Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH2:4][C@H:5]([CH2:21][OH:22])[N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]2.C(N(CC)CC)C>CS(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH2:4][C@H:5]([CH:21]=[O:22])[N:6]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:7]2
Reactant: COc1ccc(Br)c2c1CN(C(=O)OC(C)(C)C)[C@@H](CO)C2
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(Br)c2c1CN(C(=O)OC(C)(C)C)[C@@H](C=O)C2
Temperature: 0 °C
Yield: 97.7 %

Procedure:
Dissolve the tert-butyl 5-bromo-3(R)-(hydroxymethyl)-8-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (710 mg, 0.0019 mol) in dimethylsulfoxide (2.00 mL) and cool to 0° C. Add triethylamine (1.06 mL, 0.00763 mol) and sulfur trioxide-pyridine complex (0.607 g, 0.00381 mol). Warm to room temperature over one hour. Dilute diethyl ether (100 mL) and extract (3×25 mL) with 5% aqueous citric acid, (1×25 mL) saturated aqueous sodium chloride, and dry over magnesium sulfate. Concentrate the filtrate to give the desired product (687 mg, 94%) as an off-white semi-solid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([OH:12])=O)[C:4]=2[NH:3][CH:2]=1.S(Cl)([Cl:15])=O>>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([Cl:15])=[O:12])[C:4]=2[NH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc2nc[nH]c12
Product: O=C(Cl)c1cccc2nc[nH]c12

Procedure:
The above reaction conditions are as follows: benzimidazole-4-carboxylic acid is reated with thionyl chloride at temperature of 0˜80° C. in a molar molecular ratio of thionyl chloride to benzimidazole-4-carboxylic acid is 1˜20 times, to produce benzimidazole-4-carbonyl chloride, and then benzimidazole-4-carbonyl chloride is reacted with an amine in an organic solvent at temperature of 0˜100° C. to produce benzimidazole-4-carboxamide derivatives. Wherein the organic solvent comprises dichloroethane, 1,1,2-trichloroethane, chloroform, tetrachloroethylene, benzene, toluene, xylene, chlorobenzene or dichlorobenzene, and so on.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[S:20][C:19]([C:21]([O:23]C)=O)=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[N:26]1([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.C[Al](C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[S:20][C:19]([C:21]([N:36]3[CH2:35][CH2:34][N:33]([CH2:32][CH2:31][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)[CH2:38][CH2:37]3)=[O:23])=[N:18][N:17]=2)(=[O:11])=[O:12])=[C:5]([CH3:25])[CH:4]=1
Reactant: C1CCN(CCN2CCNCC2)C1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)s1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(CCN4CCCC4)CC3)s2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BK using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-thiadiazole-2-carboxylate (125 mg, 0.32 mmol), 1-(2-pyrrolidin-1-yl-ethyl)-piperazine (71 mg, 0.39 mmol), trimethylaluminium (2 M in toluene, 0.35 mL) and THF (10 mL).
Reaction SMILES: [CH3:1][C:2]1[NH:13][C:12](=O)[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:12]1[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=[C:2]([CH3:1])[N:13]=1
Reactant: CSc1ncc2cc(C)[nH]c(=O)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1ncc2cc(C)nc(Cl)c2n1
Yield: 52 %

Procedure:
A solution of 6-methyl-2-(methythio)pyrido[3,4-d]pyrimidin-8(7H)-one (Preparation 51, 100 mg, 0.483 mmol) in POCl3 (5 mL) was heated to 70° C. for 1 hour. The reaction mixture was concentrated in vacuo. The residue was partitioned between EtOAc (30 mL) and washed with water (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-20% EtOAc in cyclohexane to give the title compound (28.4 mg, 52%).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)c1cc(Br)oc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2OC)oc1C
Reaction time: 8 h
Yield: 93 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.2 g), 2-methoxyphenylboronic acid (1.8 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.3 g, 92%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.Cl.[CH2:20]([N:22]([CH2:32][CH3:33])[C:23]1[CH:31]=[CH:30][C:26]([CH2:27][NH:28][NH2:29])=[CH:25][CH:24]=1)[CH3:21].C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:28]([CH2:27][C:26]2[CH:30]=[CH:31][C:23]([N:22]([CH2:32][CH3:33])[CH2:20][CH3:21])=[CH:24][CH:25]=2)[N:29]=1
Reactant: CCN(CC)c1ccc(CNN)cc1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(Cn2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1

Procedure:
5.0 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one are boiled under reflux for 18 h with 5.4 g of 4-diethylaminobenzylhydrazine hydrochloride and 6.7 ml of triethylamine in 50 ml of ethanol. The mixture is poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, 3,5-bis(2-hydroxyphenyl)-1-(4-diethylaminobenzyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 125-127° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:13][CH2:14][N:15]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[C:16](=O)[CH3:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC>[CH2:16]([N:15]([CH2:14][CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[CH:21][CH:20]=1)[CH3:17]
Reactant: CC(=O)N(CCc1ccccc1)c1ccnc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCN(CCc1ccccc1)c1ccnc2ccccc12
Yield: 36.5 %

Procedure:
To a suspension of 0.59 g of lithium aluminum hydride in 100 mL of dry ether was added, dropwise, a solution of 2.3 g of N-(2-phenylethyl)-N-(4-quinolinyl)acetamide dissolved in 50 mL of dry ether. The mixture was heated to reflux for seven hours. Excess lithium aluminum hydride was then destroyed by adding 100 mL of water to the mixture. The solvent was then removed, and the residue was dissolved in chloroform. After washing with water, the mixture was then dried and concentrated. Using HPLC (silica gel, CH2Cl2 →EtOAc), 0.80 g of the title product was isolated. Yield 36.7%. M.P. oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:5](=[O:8])[CH2:6]Br.C(=O)(O)[O-].[Na+].[SH:18][C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21]>C1COCC1.O.C(OCC)C.Cl>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:8])[CH2:6][S:18][C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])[CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: CC(C)(S)C(=O)O
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(SCC(=O)c1cc(F)cc(F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,5-difluorophenacyl bromide (845 mg, 3.60 mmol) in THF (12 mL) and water (12 mL) was added sodium bicarbonate (317 mg, 3.78 mmol) and 2-mercaptoisobutyric acid (432 mg, 3.60 mmol). The reaction mixture was allowed to stir at ambient temperature for 1.0 h under a stream of nitrogen. The reaction mixture was diluted with diethyl ether (50 mL) and 1 M HCl (15 mL). The organic layer was then washed with 20 mL saturated brine. The organics were then dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound, which was used without further purification. MS: m/z=229 (M−CO2H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[I-:36].[Na+].I.C(=O)(O)[O-].[Na+]>CC(C)C(=O)C.COC(C)(C)C>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([I:36])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: [I-]
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)C(C)C
Solvent: COC(C)(C)C
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(I)cc1-c1ccccc1Cl
Temperature: 80 °C
Yield: 74.5 %

Procedure:
A mixture of 250 mg (0.467 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide (Example 24), 250 mg (1.64 mmol) sodium iodide and 0.12 ml (0.99 mmol) hydroiodic acid (57% in water) in 5 ml 3-methyl-2-butanone was heated at 80° C. for 5 h in a sealed tube. After cooling to room temperature the mixture was diluted with tert-butyl methyl ether and treated with saturated aqueous sodium bicarbonate solution. The layers were separated, the organic layer washed with water, dried with magnesium sulfate and concentrated. Flash column chromatography gave 218 mg (48%) of the title compound as a light brown solid.
Reaction SMILES: [O:1]=[C:2]([CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[CH:3]=[CH:4]/[C@@H:5]1[C@@H:13]2[C@@H:8]([S:9][C@@H:10]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:12]2)[CH2:7][C@H:6]1[O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.CO>O1CCCC1.C(OCC)(=O)C>[OH:1][C@@H:2]([CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[CH:3]=[CH:4]/[C@@H:5]1[C@@H:13]2[C@@H:8]([S:9][C@@H:10]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:12]2)[CH2:7][C@H:6]1[O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1
Reactant: COC(=O)CCC[C@H]1CC[C@@H]2[C@@H](/C=C/C(=O)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2S1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCC[C@H]1CC[C@@H]2[C@@H](/C=C/[C@@H](O)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2S1
Reaction time: 0.17 h
Yield: 87.6 %

Procedure:
The compound 12 (250 mg) and (R)-2-methyl-CBS-oxazaborolidine (1M toluene solution; 0.135 mL) were dissolved in anhydrous tetrahydrofuran (1 mL), and a 1M borane-tetrahydrofuran complex (0.323 mL) was added at room temperature. The mixture was stirred for 10 minutes, methanol was then added, and the mixture was stirred for several minutes. This reaction liquid was diluted with ethyl acetate. This solution was washed with 1 M hydrochloric acid, water and a saturated saline, dried with anhydrous magnesium sulfate, and then concentrated to obtain a titled compound (220 mg) having the following physical property values.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[N:13]#[C:14]Br.C(=O)(O)[O-].[Na+].CCCCCC>O1CCOCC1>[NH2:13][C:14]1[O:6][C:5]([C:4]2[CH:9]=[C:10]([OH:12])[CH:11]=[C:2]([Br:1])[CH:3]=2)=[N:7][N:8]=1
Reactant: NNC(=O)c1cc(O)cc(Br)c1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCCCCC
Product: Nc1nnc(-c2cc(O)cc(Br)c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
3-Bromo-5-hydroxybenzohydrazide (400 mg, 1.04 mmol) was suspended in 5 ml dioxane. Cyanogen bromide (110 mg, 1.04 mmol) and sodium bicarbonate (4%, 1 ml, 12 mmol) were added and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and re-dissolved in ethyl acetate. The organic was washed with water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. The oil obtained was precipitate with hexane and filtered to give 126 mg (43% yield) of the title compound. Purity 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.ClC(Cl)(Cl)S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O.CCN(C(C)C)C(C)C>CN(C=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([CH2:41][C:42]([F:45])([F:44])[F:43])[CH2:19]4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCNC4)n3)c3cc(Cl)cnc32)cc1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCN(CC(F)(F)F)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-N-[(3S)-3-piperidyl]pyrimidin-4-amine, 1c, (0.17 g, 0.34 mmol) in DMF (1.5 mL) was added 2,2,2-trifluoroethyl trichloromethanesulfonate (0.19 g, 0.68 mmol), followed by iPr2NEt (0.24 mL, 1.36 mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was poured into brine and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) afforded the desired product, 3a, as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C>ClCCl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18]([O:20][CH3:21])=[O:19])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1sccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1sccc1NC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
A mixture of 4-cyanobenzoyl chloride (1.0500 g, 6.4 mmol), methyl 3-aminothiophenecarboxylate (1.0000 g, 6.4 mmol), and triethylamine (1 mL, 7.0 mmol) in dichloromethane was stirred at room temperature for 18 hours. The mixture was poured into a separatory funnel and washed by 1 N HCl. The organic layers were combined, dried over MgSO4, concentrated in vacuo, and chromatographed through a silica gel column to give the title compound 1.6588 g (91%). ES-MS 287 (M+1).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[C:35]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH3:46])=[CH:40][CH:39]=3)[C:34]([Cl:47])=[C:33]([O:48][CH2:49][CH2:50]Cl)[C:32]=2Br)[O:11][C@@H:10]1[CH2:53][O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC>C1COCC1>[Cl:47][C:34]1[C:33]2[O:48][CH2:49][CH2:50][C:32]=2[C:31]([C@H:12]2[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:10]([CH2:53][O:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[O:11]2)=[CH:36][C:35]=1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([O:44][CH2:45][CH3:46])=[CH:42][CH:43]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(Br)c(OCCCl)c2Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3)cc1
Reaction time: 18 h
Yield: 88.3 %

Procedure:
To a solution of compound 80 (2.59 g, 2.79 mmol) in THF (28 mL) was added dropwise n-butyllithium (2.5 M in hexane, 2.2 mL, 5.59 mmol) at −78° C. under an atmosphere of nitrogen. The mixture was stirred for 18 hours at −78° C. to 10° C. The mixture was quenched with 1 N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 81 (2.0 g, 88%) as brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:24]1([NH:30][C:31]([N:13]2[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:8][C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:11][CH2:12]2)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Solvent: ClCCl
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.1 %

Procedure:
To a cold (0° C.), stirred solution of COMPOUND 249 (66 mg, 0.21 mmol) in CH2Cl2 (2 mL) was added phenyl isocyanate (30 μL, 0.28 mmol). After 15 minutes, the cooling bath was removed and the reaction mixture was warmed to room temperature. After an additional 45 minutes, the mixture was concentrated under reduced pressure. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 25:1:1 CH2Cl2-MeOH—NH4OH) provided 84 mg (84%) of COMPOUND 270 as a white solid. 1H NMR (CDCl3) δ 1.62-1.78 (m, 2H), 1.95-1.99 (m, 2H), 2.09 (s, 6H), 2.68-2.79 (m, 3H), 3.83 (s, 4H), 4.14 (d, 2H, J=13.5 Hz), 6.39 (br s, 1H), 6.99-7.12 (m, 3H), 7.25-7.39 (m, 6H), 8.34 (d, 2H, J=3.6 Hz); 13C NMR (CDCl3) δ 18.39, 27.45, 44.86, 54.98, 57.83, 120.41, 122.86, 123.17, 129.13, 133.86, 138.50, 139.80, 146.23, 155.40, 157.50; ES-MS m/z 430 (M+H). Anal. Calcd. For C26H31N5O.0.5CH2Cl2: C, 67.43; H, 6.83; N, 14.84. Found: C, 67.77; H, 6.99; N, 14.90.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([OH:14])[C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])[OH:6].CO[C:18](OC)([CH3:20])[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]([C@H:4]1[C@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[O:6][C:18]([CH3:20])([CH3:19])[O:14]1)=[O:15]
Reactant: COC(C)(C)OC
Reactant: COC(=O)[C@H](O)[C@@H](O)c1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)[C@@H]1OC(C)(C)O[C@H]1c1ccccc1Cl
Temperature: 0 °C
Yield: 82.4 %

Procedure:
Dichloromethane(DMC) was added to (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (24.4 g, Preparation example 25) and cooled to 0° C. 2,2-Dimethoxypropane (26 ml, 211.77 mmol) and p-toluenesulfonic acid (2 g, 10.58 mmol) was added and stirred at room temperature. The reaction mixture was quenched with H2O, extracted with DCM, washed with H2O, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (23.6 g, 70˜95%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][N:17]=[C:16]3[NH:20][N:21]=[CH:22][C:15]=23)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>O1CCOCC1.C(OCC)C>[ClH:23].[ClH:23].[N:11]1([C:14]2[N:19]=[CH:18][N:17]=[C:16]3[NH:20][N:21]=[CH:22][C:15]=23)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]ncc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: c1nc(N2CCNCC2)c2cn[nH]c2n1
Reaction time: 2 h
Yield: 99 %

Procedure:
The 4-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (600 mg, 1.97 mmol) was dissolved in 4 mL of 1,4-dioxane and treated with 10 mL of 4M HCl in 1,4-dioxane at room temperature. The solution was allowed to stir for two hours to afford a light-yellow suspension of product. The solvent was diluted with diethyl ether, stirred for ten minutes, and filtered. The pad of product was washed with diethyl ether and allowed to dry under a stream of nitrogen to give the 4-piperazin-1-yl-1H-pyrazolo[3,4-d]pyrimidine bis-hydrochloride salt as a light-yellow solid (539 mg, 99%). 1H NMR (D6O, 400 MHz) δ 8.59 (s, 1H), 8.42 (s, 1H), 4.29 (appt, J=5.6 Hz, 4H), 3.42 (appt, J=5.6 Hz, 4H). LCMS (APCI+) m/z 205 [M+H]+; Rt=0.34 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[S:16][C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][C:13]=2[NH2:24])=[O:11])=[CH:6][CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[S:16][C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][C:13]=2[NH2:24])=[O:11])=[CH:6][CH:5]=1
Reactant: Nc1nc(Nc2ccccc2)sc1C(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: Nc1ccc(C(=O)c2sc(Nc3ccccc3)nc2N)cc1

Procedure:
The title compound was prepared in a manner like that described for Example D(1). Catalytic reduction of the title compound of Example A(2) ((4-nitro-phenyl)-(4-amino-2-phenylamino-thiazol-5-yl)-methanone) provided, after recrystallization from ethanol, 410 mg (90% yield) of red amorphous powder, mp >300° C.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH:10](O)[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC.C(Cl)(Cl)(Cl)[Cl:45]>C(Cl)Cl>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH:10]([Cl:45])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1C=CC(c2ccccc2)(c2ccccc2)C1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: ClC1C=CC(c2ccccc2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4,4-diphenyl-2-cyclopenten-1-ol (0.30 g), and triphenylphosphine (0.43 g) in carbon tetrachloride (3 ml) was refluxed for 8 hours and cooled. To the mixture was added n-hexane (5 ml), and the mixture was stirred for 10 minutes at room temperature. The insoluble material was filtered off and the filtrate was condensed under reduced pressure. The residue was dissolved in methylene chloride, and to the solution was added silica gel (1 g). After being stirred for 10 minutes, silica gel was filtered off and the filtrate was evaporated in vacuo to give 4,4-diphenyl-2-cyclopentenyl chloride (0.30 g).