Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH:34](=O)[C:35]1[CH:42]=[CH:41][CH:40]=[C:37]([CH:38]=[O:39])[CH:36]=1.CCCCCC>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH:38]([C:37]1[CH:36]=[C:35](/[CH:34]=[CH:8]/[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH:42]=[CH:41][CH:40]=1)=[O:39]
Reactant: c1ccc([P+](Cc2ccccn2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1cccc(/C=C/c2ccccn2)c1
Yield: 374.8 %

Procedure:
3.9 g of (2-pyridyl)methyltriphenylphosphonium chloride was suspended in 20 ml of tetrahydrofuran, and with stirring, 5.3 ml of a 20% aqueous solution of potassium carbonate and 0.13 g of isophthalaldehyde were added. The mixture was stirred overnight at room temperature. Hexane was added, and the resulting aqueous layer was discarded, and concentrated under reduced pressure. Hexane was added to the residue. The insoluble matter was removed by filtration, and the filtrate was evaporated under reduced pressure. The residue was purified by medium-pressure liquid chromatography [column: Lobar column, size B, Lichroprep Si 60 (a product of E. Merck Co.); eluting solvent: hexane/ethyl acetate=7/1→4/1]to give 0.76 g (yield 36%) of (E)-2-[2-(3-formylphenyl)vinyl]pyridine.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#N.Cl.C(OCC)(=[O:21])C>C1COCC1>[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12](=[O:21])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C[Zn]Br
Reactant: CCOC(C)=O
Reactant: N#Cc1ccccc1F
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccccc1F
Reaction time: 1 h
Yield: 92 %

Procedure:
Under nitrogen atmosphere, 30 mL of THF was added to 6.09 g (10 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 1.21 g (10 mmol) of 2-fluorobenzonitrile in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20° C.˜25° C. for 46 hours. 15 mL of 10% hydrochloric acid added dropwise at 20° C. or lower, and the mixture was stirred at 20˜25C. for 1 hour, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 15 mL of 1N hydrochloric acid, 20 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 20 mL of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.94 g of the desired product (yield 92%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)[N:16]=[C:15]([C:25]([OH:27])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:49]3[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Cl:24][C:20]1[CH:19]=[C:18]([N:17]2[C:13]([C:4]3[CH:5]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:14][C:15]([C:25]([N:49]3[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]3)=[O:27])=[N:16]2)[CH:23]=[CH:22][N:21]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Reactant: O=C(O)c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2ccnc(Cl)c2)n1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(OC(F)(F)F)c3)n(-c3ccnc(Cl)c3)n2)CCN1

Procedure:
40 mg (0.08 mmol) of the compound of Example 35A is reacted analogously to the synthesis of the compound of Example 4 with 8 mg (0.08 mmol) of 2-oxopiperazine. 27 mg (71% of theory) of the title compound is obtained.
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:20][CH3:21])[C:8]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=2[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][S:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.O>[CH:1]1([CH2:6][N:7]([CH2:20][CH3:21])[C:8]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:9]=2[CH2:10][NH:33][C:30]2[N:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][S:23][CH3:22])=[CH:32][N:31]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN(CC1CCCC1)c1ccc(C(F)(F)F)cc1C=O
Reactant: CSCCOc1cnc(N)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCN(CC1CCCC1)c1ccc(C(F)(F)F)cc1CNc1ncc(OCCSC)cn1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
To a solution of 2-[(cyclopentylmethyl)(ethyl)amino]-5-(trifluoromethyl)benzaldehyde (3.34 g, 11.2 mmol) obtained in Step 3 and 5-[2-(methylthio)ethoxy]pyrimidin-2-amine (2.27 g, 12.3 mmol) obtained in Step 1 in toluene (80 mL) was added acetic acid (317 mg, 5.19 mmol), and the mixture was refluxed by heating for 4 hours with a Dean-Stark apparatus. The reaction mixture was left to cool to room temperature, and then added with sodium triacetoxyborohydride (4.73 g, 22.3 mmol) on an ice bath with stirring, and the mixture was stirred at room temperature for 60 hours. The reaction mixture was added with water, and extracted with chloroform, and then the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1→10:1→4:1) to obtain N-({2-[(cyclopentylmethyl)(ethyl)amino]-5-(trifluoromethyl)phenyl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (4.39 g, 84%) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH:26]=[CH:25]3)=[C:17]([NH:29][CH:30]3[CH2:35][CH2:34][N:33](CC4C=CC=CC=4)[CH2:32][CH2:31]3)[N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.O.[Pd]>[C:1]([O:5][C:6](=[O:43])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH:26]=[CH:25]3)=[C:17]([NH:29][CH:30]3[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]3)[N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(NC3CCN(Cc4ccccc4)CC3)c3ncn(C4C=CCC4)c3n2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(NC3CCNCC3)c3ncn(C4C=CCC4)c3n2)CC1

Procedure:
Add to a solution of trans-{4-[6-(1-benzyl-piperidin-4-ylamino)-9-cyclopent-2-enyl-9H-purin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (8c,1.0-mmol) in 40 mL of methanol, a suspension of Pd black (0.5 wt %) in a small amount of water. Then add a solution of ammonium formate (2.2 mmol) in 10 mL of water, and heat at a gentle reflux overnight. Remove the catalyst by filtration through Celite® and concentrate the filtrate. Dissolve the residue in DCM and extract with water. Remove the white precipitate by filtration through a pad of Celite®, wash the filtrate with brine, dry over sodium sulfate and filter. Concentrate the filtrate and purify the residue on silica gel (50 g) using DCM:methanol (4:1) to give trans-{4-[9-cyclopent-2-enyl-6-(piperidin-4-ylamino)-9H-purin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (9c.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:9](=[O:19])[CH:8]([NH:20][C:21](=[O:41])[C@H:22]([NH:27][C:28](=[O:40])[C:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:31])[CH3:30])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:7]2.[CH:42](=O)[CH3:43].C(#N)C.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH2:42]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:9](=[O:19])[CH:8]([NH:20][C:21](=[O:41])[C@H:22]([NH:27][C:28](=[O:40])[C:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:30])[CH3:31])[CH2:23][CH:24]([CH3:25])[CH3:26])[CH2:7]2)[CH3:43]
Reactant: CC(C)C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N)c2N(Cc2ccccn2)C1=O
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCNc1cccc2c1N(Cc1ccccn1)C(=O)C(NC(=O)[C@@H](CC(C)C)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2
Reaction time: 0.08 h

Procedure:
tert-Butyl 1-((2R)-1-(8-amino-2-oxo-1-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylamino)-4-methyl-1-oxopentan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (59 mg) and acetaldehyde (29 μL) were sequentially added to acetonitrile (730 μL), and sodium cyanoborohydride (7 mg) and acetic acid (18 μL) were added to the mixture under cooling on ice, followed by stirring for 5 minutes. The resultant mixture was extracted with ethyl acetate and saturated aqueous sodium bicarbonate solution, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined, and the combined organic layer was washed with saturated aqueous sodium chloride solution, followed by drying over sodium sulfate. The solvent was evaporated under reduced pressure, and the thus-recovered residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1), whereby the title compound (58 mg) was yielded.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[O-2].[Nb+5:7].[O-2].[O-2].[O-2].[O-2].[Nb+5]>>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Nb+5:7].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Nb+5:7].[Nb+5:7]
Reactant: O=P(O)(O)O
Agent: [Nb+5]
Agent: [O-2]
Product: O=P([O-])([O-])[O-]
Temperature: 150 °C

Procedure:
A mixture is prepared containing niobic acid, Nb2O5.xH2O, (60.33 g; 0.211 moles) and 85% phosphoric acid (602.20 g; 5.22 moles). The mixture is heated to 150° C. with stirring. The niobium oxide dissolves to form a pink solution, and upon further heating a precipitate forms. The precipitate is boiled in the phosphoric acid for about 2 hours. The mixture is cooled to room temperature, and the liquid is decanted from the precipitate. The precipitate is washed by adding 500 ml of water with stirring, after which the mixture is filtered. The washing and filtering cycle is repeated five times. The filtered solid is dried at 110° C. under air for 21/2 days to yield a catalyst of niobium phosphate. The elemental analysis and X-ray diffraction spectrum of the catalyst are consistent with the composition NbOPO4.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[C:21]([C:24](Cl)=[O:25])[NH:22][N:23]=1>N1C=CC=CC=1>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][C:24]([C:21]2[NH:22][N:23]=[C:19]([C:13]3[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=3[Cl:11])[CH:20]=2)=[O:25])=[CH:5][CH:6]=1
Reactant: NCCc1ccc(O)cc1
Reactant: O=C(Cl)c1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Solvent: c1ccncc1
Product: O=C(NCCc1ccc(O)cc1)c1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Yield: 70.6 %

Procedure:
In pyridine (6 ml), 4-(2-amino-ethyl)-phenol (72 mg) was dissolved, and 5-(2,4-dichlorophenyl)-2H-pyrazole-3-carboxylic acid chloride (137 mg) was added thereto under an ice cooling while stirring. Thereafter, the mixture was stirred at a room temperature for 17 hours and then concentrated under a reduced pressure, and the concentrate was purified by silica gel column chromatography (5% methanol-chloroform) to give the title compound (132 mg, 70%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[NH2:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.O>CC(C)=O>[NH:11]1[C:10]([NH:9][C:7]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[S:8])=[CH:14][CH:13]=[N:12]1
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)N=C=S
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)NC(=S)Nc1ccn[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Ethoxycarbonyl isothiocyanate (3.16 g, 24.07 mmol) was added to 3-aminopyrazole (Aldrich) (2.0 g, 24.07 mmol) in acetone (20 mL). The reaction mixture was stirred at room temperature for 1 hour. Then cold water (100 mL) was added to the reaction mixture. The solid precipitate was collected through filtration, washed with water (50 mL), and then air dried to give 4.64 g (90%) of ethyl 1H-pyrazol-5-ylcarbamothioylcarbamate.
Reaction SMILES: [Na].[OH:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)S(O)(=O)=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[C-:30]#[N:31].[Na+]>O>[C:30]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)[OH:2])#[N:31]
Reactant: [C-]#N
Reactant: O=S(=O)(O)C(O)c1cccc(Oc2ccccc2)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: N#CC(O)c1cccc(Oc2ccccc2)c1
Temperature: 15 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Into a flask were placed 755.7 g (2.5 moles) of the sodium salt of (hydroxy)(3-phenoxyphenyl)methanesulfonic acid, 237.6 g (1.25 moles) of sodium metabisulfite, and 2273 ml of water. The flask was cooled to 15° C. and a solution of 245.1 g (5.0 moles) of sodium cyanide in 302 ml of water was added dropwise. The reaction mixture was allowed to warm to room temperature, was stirred for 3 hours, then extracted three times with 800 ml of diethyl ether. The extract was washed once with 800 ml of a solution of 25% sodium metabisulfite and 1 N hydrochloric acid and twice with distilled water. After being dried over magnesium sulfate, the ether was evaporated, leaving a residue of 498.5 g of 94% (cyano)(3-phenoxyphenyl)methanol by gc analysis.
Reaction SMILES: [C:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=2)[NH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[NH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)c1c[nH]c2ccc(N)cc12
Temperature: 15 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
To a solution of 3-tert-butyl-5-nitro-1H-indole (2.5 g, 11.6 mmol) in MeOH (30 mL) was added Raney Nickel (0.2 g) under N2 protection. The mixture was stirred under hydrogen atmosphere (1 atm) at 15° C. for 1 hr. The catalyst was filtered off and the filtrate was concentrated under vacuum to dryness. The residue was purified by preparative HLPC to afford 3-tert-butyl-1H-indol-5-amine (0.43 g, 19%). 1H NMR (CDCl3, 400 MHz) δ 7.72 (brs, 1H), 7.11 (d, J=8.4 Hz, 1H), 6.86 (d, J=2.0 Hz, 1H), 6.59 (dd, J=2.0, 8.4 Hz, 1H), 6.09 (d, J=1.6 Hz, 1H), 1.37 (s, 9H); MS (ESI) m/e (M+H+) 189.1.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH3:8])=[N:3]1.[CH2:9]([O:11][C:12](=[O:25])[C:13](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[C:14]([CH3:16])=O)[CH3:10]>>[ClH:24].[CH2:9]([O:11][C:12]([C:13]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:5]2[C:4]([CH3:8])=[N:3][N:2]([CH3:1])[C:6]=2[NH:7][C:14]=1[CH3:16])=[O:25])[CH3:10]
Reactant: Cc1cc(N)n(C)n1
Reactant: CCOC(=O)C(=Cc1ccccc1Cl)C(C)=O
Product: CCOC(=O)C1=C(C)Nc2c(c(C)nn2C)C1c1ccccc1Cl
Product: Cl

Procedure:
Starting from 1,3-dimethyl-5-pyrazolamine and ethyl-2-(2-chlorobenzyliden)acetoacetate. M.p. 240°-242° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11]C)=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].C[O:14][C:15]1[CH:23]=[CH:22][C:18](C(Cl)=O)=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:3]([OH:11])=[CH:4][C:5]2[O:9][C:10]([C:18]3[CH:22]=[CH:23][C:15]([OH:14])=[CH:16][CH:17]=3)=[N:7][C:6]=2[CH:8]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1cc(OC)c(Cl)cc1N
Product: Oc1ccc(-c2nc3cc(Cl)c(O)cc3o2)cc1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 16, from 5-chloro-2,4-dimethoxyaniline, and 4-methoxybenzoyl chloride and was obtained as an off-white solid, m.p. 254-256° C.; MS m/e 262 (M+H)+.
Reaction SMILES: [C:1]([OH:17])(=O)[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:30]([O:32][C:33](=[O:47])[CH:34]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[N:35]1[CH:39]=[C:38]([NH2:40])[N:37]=[CH:36]1)[CH3:31]>CN(C=O)C>[CH2:30]([O:32][C:33](=[O:47])[CH:34]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[N:35]1[CH:39]=[C:38]([NH:40][C:1](=[O:17])[C:2]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[OH:3])[N:37]=[CH:36]1)[CH3:31]
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Reactant: CCCCCCC(C(=O)OCC)n1cnc(N)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCCCCCC(C(=O)OCC)n1cnc(NC(=O)C(O)(c2ccccc2)c2ccccc2)c1
Reaction time: 1 h
Yield: 15.3 %

Procedure:
A mixture of 4.6 g of benzilic acid, 3.2 g of 1,1'-carbonyldiimidazole, and 150 ml of DMF were mixed and stirred for 1 hour. A solution of 5.0 g of 4-amino-α-hexyl-1H-imidazole-1-acetic acid ethyl ester in DMF was added and the mixture stirred at room temperature over-night. The reaction mixture was concentrated in vacuo, ethyl acetate was added, and the organic solution was washed sequentially with water, a 10% sodium hydroxide solution, and water. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by HPLC eluting with 30% ethyl acetate in toluene. The appropriate fractions were combined and concentrated in vacuo to provide 1.4 g of the desired titled product.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:16][C:17]([OH:19])=O)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH3:20][N:21]([CH3:24])[CH:22]=O>>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16](=[CH:20][N:21]([CH3:24])[CH3:22])[CH:17]=[O:19])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C(C=O)=CN(C)C)cc1OC
Temperature: 70 °C

Procedure:
The intermediate 2-(3,4-dimethoxyphenyl)-3-dimethylamino-2-propenal was prepared as follows: To a chilled 1260 ml. portion of dimethylformamide was added dropwise 230 ml. of phosphorus oxychloride followed by addition of 196 g. of α-(3,4-dimethoxyphenyl)acetic acid. The reaction mixture was heated at about 70° C. on a steam both for 3 hours, allowed to cool and then concentrated in vacuo to remove the solvent and excess volatile reactants. The resulting product was used directly in the above procedure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[N:12][N:13]([CH3:15])[CH:14]=[C:9]3[C:8]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:7][C:6]=2[CH:22]=1.Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.C(N(CC)CC)C.O>C(#N)C>[CH:25]1([CH2:24][N:19]2[CH2:20][CH2:21][N:16]([C:8]3[C:9]4[C:10](=[N:12][N:13]([CH3:15])[CH:14]=4)[NH:11][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:22][C:6]=4[N:7]=3)[CH2:17][CH2:18]2)[CH2:27][CH2:26]1
Reactant: BrCC1CC1
Reactant: Cn1cc2c(n1)Nc1ccc(F)cc1N=C2N1CCNCC1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1cc2c(n1)Nc1ccc(F)cc1N=C2N1CCN(CC2CC2)CC1

Procedure:
A solution of 7-fluoro-2,10-dihydro-2-methyl-4-(1-piperazinyl)pyrazolo[3,4-b][1,5]benzodiazepine (1.0 g), bromomethylcyclopropane (0.5 g) and triethylamine (0.0375 g) in acetonitrile (30 ml) was stirred at ambient temperature for 20 hours. The solution was poured into water and the product extracted with chloroform (3×). The organic extract was washed with saturated brine and water, dried over magnesium sulphate, the solvent removed and the residue crystallised from ethyl acetate to give the title compound m.p. 188°-189° C. 4-(4-Benzyl-1-piperazinyl)-7-fluoro-2,10-dihydro-2-methyl-pyrazolo[3,4-b][1,5]benzodiazepine was similarly prepared, m.p. 241°-245° C. (ethyl acetate-diethyl ether).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][CH2:6][C@@:7]([OH:12])([CH3:11])[C:8](O)=[O:9].[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[NH2:17].O>CC(N(C)C)=O>[Br:5][CH2:6][C@@:7]([OH:12])([CH3:11])[C:8]([NH:17][C:16]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:14]([CH3:13])[CH:15]=1)=[O:9]
Reactant: C[C@](O)(CBr)C(=O)O
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(NC(=O)[C@@](C)(O)CBr)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
Thionyl chloride (0.48 ml, 6.6 mmol) was added dropwise to a solution of (2R)-3-Bromo-2-hydroxy-2-methylpropionic acid (1.0 g, 5.5 mmol) in 10 ml of DMA at −5 to −10° C. The mixture was stirred for 2 h, and a solution of 3-methyl-4-nitroaniline (0.83 g, 5.5 mmol) in 7 ml of DMA was added to the above mixture. The resulting mixture was stirred for 3 h at room temperature and poured into water (250 ml). The aqueous phase was extracted with ethyl acetate (4×50 ml), dried over Na2SO4 and evaporated. The yield of the desired compound was 2.5 g (contains also DMA), and it was used without further purifications. 1H NMR (DMSO-d6): 1.48 (3H, s), 2.53 (3H, s), 3.58 (1H, d, J=10.4 Hz), 3.82 (1H, d, J=10.4 Hz), 6.34 (1H, bs), 7.86 (1H, dd, J=9.0 Hz and 2.2 Hz), 7.91 (1H, d, J=2.2 Hz), 8.04 (1H, d, J=9.0 Hz), 10.09 (1H, bs).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[C:4]2[NH:10][C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1.[C:19]([C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)#[N:20]>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:18])=[C:4]2[NH:10][C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH:15][S:27]([C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([C:19]#[N:20])[CH:22]=4)(=[O:29])=[O:28])=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1c(Br)cnc2nc(-c3ccc(N)cc3)[nH]c12
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Product: Cc1c(Br)cnc2nc(-c3ccc(NS(=O)(=O)c4cccc(C#N)c4)cc3)[nH]c12
Temperature: 60 °C

Procedure:
4-(6-Bromo-7-methyl-1H-imidazo[4,5-b]pyridin-2-yl)aniline (Example 260) (0.020 g, 0.07 mmol) was dissolved in pyridine and 3-cyanobenzenesulfonyl chloride (0.013 g, 0.07 mmol) was added. The mixture was heated to 60° C. for 3 h. Thereafter the solvent was removed in vacuo and the residue was submitted to HPLC-C18 purification. Yield: 0.006 g (15%) of the title compound as the trifluoroacetate.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[C:10]([F:17])[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][C:26]=2[F:36])=[CH:21][CH:20]=1.C(OC1(C2C=CC(CCCCC)=CC=2)C(F)=CC(C2C=CC=CC=2)=C(F)C1)CCCCC>>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][C:26]=3[F:36])=[CH:23][CH:24]=2)=[C:10]([F:17])[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCc1ccc(-c2ccc(Br)cc2)c(F)c1
Reactant: CCCCCCOc1ccc(B(O)O)c(F)c1
Agent: CCCCCCOC1(c2ccc(CCCCC)cc2)CC(F)=C(c2ccccc2)C=C1F
Product: CCCCCCOc1ccc(-c2ccc(-c3ccc(CCCCC)cc3F)cc2)c(F)c1

Procedure:
The product from 3B is coupled with 4'-bromo-2-fluoro-4-pentylbiphenyl in an analogous manner as described for 1G.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[C:15]([C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1)#[N:16].C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[C:15]([C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=[CH:7]3)[CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1)#[N:16]
Reactant: ClCCCCn1cnc2ccccc21
Reactant: N#Cc1cccc(N2CCNCC2)c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(N2CCN(CCCCn3cnc4ccccc43)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.1 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-cyanophenyl piperazine (5.6 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 10-15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.7 g compound (I-10) with a yield of 62.4%. ESI-MS [M+H]+: m/z 360.2.