 30 minutes at room temperature. Chloroform was distilled off and the residue was dissolved in ethyl acetate and the mixture was washed with an aqueous solution of sodium chloride and then dried with sodium sulfate. Ethyl acetate was distilled off and the residue was purified by silica gel column chromatography with benzene and chloroform eluent to give 8.37 g of ethyl N-trityl-1,2,3-triazole-4-carboxylate with mp 201°-203° C.
Reaction SMILES: Br[CH:2]([CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[N:19]1([CH:2]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: c1nc[nH]n1
Reactant: CC(c1ccccc1)C(Br)C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(c1ccccc1)C(C(=O)c1ccccc1)n1cncn1
Temperature: 25 °C

Procedure:
2-Bromo-3-phenyl-butyrophenone (0.02 mol), 1,2,4-triazole (0.02 mol) and potassium carbonate (0.04 mol) were refluxed in methyl ethyl ketone (100 ml) for 36 hours. After cooling to room temperature, the solution was filtered and the solvent removed in vacuo. Recrystallisation of the residue from ethanol/petroleum ether (60°-80°) gave the title compound as a colourless solid, m.p. 166°-8°.
Reaction SMILES: [C:1]([NH:4][C:5](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[H][H]>>[C:1]([NH:4][C@H:5]([C:6]([OH:8])=[O:7])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC(=Cc1ccc(O)c(O)c1)C(=O)O
Reactant: [H][H]
Product: CC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O

Procedure:
reacting α-acetamido-3,4-dihydroxycinnamic acid with hydrogen in the presence of a catalytic amount of a chiral hyrogenation catalyst of the formula ##STR36## to produce N-acetyl-3,4-dihydroxy-L-phenylalanine; and (b) hydrolyzing the N-acetyl-3,4-dihydroxy-L-phenylalanine to produce 3,4-dihydroxy-L-phenylalanine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][CH2:35][CH:36]4CC4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[CH3:39][O:40]CCN>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][CH2:35][CH2:36][O:40][CH3:39])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1
Reactant: COCCN
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNCC2CC2)CC1
Product: COCCNCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using 2-methoxyethylamine instead of cyclopropylmethylamine. LC-MS: (M+1=533, obsd.=533).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:18][CH2:17][CH2:16][N:15]([C:19](=[O:23])[CH2:20][C:21]#[N:22])[C:14]=3[CH:24]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:26](N)[CH2:27][NH2:28]>>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:18][CH2:17][CH2:16][N:15]([C:19](=[O:23])[CH2:20][C:21]4[NH:28][CH2:27][CH2:26][N:22]=4)[C:14]=3[CH:24]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCN
Reactant: N#CCC(=O)N1CCOc2ccc(S(=O)(=O)c3ccccc3)cc21
Agent: Cl
Product: O=C(CC1=NCCN1)N1CCOc2ccc(S(=O)(=O)c3ccccc3)cc21

Procedure:
1-(6-Benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-2-(4,5-dihydro-1H-imidazol-2-yl)-ethanone was prepared by treatment of 3-(6-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-3-oxo-propionitrile with HCl followed by ethylene diamine using the procedure described in Example 2. mp: 114-116.1° C.
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30]CC)=[O:29])=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(O)C.[OH-].[Na+].Cl>O>[CH2:1]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:33][CH:34]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1

Procedure:
To a solution of docosyl bromide (25 g, 0.064 mol), potassium carbonate (9.0 g) and sodium iodide (9.6 g) in acetone (150 ml), ethyl p-hydroxybenzoate (10.2 g, 0.061 mol) was added, and then reacted for 12 h under reflux with stirring. After cooling, the reaction mixture was filtered to remove inorganic materials, taken up in H2O (500 ml), and extracted with CH2Cl2 (3×100 ml). The organic layer was separated, washed with H2O, dried over MgSO4, and evaporated to dryness. The resultant residue was recrystallized from ethyl acetate to give ethyl 4-docosyloxybenzoate (27 g) as a white crystals; mp 56.5°-59.5° C. Then ethyl 4-docosyloxybenzoate (27 g) was stirred in H2O (120 ml) and ethanol (150 ml) containing sodium hydroxide (4.6 g) for 6 h under reflux. After cooling, the reaction mixture was acidified with hydrochloric acid, the resultant precipitate was filteted, washed with H2O and recrystallized from acetic acid to give the title compound as a white needles; yield: 18.5 g (72.7%); mp 99.0°-101.5° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.[H-].[Na+].Br[CH2:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:19])=[CH:16][C:15]=1[O:33][CH3:34]>CN(C)C=O>[CH:26]1([N:20]([CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:18](=[O:19])[C:17]2[CH:31]=[CH:32][C:14]([CH2:13][N:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2][N:3]=[C:4]34)=[C:15]([O:33][CH3:34])[CH:16]=2)[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: COc1cc(C(=O)N(C2CCCC2)C2CCCC2)ccc1CBr
Reactant: c1cnc2nc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N(C2CCCC2)C2CCCC2)ccc1Cn1cccc2ncnc1-2
Reaction time: 2 h

Procedure:
To a stirred solution of imidazo[4,5-b]pyridine (350 mg, 2.94 mmol) in N,N-dimethylformamide (25 mL), sodium hydride (118 mg, 60% dispersion in mineral oil, 2.94 mmol) was added. After stirring for 2 hr, 4-bromomethyl-3-methoxy-N,N-dicyclopentyl benzamide (1.4 g, 3.57 mmol) was added in small installments over 10 min. The reaction mixture was stirred under argon at 25° C. After 18h, the reaction was quenched by adding acetic acid (0.5 mL) and the solvent was removed under reduced pressure at <45° C. The crude mixture (2 g) was chromatographed (silica gel, CH2Cl2 -MeOH-NH4OH 90-10-1) to give the title compound. (145 mg, 12%) mp 223°-224° C.; Anal calcd. for C25H30N4O2.1.0H2O: C, 68.78; H, 7.39; N, 12.83. Found C, 68.88; H, 7.13; N, 12.55.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[CH:22][N:21]=1>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:22][N:21]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2ccnc(F)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (51 mg, 64%), MS (ISP) m/z=321.4 [(M+H)+], mp 275° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 2-fluoro-pyridin-4-ylboronic acid (45.8 mg, 0.325 mmol).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[N:5]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:4]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][N:5]2[C:6]([C:8]3[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=3)=[CH:7][C:3]([CH2:2][N:27]3[CH2:32][CH2:31][N:30]([CH2:2][C:3]4[CH:7]=[C:6]([C:8]5[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=5)[N:5]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)[N:4]=4)[CH2:29][CH2:28]3)=[N:4]2)[CH:22]=1
Reactant: C1CNCCN1
Reactant: COc1cc(-c2cc(CCl)nn2Cc2cccnc2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)n(Cc5cccnc5)n4)CC3)nn2Cc2cccnc2)cc(OC)c1OC

Procedure:
3-Chloromethyl-1-(3-pyridylmethyl) -5-(3,4,5-trimethoxyphenyl)pyrazole (110 mg) and piperazine (12 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH:19]=[N:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[C:13]=3[CH:14]=[N:15][CH:16]=2)=[O:10])=[CH:5][N:6]=1.[CH3:27][O-:28].[Na+].CO>CS(C)=O>[CH3:27][O:28][C:2]1[S:3][C:4]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH:19]=[N:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[C:13]=3[CH:14]=[N:15][CH:16]=2)=[O:10])=[CH:5][N:6]=1
Reactant: O=C(NCc1cnc(Br)s1)c1cncc2c1cnn2-c1ccc(F)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: COc1ncc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)s1
Temperature: 50 °C

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (2-bromo-thiazol-5-ylmethyl)-amide (30 mg, 0.07 mmol) in DMSO (5 mL) was added a 0.5 M solution of NaOMe in MeOH (2.0 mL, 1.0 mmol). The solution was warmed at 50° C. and after 48 hours, was partitioned between saturated aqueous sodium bicarbonate (50 mL) and EtOAc (50 mL). The organic phase was separated and washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane. The material was further purified by preparative thin layer silica gel chromatography eluting with methanol-dichloromethane (2:98) to afford the title compound.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:15]=[CH:14][S:13][N:12]=1)([O-:3])=[O:2].[CH2:18]([NH2:20])[CH3:19]>>[N+:1]([CH:4]=[C:5]([NH:20][CH2:18][CH3:19])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:15]=[CH:14][S:13][N:12]=1)([O-:3])=[O:2]
Reactant: CCN
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1ccsn1
Product: CCNC(=C[N+](=O)[O-])NCCSCc1ccsn1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-(3isothiazolylmethylthio)ethylamino]ethylene (see Example 72(ii)) with ethylamine by the procedure of Example 8(ii) gives the title product.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C[O:9][C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=O>>[CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:10]([C:12]2[C:16]([NH:17][C:18]([C:20]3[C:25]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[N:31][CH:32]=4)=[CH:24][CH:23]=[C:22]([CH:33]4[CH2:35][CH2:34]4)[N:21]=3)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=2)=[O:9])[CH2:4]1
Reactant: COC1CCNC1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: COC1CCN(C(=O)c2nn(C)cc2NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)C1
Yield: 23 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 3-methoxypyrrolidine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (23%) as amorphous yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22]C)=[O:21].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:16][C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([OH:22])=[O:21])(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Temperature: 25 °C
Yield: 28 %

Procedure:
A solution of 5-chloro-3-methylbenzothiophene-2-sulfonyl chloride (200 mg, 0.711 mmol) in CH2Cl2 (5 mL) was added to a mixture of methyl 3-aminobenzoate (107 mg, 0.711 mmol) and pyridine (1 mL) in CH2Cl2 (5 mL). The reaction mixture was stirred at room temperature over night. The solvent was evaporated and the crude methyl 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate (100 mg) was slurried in water (4 mL). LiOH (300 mg) was added and the mixture was stirred at room temperature for 2 h. The reaction was acidified by aqueous 2 M HCl and the white precipitate was collected by filtration, washed with CH2Cl2 (5 mL) and dried. The title compound was obtained in 28% yield (75 mg, over two steps). MS (ESI+) calcd for C16H12ClNO4S2 380.989627, found 380.989527.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[CH2:4].[Cl:12][C:13]1[CH:14]=[C:15]([OH:21])[C:16](=[CH:19][CH:20]=1)[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[C:15]([O:21][CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)=[CH2:4])[CH:14]=1
Reactant: C=C(CBr)c1ccc(Cl)cc1
Reactant: O=Cc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(COc1cc(Cl)ccc1C=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 106.8 %

Procedure:
A mixture of 19.2 g (0.083 mol) of the product from Step A, 10.0 g (0.064 mol) of 4-chlorosalicylaldehyde, 17.6 g (0.13 mol) of potassium carbonate and 64 mL of DMF was stirred at RT for 72 h. Resulting mixture treated with 125 mL of H2O and filtered. Solids were washed with several portions of H2O and dried in a vacuum oven at 40° C. to give 21.0 g of a brown solid. 1H NMR (CDCl3, 200 MHz) δ4.99 (s, 2H), 5.51 (s, 1H), 5.65 (s, 1H), 7.04-7.07 (m, 2H), 7.25-7.45 (m, 4H), 7.77 (d, 1H), 10.28 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:3]12.[CH2:32]([N:34](C(C)C)C(C)C)C.Cl.CN>CN(C=O)C>[CH3:32][NH:34][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[N:20][CH:21]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
(S)-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (75 mg, 0.178 mmol) was taken up in DMF (0.9 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (93 μl, 0.53 mmol), O-(7-Azabenzotriazole-1-yl)-N, N,N′N′-tetramethyluronium hexafluorophosphate (101 mg, 0.266 mmol), and methanamine hydrochloride (13.2 mg, 0.195 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (10-80 MeCN/H2O, TFA buffered). The fractions were collected and lyophilized to yield 23.8 mg (30%) of the product as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.48 (s, 1H), 8.56 (d, J=2.3 Hz, 1H), 8.20 (d, J=4.5 Hz, 1H), 7.92 (dd, J=9.0, 2.1 Hz, 1H), 7.65 (s, 1H), 6.98 (d, J=1.5 Hz, 1H), 6.82 (d, J=8.8 Hz, 1H), 4.50 (d, J=12.9 Hz, 1H), 3.77-3.94 (m, 1H), 3.56 (d, J=2.3 Hz, 4H), 3.34 (s, 2H), 2.74 (d, J=4.5 Hz, 3H), 2.53-2.69 (m, 1H), 2.41 (br. s., 4H), 1.99-2.08 (m, 1H), 1.84 (br. s., 1H), 1.59-1.69 (m, 1H), 1.31-1.57 (m, 3H). [M+H] calc'd for C25H33N7O2, 436. found, 436.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:29])=[C:6]([Cl:28])[C:7]([Cl:27])=[C:8]([CH:26]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([S:18]([N:21]=[CH:22][N:23]([CH3:25])[CH3:24])(=[O:20])=[O:19])[CH:12]=1)=[O:10])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:38])C=1>C(Cl)Cl>[Cl:27][C:7]1[C:8]([C:9](=[O:10])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([S:18]([N:21]=[CH:22][N:23]([CH3:24])[CH3:25])(=[O:19])=[O:20])[CH:12]=2)=[CH:26][C:4]2[CH2:1][CH:2]([CH2:3][OH:38])[O:29][C:5]=2[C:6]=1[Cl:28]
Reactant: C=CCc1cc(C(=O)c2ccc(Cl)c(S(=O)(=O)N=CN(C)C)c2)c(Cl)c(Cl)c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CN(C)C=NS(=O)(=O)c1cc(C(=O)c2cc3c(c(Cl)c2Cl)OC(CO)C3)ccc1Cl
Temperature: 35 °C
Reaction time: 1 h

Procedure:
14.7 g (31 mmol) of 5-allyl-4-hydroxy-3'-dimethylaminomethyleneaminosulfonyl-2,3,4'-trichlorobenzophenone are suspended, with exclusion of moisture, in 60 ml of methylene chloride and, while cooling in an icebath, a solution of 7.4 g (43 mmol) of 90% pure metachloroperbenzoic acid in 60 ml of methylene chloride is added dropwise. The mixture is stirred for about one hour in the icebath and then briefly heated to 35° to 40° C., whereupon a clear solution is obtained. After allowing to stand at room temperature overnight, a further 0.7 g of metachloroperbenzoic acid is added, the mixture is stirred at room temperature for 4 hours and then again heated to 35° C. The precipitate is filtered off, washed twice with 10 ml of methylene chloride each time, and then washed several times with aqueous sodium bicarbonate solution until the reaction is alkaline. The organic phase is dried over sodium sulfate, the solvent is distilled off, and the amorphous product is purified by chromatography on silica gel using toluene/ethyl acetate (3:1 to 1:3). After distilling off the solvent and recrystallizing from a little methanol, colorless crystals of melting point 180°-182° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:22][CH2:21]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:18][CH3:19])[CH:12]=3)[C:3]=12.[CH3:36][C:37]1[O:43][C:40]([CH:41]=O)=[CH:39][CH:38]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:27])[CH2:22][CH2:21]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][CH2:41][C:40]4[O:43][C:37]([CH3:36])=[CH:38][CH:39]=4)=[C:13]([O:18][CH3:19])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C3CCN(C(=O)OCc4ccccc4)CC3)c3ncnc(N)c23)ccc1N
Reactant: Cc1ccc(C=O)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(-c2nn(C3CCN(C(=O)OCc4ccccc4)CC3)c3ncnc(N)c23)ccc1NCc1ccc(C)o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
A mixture of benzyl 4-[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (3.0 g, 0.0063 mol), 5-methylfurfural (0.77 g, 0.007 mol), and acetic acid (1.15 g, 0.019 mol) in dichloroethane (100 mL) was stirred at room temperature under an atmosphere of nitrogen for 1.5 hrs. Sodium triacetoxyborohydride (4.1 g, 0.0195 mol) was added to the mixture and the mixture was stirred at ambient temperature under an atmosphere of nitrogen for 18 hours. The reaction was quenched with an aqueous 5N solution of sodium hydroxide. The solvents were removed under reduced pressure, and the residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (3×200 mL), and the combined organic layer was washed with water and brine, and dried over magnesium sulfate. The solvents were removed under reduced pressure. The residue was purified by flash chromatography on silica gel using 2%-5% methanol/dichloromethane as mobile phase to yield benzyl 4-[4-amino-3-(3-methoxy-4-{[(5-methyl-2-furyl)methyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (2.63 g, 0.0046 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-95% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 11.59 min. MS: MH+ 568.
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:17](=[O:18])[C:16](=[C:19]([CH3:21])[CH3:20])[O:15][C:14]2=[O:22])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:32][CH:33]=[CH:34][CH3:35]>CN(C)C=O.O>[F:1][C:2]1[C:12]([N:13]2[C:17](=[O:18])[C:16](=[C:19]([CH3:20])[CH3:21])[O:15][C:14]2=[O:22])=[CH:11][C:5]2[N:6]([CH2:32][CH:33]=[CH:34][CH3:35])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CC(C)=C1OC(=O)N(c2cc3c(cc2F)OCC(=O)N3)C1=O
Reactant: CC=CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC=CCN1C(=O)COc2cc(F)c(N3C(=O)OC(=C(C)C)C3=O)cc21
Temperature: 70 °C

Procedure:
To a solution of 3-[7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl]-5-isopropylidene-1,3-oxazolidine-2,4-dione (1.1 g), potassium carbonate (0.3 g) and potassium iodide (0.1 g) in N,N-dimethylformamide (50 ml), 1-bromo-2-butene (0.5 g) was added, followed by heating at 70° C. for 4 hours. The reaction mixture was allowed to cool, combined with water and extracted with ethyl acetate. The organic layer was purified by silica gel column chromatography to give Compound No. 8 (1.0 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16]2=[O:26])=[C:9]([Cl:27])[CH:8]=1)(=O)=O.[F:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([F:39])[C:32]=1B(O)O>>[CH:20]1([N:17]2[CH2:18][CH2:19][CH:15]([CH2:14][C:10]3[C:11]([Cl:13])=[CH:12][C:7]([C:32]4[C:31]([F:30])=[CH:36][C:35]([O:37][CH3:38])=[CH:34][C:33]=4[F:39])=[CH:8][C:9]=3[Cl:27])[C:16]2=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: COc1cc(F)c(B(O)O)c(F)c1
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
Product: COc1cc(F)c(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)c(F)c1
Yield: 105.5 %

Procedure:
Using the procedure to synthesize Example 81 and using reagents 3,5-dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate (Example 240) (500 mg, 1.0 mmol) and 2,6-difluoro-4-methoxyphenylboronic acid (590 mg, 3.2 mmol) affords 494 mg (100%) of 1-Cyclohexyl-3-(3,5-dichloro-2′,6′-difluoro-4′-methoxy-biphenyl-4-ylmethyl)-pyrrolidin-2-one. Charge a flask with 1-cyclohexyl-3-(3,5-dichloro-2′,6′-difluoro-4′-methoxy-biphenyl-4-ylmethyl)-pyrrolidin-2-one (500 mg, 1.1 mmol), dissolve in dry methylene chloride (10 mL) and cool to 0° C. under nitrogen. Add BBr3 (0.25 mL, 2.7 mmol) and stir at 0° C. for 1.5 hours. Pour into saturated aqueous sodium bicarbonate and extract with methylene chloride. Dry over sodium sulfate, filter and concentrate in vacuo to yield 470 mg (97%) of the title compound.