Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCO[CH:2]1[C:6]1[O:10][C:9]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]([NH:21][CH3:22])=[CH:17][N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1.Cl.[CH3:24][NH:25][CH3:26].Cl.CNC.C([BH3-])#N.[Na+]>O.C(O)C>[CH3:24][N:25]([CH2:2][C:6]1[O:10][C:9]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]([NH:21][CH3:22])=[CH:17][N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1)[CH3:26]
Reactant: CNC(=C[N+](=O)[O-])NCCSCc1ccc(C2OCCO2)o1
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 107.9 %

Procedure:
To a stirred solution of N-[2-[[5-(1,3-dioxolan-2-yl)-2-furanylmethyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine (1.65 g) and dimethylamine hydrochloride (16.3 g) in water (3.74 ml) and ethanol (6.2 ml) was added 2 N hydrochloric acid (3.74 ml). After 15 min. at room temperature, a solution of dimethylamine in water (40%) (0.85 ml) was added followed by a solution of sodium cyanoborohydride (0.156 g) in water (1 ml). After 1h, the solution was evaporated in vacuo and to the oily residue was added acetic acid (0.5 ml). After 10 min., tetrahydrofuran (100 ml) and an excess of anhydrous sodium carbonate were added, the mixture heated to boiling and allowed to cool to room temperature. After standing for 3 h, the mixture was filtered and the combined filtrate and washings evaporated to low bulk in vacuo. Decolourising charcoal was added to the hot solution and after 1h, the mixture was filtered. The filtrate was evaporated to give an oil (1.7 g) which was chromatographed on silica using methanol:0.88 ammonia (79:1) to give an oil which was dissolved in ethanol. The solution was filtered and evaporated to give an oil (0.75 g) which was crystallised from methyl isobutyl ketone to yield the title compound (0.27 g), m.p. 68°-69.5° which was not depressed on admixture with a sample prepared according to the method of Example 15 in British Patent Specification No. 1,565,966.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[C:5]=1[O:22][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:36][CH:37]=1
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCc2ccc(S(N)(=O)=O)cc2)c1OC(F)F
Temperature: 70 °C
Yield: 33.1 %

Procedure:
To a stirring solution of 5-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.738 mmol) and 4-(bromomethyl)benzenesulfonamide (124 mg, 0.496 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-70% ethyl acetate in pet ether) to afford the title compound as a solid (40 mg, 33%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6](/[C:7](=[CH:13]/[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)/[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[F:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:37])=[C:26]([CH:28]=[N:29][C:30]([O:32][Si](C)(C)C)=[CH2:31])[CH:27]=1>C1(C)C=CC=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([CH:13]2[CH2:31][C:30](=[O:32])[NH:29][CH:28]([C:26]3[CH:27]=[C:22]([F:21])[CH:23]=[CH:24][C:25]=3[CH3:37])[C:7]32[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:9][C:8]3=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)NC(=O)/C2=C\c1cccc(Cl)c1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)NC(=O)C21C(c2cccc(Cl)c2)CC(=O)NC1c1cc(F)ccc1C
Yield: 10 %

Procedure:
In a manner similar to the method described in example 1c, E/Z-6-methoxy-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole (0.4 g, 1.10 mmol) prepared in example 168b was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 36a, in toluene to give racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-6-methoxy spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.05 g, 10%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:15])([CH3:14])[C:12]#[N:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(C1(C2C=CC(OC)=C(C=2)[CH:26]=[O:27])CC1)#N>>[C:12]([C:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([CH:7]=1)[CH:26]=[O:27])([CH3:15])[CH3:14])#[N:13]
Reactant: CC(C)Oc1ccc(C(C)(C)C#N)cc1
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Product: CC(C)Oc1ccc(C(C)(C)C#N)cc1C=O

Procedure:
This compound was prepared from Compound 40 in the same manner of Compound 2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31](=[O:40])[NH:32][C:33]2([C:36](OC)=[O:37])[CH2:35][CH2:34]2)([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.[Li+].[BH4-].Cl>C1COCC1.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31]([NH:32][C:33]2([CH2:36][OH:37])[CH2:35][CH2:34]2)=[O:40])([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:5]=[C:6]([O:8][C:9]([F:13])([F:14])[CH:10]([F:11])[F:12])[CH:7]=1
Reactant: COC(=O)C1(NC(=O)N[C@](Cc2ccccc2)(c2ccc(F)cc2)c2cc(F)cc(OC(F)(F)C(F)F)c2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(NC1(CO)CC1)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 0 °C
Reaction time: 14 h
Yield: 84.5 %

Procedure:
To a solution of (R)-methyl 1-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)-cyclopropanecarboxylate (112 mg, 0.2 mmol), prepared by the method described in Procedure 30, in THF (0.2 mL) was added LiBH4 (0.2 mL, 2 M in THF, 0.4 mmol) at room temperature. The reaction mixture was stirred for 14 h, then cooled to 0° C. and 1 N HCl was added. The reaction mixture was diluted with ether. The organic layer was washed with H2O and sat. NaCl, dried over MgSO4, filtered and concentrated to give a colorless oil. The resulting oil was purified by ISCO chromatography (4 g column, eluting with 0-100% hexane/EtOAc over 16 min) to yield (R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(1-(hydroxymethyl)cyclopropyl)urea (Example 241) as a white foam (91 mg, 84% yield). LCMS: RT=2.97 min [M+H] 539.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% CH3CN/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) ppm 0.61-0.81 (m, 4H), 2.50 (brs, 1H), 3.31-3.50 (m, 2H), 3.84 (qt, J=12 Hz, 2H), 4.93 (s, 1H), 5.84 (t, J=53 Hz, 1H), 6.53-7.05 (m, 8H), 7.05-7.24 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:11]O.[Br:13]P(Br)Br>C(Cl)(Cl)Cl>[Br:13][CH2:11][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: OCc1nc2ccccn2c1Cl
Solvent: ClC(Cl)Cl
Product: Clc1c(CBr)nc2ccccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-chloroimidazo[1,2-a]pyridin-2-yl}methanol (0.799 g, 4.39 mmol) in anhydrous chloroform (25 mL) at 0° C. was added tribromophosphane (1.20 g, 0.41 mL, 4.43 mmol), and the reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated to provide the crude 2-(bromomethyl)-3-chloroimidazo[1,2-a]pyridine, which was used for the next step without any further purification; M+1 246.2.
Reaction SMILES: [CH2:1]([CH:3]1[CH:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][CH:5]([CH2:20][CH2:21][CH2:22][C:23]([NH2:25])=O)[CH2:4]1)[CH3:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([CH2:20][CH2:21][CH2:22][C:23]#[N:25])[CH2:4]1)[CH3:2]
Reactant: CCC1CC(CCCC(N)=O)CC1c1nnc2cnc3[nH]ccc3n12
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC[C@@H]1C[C@H](CCCC#N)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Reaction time: 4 h
Yield: 15.3 %

Procedure:
To a solution of 4-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)butanamide (0.090 g, 0.264 mmol, Example #FFFF.1) in DCM (3 mL) was added TFAA (0.373 mL, 2.64 mmol). After about 4 h at ambient temperature the reaction mixture was concd in vacuo and purified by chiral preparative HPLC (Table 2, Method 33) to provide 4-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)butanenitrile (0.013 g, 15%) (rt=16.1 min, or =neg) LC/MS (Table 1, Method a) Rt=1.79 min; MS m/z: 323 (M+H)+ and 4-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)butanenitrile (0.010 g, 12%) (rt=13.7 min, or =neg) LC/MS (Table 1, Method a) Rt=1.79 min; MS m/z: 323 (M+H)+ as solids.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1[O:6][C:7](=[O:21])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:4].Cl[C:23]1[C:24]2[CH:31]=[CH:30][S:29][C:25]=2[N:26]=[CH:27][N:28]=1.C(N(CC)CC)C>CC(O)(C)C>[C:15]1([C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:21])[O:6][C:5]=2[CH:3]([NH:2][C:23]2[C:24]3[CH:31]=[CH:30][S:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH3:4])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1ncnc2sccc12
Reactant: CC(N)c1oc(=O)c2ccccc2c1-c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: CC(Nc1ncnc2sccc12)c1oc(=O)c2ccccc2c1-c1ccccc1
Yield: 46.7 %

Procedure:
3-(1-aminoethyl)-4-phenyl-1H-isochromen-1-one hydrochloride (intermediate E2 50 mg, 0.166 mmol), 4-chlorothieno[2,3-d]pyrimidine (36.8 mg, 0.215 mmol), triethylamine (0.046 ml, 0.331 mmol) were reacted in 2-methylpropan-2-ol (1 ml) at 80° C. for 6 hrs and at 50° C. for 60 hrs. 4-Chlorothieno[2,3-d]pyrimidine (5.7 mg, 0.033 mmol), triethylamine (0.09 ml, 0.066 mmol) were added and the mixture reacted at 90° C. for 4 hrs. The crude was purified via reverse phase chromatography with a Biotage C18 30 g SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give the title compound (31 mg, 47%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[C:13]([CH3:23])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[CH3:30][S-:31].[Na+].O>CS(C)=O>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:11]([C:8]3[N:6]4[N:7]=[C:2]([S:31][CH3:30])[CH:3]=[C:4]([NH:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])[C:5]4=[N:10][CH:9]=3)=[CH:12][C:13]=2[CH3:23])[CH2:20][CH2:19]1
Reactant: C[S-]
Reactant: Cc1cc(-c2cnc3c(NCC(C)(C)O)cc(Cl)nn23)ccc1C(=O)NC1CC1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1cc(NCC(C)(C)O)c2ncc(-c3ccc(C(=O)NC4CC4)c(C)c3)n2n1
Temperature: 70 °C
Yield: 54.6 %

Procedure:
To a solution of 83 mg (201 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a in 1.0 mL dimethyl sulfoxide were added 70 mg sodium methanethiolate and the mixture was heated under microwave irradiation at 70° C. for 1 hour. The mixture was poured into water and extracted with dichloromethane and methanol. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by recrystallisation to give 46.7 mg (55%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][N:11]1[C:16]2[CH:17]=[CH:18][C:19]([CH2:21][CH2:22][CH2:23][CH2:24]Br)=[CH:20][C:15]=2[O:14][CH2:13][C:12]1=[O:26]>O1CCOCC1>[CH3:10][N:11]1[C:16]2[CH:17]=[CH:18][C:19]([CH2:21][CH2:22][CH2:23][CH2:24][N:2]([CH3:1])[CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:20][C:15]=2[O:14][CH2:13][C:12]1=[O:26]
Reactant: CN1C(=O)COc2cc(CCCCBr)ccc21
Reactant: CNCc1ccccc1
Solvent: C1COCCO1
Product: CN(CCCCc1ccc2c(c1)OCC(=O)N2C)Cc1ccccc1

Procedure:
0.04 mol of N-methyl-N-benzylamine and 0.02 mol of 4-methyl-7-(4-bromobutyl)-2,3-dihydro-3-oxo-1,4-benzoxazine, the latter being dissolved beforehand in 120 cm3 of dioxane, are introduced into a 100-cm3 ground-necked flask fitted with a reflux condenser. The mixture is heated to reflux for 96 hours with magnetic stirring. After cooling, the reaction mixture is filtered and the filtrate is then evaporated on a water bath under vacuum. The residue is taken up with 50 cm3 and alkalinized with 10 cm3 of normal sodium hydroxide solution.
Reaction SMILES: Cl.Cl[C:3]([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:4]1[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]=1.[CH3:24][O-:25].[Na+]>CO>[CH3:24][O:25][C:3]([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:4]1[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]=1
Reactant: ClC(C1=NCCCCCN1)(c1ccccc1)c1ccccc1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(C1=NCCCCCN1)(c1ccccc1)c1ccccc1

Procedure:
2-(Chlorodiphenylmethyl)-1,4,5,6,7,8-hexahydro-1,3-diazocine hydrochloride (0.001 mole) is stirred at room temperature for 2 days in a solution of dry methanol (5 ml) containing sodium methoxide (0.002 mole). After removal of solvent the residue is dissolved in chloroform and washed with water. After drying over magnesium sulphate the solvent is removed to give the title compound.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:20]=[CH2:21])[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][CH3:16].B.[O:31]1CCCC1>>[CH2:1]([O:17][CH2:18][CH:19]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:20][CH2:21][OH:31])[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][CH3:16]
Reactant: C=CC(COCCCCCCCCCCCCCCCC)OCc1ccccc1
Reactant: C1CCOC1
Agent: B
Product: CCCCCCCCCCCCCCCCOCC(CCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 11.5 g of [[[1-[(hexadecyloxy)methyl]-2-propenyl]oxy]methyl]benzene in 50 ml of tetrahydrofuran was added dropwise, at 0° C., 57.12 ml of 1M borane in tetrahydrofuran. After stirring at room temperature for 3 hours the excess borane was destroyed by the addition of water. The mixture was cooled in an ice bath, 100 ml of 3N sodium hydroxide was added followed by 100 ml of 30% hydrogen peroxide and after 10 minutes the mixture was stirred for 1/2 hour at room temperature and then diluted with ether. The ether layer was separated, washed with brine, then saturated sodium bisulfite, dried over magnesium sulfate and the solvent removed. The residue was purified by HPLC [hexane: ethyl acetate (9:1)] giving 7.8 g of the desired compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][N:3]=1.[OH-].[Na+].[CH3:16][N:17]=[C:18]=[S:19].Cl>O1CCCC1>[NH2:1][C:2]1[N:3]([C:18]([NH:17][CH3:16])=[S:19])[N:4]=[C:5]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:6]=1
Reactant: Nc1n[nH]c(Cc2ccccc2)n1
Reactant: CN=C=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNC(=S)n1nc(Cc2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 17 h
Yield: 40 %

Procedure:
The synthesis method of Example 7-(3) was applied. The compound (6.17 g) obtained in (1) above, a 0.77N aqueous sodium hydroxide solution (40 ml), methyl isothiocyanate (2.86 g) and tetrahydrofuran (40 ml) were used as reagents and the mixture was stirred at room temperature for 17 hours. 2N Hydrochloric acid (19 ml) was added to neutralize the mixture. The resulting crystals were collected by filtration and washed with hexane-ethyl acetate to give 3.55 g of white powdery crystals (yield 40%).
Reaction SMILES: Cl[CH:2]([CH:13]1[CH2:15][CH2:14]1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].N12CCCN=C1CCCCC2>O1CCOCC1>[CH:13]1([CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N+:10]([O-:12])=[O:11])[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccccc1CC(Cl)C1CC1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: O=[N+]([O-])c1ccccc1C=CC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
To 1 g (4.25 mmol, purity 96%) of 1-(2-chloro-2-cyclopropylethyl)-2-nitrobenzene in 20 ml of dioxane is added 0.65 g (4.25 mmol) of 1,8-diazabicyclo(5.4.0)undec-7-ene, and the mixture is stirred at room temperature for 12 h. Subsequently, the solvent is concentrated under reduced pressure and the residue is admixed with ethyl acetate and water. After the organic phases have been removed and the solvent has been concentrated by evaporation, 0.7 g (79% of theory) of 1-[2-cyclopropylvinyl]-2-nitrobenzene is obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]2[NH:9][NH:10][C:11](=O)[C:6]2=[CH:5][N:4]=1.P(Br)(Br)([Br:15])=O.O.[OH-].[NH4+]>CC#N>[Br:15][C:11]1[C:6]2[C:7](=[N:8][C:3]([S:2][CH3:1])=[N:4][CH:5]=2)[NH:9][N:10]=1
Reactant: O=P(Br)(Br)Br
Reactant: CSc1ncc2c(=O)[nH][nH]c2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CSc1ncc2c(Br)n[nH]c2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a suspension of 6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (0.50 g, 2.7 mmol) in CH3CN (15 mL) was added a CH3CN solution of P(O)Br3 (1.57 g, 5.5 mmol) in a pressure vessel. The mixture was sonicated for 30 min before being heated to 100° C. for 16 h (overnight). After it was cooled to 0° C., H2O and aqueous ammonium hydroxide were added to basify the mixture. The mixture was stirred at 0° C. for 1 h. The aqueous layer was extracted with EtOAc (10×). The combined EtOAc layer was dried (Na2SO4), and concentrated to give 3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine (0.51 g, 77%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.00 (s, 1H), 5.57 (s, 3H); MS m/z 245.00 [M+H]+.
Reaction SMILES: [BrH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[C:11]2[NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=1.[O:26]1[CH2:28][CH2:27]1>CO>[BrH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[C:11]2[NH:19][CH:20]2[CH2:21][CH2:22][N:23]([CH2:28][CH2:27][OH:26])[CH2:24][CH2:25]2)=[CH:5][CH:4]=1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: C1CO1
Agent: Br
Solvent: CO
Product: OCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 8 h
Yield: 64 %

Procedure:
To a stirred mixture of 40.4 parts of 1-(4-fluorophenylmethyl)-N-(4-piperidinyl)-1H-benzimidazol-2-amine hydrobromide and 400 parts of methanol are added 8.8 parts of oxirane and stirring is continued overnight at room temperature. The reaction mixture is evaporated and the residue is taken up in water. The precipitated product is filtered off and dried, yielding 29 parts (64%) of 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidineethanol monohydrobromide; mp. 248.2° C.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([OH:20])=O)=[C:10]1[CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:41][CH2:42][C:43]1[C:44]([OH:51])=[N:45][C:46]([CH3:50])=[CH:47][C:48]=1[CH3:49]>ClCCl>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([NH:41][CH2:42][C:43]2[C:44]([OH:51])=[N:45][C:46]([CH3:50])=[CH:47][C:48]=2[CH3:49])=[O:20])=[C:10]1[CH3:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)c2ccccc2n1C(=O)c1ccccc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(C(=O)c3ccccc3)c3ccccc23)c(O)n1
Temperature: 20 °C
Reaction time: 13 h
Yield: 26.9 %

Procedure:
To a solution of 1-benzoyl-2-methyl-1H-indole-3-carboxylic acid (125 mg, 0.45 mmol), 1-hydroxybenzotriozole (122 mg, 0.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (173 mg, 0.9 mmol), triethylamine (0.4 mL) in dichloromethane (20 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (137 mg, 0.9 mmol). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the residue, which was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give 1-benzoyl-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide as a white solid (50 mg, 53%). LRMS (M+H+) m/z: calcd 413.17. found 413. HPLC Purity (214 nm): 96%. 1H NMR (300 MHz, do-DMSO): (11.57 (s, 1H), 8.13 (q, J=5.1 Hz, 1H), 7.74-7.70 (m, 4H), 7.60-7.58 (m, 2H), 7.20-7.00 (m, 3H), 5.88 (s, 1H), 4.32 (d, J=5.1 Hz, 2H), 2.37 (s, 3H), 2.267 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[O:32]([CH2:39][CH2:40][NH2:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:41][CH2:40][CH2:39][O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:24])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NCCOc1ccccc1
Product: O=C(NCCOc1ccccc1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-phenoxyethylamine as in General Procedure 10 to give the title compound. LCMS: m/z=566.93 (M+H+); retention time=0.93 minutes.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][NH:6][CH3:7].C(N(CC)C(C)C)(C)C.[C:18](Cl)(=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][N:6]([C:18](=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:7]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CNCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCC(=O)N(C)CCCN(C)C

Procedure:
A mixture of 3.89 g. (0.0335 mol) of N,N,N'-trimethyl-1,3-propylenediamine and 4.33 g. (0.0335 mol) of N,N-diisopropylethylamine in 50 mL chloroform was added to 7.33 g. (0.0335 mol) of lauroyl chloride dropwise, on an icebath, and was then reacted for another two hours at room temperature. 75 mL of aqueous sodium bicarbonate was then added to this reaction mixture, and the chloroform layer was separated and washed with 125 mL aqueous sodium bicarbonate followed by 100 mL water. The chloroform layer was then dried (MgSO4) filtered and concentrated in vacuo.