Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C@@H:11]([CH2:15][NH2:16])[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1.O>C1C=CC=CC=1>[C:19]1([CH3:18])[C:24]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:37]([O:13][C:12](=[O:14])[C@@H:11]([NH:10][S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:17])=[CH:6][CH:5]=1)(=[O:8])=[O:9])[CH2:15][NH2:16])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CN)C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N[C@@H](CN)C(=O)OCc2ccccc2)cc1
Product: Cc1ccccc1S(=O)(=O)O

Procedure:
14-3 (5.0 g, 19.4 mmol) was suspended in 150 ml anhydrous benzene along with benzyl alcohol (10 ml, 97 mmol), and p-toluene sulfonic acid mono hydrate (3.87 g, 20.4 mmol). The mixture was refluxed until the theoretical amount of water had collected in a Dean-Stark trap (8.5 h). The resulting solution was cooled and 100 ml anhydrous ether added giving 14-6 as a white solid. 1H NMR (300 MHz, CD3OD) δ7.81 (d, J=8.5 Hz, 2H), 7.71 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 7.28 (m, 5H); 4.98 (m, 2H), 3.91 (m, 1H), 2.89 (m, 2H), 2.35 (s, 3H), 2.31 (s, 2H). ##STR135##
Reaction SMILES: [CH3:1][C:2]([S:28]([CH3:31])(=[O:30])=[O:29])([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].Cl.CO>C(Cl)Cl>[OH:6][NH:5][C:3](=[O:4])[C:2]([CH3:1])([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:20]=1
Reactant: CC(CCc1ccc(Sc2ccccc2)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(CCc1ccc(Sc2ccccc2)cc1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-methyl-2-(methylsulfonyl)-4-[4-(phenylthio)phenyl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (268.4 mg, 0.579 mmol) in methylene chloride (3 mL) at ambient temperature was added HCl (4M in 1,4-dioxane, 4.34 mL, 17.4 mmol) and the resulting solution was stirred at RT for 5 minutes. Methanol (500 uL) was added followed by silica gel and the mixture was concentrated to dryness. The crude material was purified via silica gel chromatography eluting with methylene chloride/methanol to afford N-hydroxy-2-methyl-2-(methylsulfonyl)-4-[4-(phenylthio)phenyl]butanamide as a solid. 7.8 mg. LCMS: (M+1) 380.1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[C:27]([NH:32][CH3:33])[N:26]=[CH:25]3)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][C:13]1[CH:14]=[C:15](CC=O)[CH:16]=[CH:17][CH:18]=1)=[N:7][N:6]=[CH:5]2.[CH2:34]1[CH2:38][O:37]CC1.[CH3:39][Mg]Br.C1(C)C=CC=CC=1.O1CCCC1>O>[CH3:1][C:2]1[C:3]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[C:27]([NH:32][CH3:33])[N:26]=[CH:25]3)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][C:13]1[CH:14]=[C:15]([C:38]([OH:37])([CH3:34])[CH3:39])[CH:16]=[CH:17][CH:18]=1)=[N:7][N:6]=[CH:5]2
Reactant: C[Mg]Br
Reactant: C1CCOC1
Reactant: CNc1ncc2cc(-c3c(C)ccc4c(Nc5cccc(CC=O)c5)nncc34)ccc2n1
Solvent: O
Solvent: Cc1ccccc1
Product: CNc1ncc2cc(-c3c(C)ccc4c(Nc5cccc(C(C)(C)O)c5)nncc34)ccc2n1
Reaction time: 2 h

Procedure:
To a solution of 2-(3-(6-methyl-5-(2-(methylamino)quinazolin-6-yl)phthalazin-1-ylamino)phenyl)ethanone (0.056 g, 0.13 mmol)n THF (2.0 ml), charged to a 50 mL round bottom, methylmagnesium bromide, 1.4 m solution in toluene/tetrahydrofuran (75:25) (0.19 ml, 0.27 mmol) was added at 0° C. The reaction mixture was stirred for 2 h. The reaction mixture was diluted with water and extracted with DCM. The combined organics were washed with brine, dried over magnesium sulfate and concentrated under vacuum. The resulting residue was loaded on to silica and purified by column Chromatography. (ISCO 12.0 g, 1-7% MeOH in DCM, 25 min.) to give 2-(3-(6-methyl-5-(2-(methylamino)quinazolin-6-yl)phthalazin-1-ylamino)phenyl)propan-2-ol. MS (M+H)+ 451.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:38][CH2:37][C:36]1[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=1)=[O:29]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC(=O)CN2CCc3cc(OC)c(OC)cc3C2Cc2ccc(OC)c(OC)c2)cc1

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 4-methoxybenzylamine
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:4]1([C@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H](O)c1ccccc1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
To a 100 mL autoclave with a stirrer bar, acetophenone (1.2 g, 10 mmol) and {Ru[(S)-daipena][(S)-xylbinap]}PF6 obtained from Example 2 above (12.9 mg, 0.01 mmol, 1/1000 molar fold of acetophenone) were added. After purging with a nitrogen gas, toluene (5 mL) and 1,8-diazabicyclo[5,4,0]undeca-7-ene (15.2 mg, 0.1 mmol) were added thereto. Subsequently, purging with a hydrogen gas, the mixture was stirred at 30° C. for 3 hours under hydrogen pressure 1 MPa. As a result of analysis of the reaction mixture by gas chromatography (Chirasil-DEX CB), it was found that the conversion rate is 99.6% and optical purity is 99.6% ee.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:31]=[CH:30][C:7]([CH2:8][N:9]([CH2:21][CH2:22][CH2:23][CH2:24]N2CCCC2)[C:10]([NH:12]CC2C=CC(Cl)=CC=2)=[NH:11])=[CH:6][CH:5]=1.[H-].[Na+].Br[CH2:35][CH2:36][CH2:37][CH2:38]CBr.[CH3:41][N:42](C=O)C>>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:41][N:42]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:10]([NH2:12])=[NH:11])=[CH:30][CH:31]=1
Reactant: BrCCCCCBr
Reactant: N=C(NCc1ccc(Cl)cc1)N(CCCCN1CCCC1)Cc1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: N=C(N)N(CCCCCN1CCCC1)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled stirred solution of the product from Example 52 step a (725 mg, 3.00 mmol) in DMF (9 ml) was added, in a single portion, sodium hydride (60% dispersion in mineral oil, 144 mg, 3.60 mmol). The coolant was removed and the suspension was stirred at ambient temperature for 30 minutes. The suspension was cooled in ice and 1,5-dibromopentane (1.23 ml, 9.03 mmol) was added in three portions. The coolant was removed and the reaction mixture was stirred at ambient temperature for 18 h. The reaction was quenched with water (40 ml) and then extracted with ethyl acetate (40 ml). The aqueous phase was discarded and the organic phase washed twice with brine (40 ml). The organic phase was dried over anhydrous magnesium sulfate and the filtrate evaporated at reduced pressure. The residue was purified by flash column chromatography (5:1 hexane:ethyl acetate) to afford the title product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[NH2:41][CH2:42][CH2:43][CH2:44][N:45]1[CH:49]=[CH:48][N:47]=[CH:46]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.C(O)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][NH:41][CH2:42][CH2:43][CH2:44][N:45]4[CH:49]=[CH:48][N:47]=[CH:46]4)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: NCCCn1ccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(-c3ccc(CNCCCn4ccnc4)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 43.6 %

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (Intermediate 2) (0.075 g, 0.14 mmol), 1-(3-aminopropyl)imidazole (0.034 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken at room temperature for 3 days. Additional portions of 1-(3-aminopropyl)imidazole (0.1 mL) and sodium triacetoxyborohydride (0.086 g, 0.40 mmol) were added and the reaction mixture was shaken for 3 days. Acetic acid (0.1 mL) was added and the reaction mixture was shaken for 4 days. 1N NaOH (1 mL) was added and the reaction mixture was concentrated, dissolved in DMF (2 mL), filtered through a syringe-tip Acrodisc filter, and purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 20-80% acetonitrile—0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 14.0-15.7 min was collected, concentrated, and lyopholyzed to afford N1-(4-{4-amino-1-[4-{([3-(1H-1-imidazolyl)propyl]amino}methyl)phenyl]-1H-pyrazolo [3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.040 g, 0.061 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.94 (1H, s), 8.35-8.40 (2H, m), 8.16 (2H, d, J=7.6 Hz), 7.99 (1H, t, J=7.6 Hz), 7.89 (1H, d, J=10.0 Hz), 7.75 (1H, d, J=8.4 Hz), 7.59 (1H, s), 7.52 (2H, d, J=3.8 Hz), 6.45 (1H, s), 7.40 (1H, d, J=8.0 Hz), 7.16 (1H, s), 6.87 (1H, s), 4.04 (2H, t, J=7.0 Hz), 3.96 (3H, s), 3.77 (2H, S), 2.45-2.46 (2H, m), 1.91 (3H, s), and 1.86-1.90 (2H, m); RP-HPLC (Hypersil C18, 5 μm 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.28 min. MS: MH+660.2.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:4](=[O:11])[C:5]2[N:10]=[N:9][NH:8][C:6]=2[N:7]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=O.C(OC(=O)C)(=O)C>O1CCOCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[CH:1][C:2]1[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:4](=[O:11])[C:5]2[N:10]=[N:9][NH:8][C:6]=2[N:7]=1
Reactant: Cc1ccccc1-n1c(C)nc2[nH]nnc2c1=O
Reactant: O=Cc1ccccn1
Solvent: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: Cc1ccccc1-n1c(C=Cc2ccccn2)nc2[nH]nnc2c1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 3.4 %

Procedure:
To a mixture of fused zinc chloride (0.551 g, 4.04 mmol) and dioxane (20 mL) was added 5-methyl-6-o-tolyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one (0.488 g, 2.02 mmol),2-pyridinecarboxaldehyde (0.58 mL, 6.06 mmol), and acetic anhydride (0.57 mL, 6.06 mmol). The mixture was heated to 70° C. for 6 hours, cooled, and quenched with saturated sodium bicarbonate. This mixture was stirred overnight at ambient temperature. The dioxane was removed at reduced pressure and the resulting black liquid was extracted with methylene chloride. The organic phase was dried over magnesium sulfate, treated with activated carbon, filtered, and concentrated. The residue (1.5 g) was flash chromatographed on silica gel (50 g). Elution with 50% and 60% ethyl acetate/hexane gave 5-(2-pyridin-2-yl-vinyl)-6-o-tolyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one (0.023 g, 3.5%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:23][C:24]1[N:28](C(OC(C)(C)C)=O)[N:27]=[C:26]([O:36][CH2:37][C:38]2[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([O:46][CH3:47])[CH:39]=2)[CH:25]=1.N1C=CC=CC=1.Cl>C1COCC1.O1CCOCC1>[CH3:45][O:44][C:42]1[CH:43]=[C:38]([CH2:37][O:36][C:26]2[NH:27][N:28]=[C:24]([NH:23][C:17](=[O:19])[C:16]3[CH:20]=[CH:21][CH:22]=[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:15]=3)[CH:25]=2)[CH:39]=[C:40]([O:46][CH3:47])[CH:41]=1
Reactant: COc1cc(COc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)O)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(COc2cc(NC(=O)c3cccc(N4CCNCC4)c3)n[nH]2)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.6 %

Procedure:
1-Chloro-N,N-2-trimethyl-1-propenylamine (78 μl, 0.588 mmol, 1.2 eq) was added dropwise to a stirred solution of 3-[4-(tert-butoxycarbonyl)piperazin-1-yl]benzoic acid (150 mg, 0.588 mmol, 1.2 eq) in THF (10 ml) under nitrogen. The mixture was stirred at room temperature overnight. tert-Butyl 5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (172 mg, 0.490 mmol, 1 eq) and pyridine (48 μl, 0.588 mol, 1.2 eq) were added and the mixture was heated at 65° C. overnight. The mixture was allowed to cool to room temperature and 4M HCl in dioxane (2 ml) was added. Stirring was continued at room temperature overnight. The precipitated yellow solid was collected by filtration and washed with THF. The solid was triturated with aq NaHCO3 (4 ml) and DCM (2 ml). A small amount of a brown gum remained out of solution. The gum was collected by filtration and washed with water and ether. The aqueous filtrate was extracted with ethyl acetate (3×10 ml) and the combined extracts were dried over MgSO4, filtered and evaporated. The extracted product was combined with the gum from filtration and purified by silica column chromatography, eluting with a gradient of 10-12% MeOH in DCM. Product fractions were evaporated to give the title compound as a white solid (27 mg, 10% yield); 1H NMR (399.902 MHz, DMSO+d4-AcOD) δ 3.13-3.21 (m, 4H), 3.33-3.40 (m, 4H), 3.68 (s, 6H), 5.02 (s, 2H), 5.71 (s, 1H), 6.38 (t, 1H), 6.52 (d, 2H), 7.12-7.17 (m, 1H), 7.33 (t, 1H), 7.37-7.41 (m, 1H), 7.46-7.49 (m, 1H). MS: m/z 438 (MH+)
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.[Mn:13]([Cl:16])([Cl:15])=[O:14]>CCCCCC.C1COCC1>[N:6]1[CH:11]=[CH:10][C:9]([CH2:12][Mn:13]([Cl:16])([Cl:15])=[O:14])=[CH:8][CH:7]=1
Reactant: Cc1ccncc1
Reactant: O=[Mn](Cl)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=[Mn](Cl)(Cl)Cc1ccncc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, butyl lithium in hexane (8.35 ml, 1.6 M solution) was added to a solution of 4-picoline (1.23 g) in THF (25 ml) at -30° C. slowly over 20 mins. The solution was then stirred at room temperature for 1 hr and anhydrous manganous chloride (1.51 g) added at 0° C. The suspension was stirred for ca. 3/4 hr at room temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([S:9][C:10]#[N:11])[CH:6]=[CH:5][C:3]=1[NH2:4].CC(C)=O.[C:16](Br)#[N:17].[OH-].[Na+]>C(O)C>[NH2:17][C:16]1[NH:4][C:3]2[CH:5]=[CH:6][C:7]([S:9][C:10]#[N:11])=[CH:8][C:2]=2[N:1]=1
Reactant: N#CBr
Reactant: N#CSc1ccc(N)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: N#CSc1ccc2[nH]c(N)nc2c1
Reaction time: 8 h

Procedure:
8.25 g. of 2-amino-4-thiocyanato-aniline are dissolved in 60 ml. of acetone, whereupon a solution of 6.1 g. of bromo cyane and 20 ml. of ethanol is added dropwise. The reaction mixture is allowed to stand overnight, whereupon it is evaporated to dryness. The residue is taken up in water and the pH of the solution formed is adjusted to 8 by adding a 2N sodium hydroxide solution. The precipitated crystals are filtered off, washed with water and dried. Thus 8.3 g. of 2-amino-5-thiocyanato-1H-benzimidazole are obtained. M.p.: 204°-205° C. (decomposition).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([CH:19]2[NH:23][C:22](=[O:24])[CH2:21][CH2:20]2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([CH:19]2[CH2:20][CH2:21][C:22](=[O:24])[N:23]2[CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C2CCC(=O)N2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)CCC1C(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a stirring solution of 5-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}pyrrolidin-2-one obtained in Example 62 (0.40 g, 1.21 mmol) in DMF (7 mL) was added sodium hydride (54 mg, 60% in mineral oil, 1.34 mmol) and the mixture was stirred at room temperature for 30 min. After this time, to the mixture was added methyl bromoacetate (0.20 g, 1.34 mmol) and the mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride solution, and the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water, saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was washed with hexane-diisopropyl ether solution to give the title compound (0.41 g, 84%) as a white amorphous solid.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)(=O)=O)C=CC=CC=1.[OH-].[K+].O>CO>[CH3:22][S:19]([C:17]1[CH:18]=[C:13]2[CH:12]=[C:11]([C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[NH:10][C:14]2=[N:15][CH:16]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncccn1)n2S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1cnc2[nH]c(-c3ncccn3)cc2c1
Temperature: 22.5 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a suspension of the compound obtained in Example 6 (2) (1.10 g) in methanol (24 ml), a 1N aqueous potassium hydroxide solution (4.8 ml) was added and the mixture was stirred at 15 to 30° C. for 1 hour. The mixture was further heated under reflux for 15 minutes. After completion of the reaction, the reaction solution was poured into water, extracted with chloroform, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was washed with methanol/water and filtered off. Further, the unnecessary substances in the aqueous layer during extraction were filtered off, and they were combined and heated to dryness to obtain 417 mg of the desired product as a white powder.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[H-].[Na+].[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17].Cl>CN(C)C=O>[CH2:16]([O:15][C:14](=[O:18])[CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3])[CH3:17]
Reactant: CCOC(=O)OCC
Reactant: COc1ccc(C(C)=O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of 4-methoxyacetophenone (100 g, 0.66 mol) in dry dimethylformamide (400 mL), 60% sodium hydride (34.3 g, 0.85 mol) was added slowly at 10° C. under a nitrogen atmosphere. This mixture was stirred at 25° C. for 30 minutes and again cooled to 10° C. This was added to solution of diethyl carbonate (94.5 g, 0.80 mol) and dissolved in minimum quantity of dry dimethylformamide at the same temperature. The mixture was then stirred at 25° C. for 5 to 6 hours and poured into ice cold water (100 mL) with vigorous stirring. The mixture was then acidified (pH˜6-7) using cold 2 N hydrochloric acid and extracted with ethyl acetate. The organic layers were collected, combined, washed with water, dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to afford the desired compound as yellow oil (133 g). Yield: 90%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=3)[C:12]([NH:21][S:22]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)(=[O:24])=[O:23])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:38]([O:41][C:42]([CH3:47])([CH3:46])[C:43](Cl)=[O:44])(=[O:40])[CH3:39]>ClCCl>[C:38]([O:41][C:42]([CH3:47])([CH3:46])[C:43]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=3)[C:12]([NH:21][S:22]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)(=[O:24])=[O:23])=[N:11]2)[CH:4]=1)=[O:44])(=[O:40])[CH3:39]
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)C(C)(C)OC(C)=O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A stirring suspension of N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (40.5 g, 87 mmol) in dichloromethane (1000 mL) and triethylamine (36.4 mL, 262 mmol) was cooled down and then 2-chloro-1,1-dimethyl-2-oxoethyl acetate (12.52 mL, 87 mmol) was added dropwise. The reaction mixture was stirred at room temperature under nitrogen for 1 h and 20 min. It was then washed with 2M HCl (300 ml), NaHCO3 solution (300 ml), brine, dried over magnesium sulphate and filtered. The filtrate was evaporated in vacuo to give a white solid. The residue was dissolved in DCM and loaded onto a 1500 g silica column and eluted with 40-100% ethyl acetate in cyclohexane over 8 CV. The required fractions were combined and evaporated in vacuo to give the title compound in two batches (37.87 g, 73%) and (3.39 g) as white foams. HPLC showed that the latter batch was not pure, therefore it was purified again on a 120 g silica column using a gradient of 40-75% ethyl acetate in cyclohexane over 8 CV. The required fractions were combined and evaporated in vacuo to give the title compound (2.16 g, 4%) as a white foam.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[N:31][CH:32]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[C:29]([OH:33])[CH:30]=[N:31][CH:32]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: Oc1cncc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Oc1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 5-bromo-3-pyridinol (156 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (280 mg, 62%). MS (ISP) 449.2[(M+H)+]; mp 258–260° C.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1>CN1C(=O)CCC1>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: Fc1ccc2nnc(Cl)n2c1
Reactant: OCC1CCNCC1
Solvent: CN1CCCC1=O
Product: OCC1CCN(c2nnc3ccc(F)cn23)CC1
Yield: 55.7 %

Procedure:
A solution of Intermediate 14b (593 mg, 3.45 mmol) and 4-piperidinemethanol (1.59 g, 13.8 mmol) in NMP (10 mL) was heated in the microwave at 170° C. for 3 h. The cooled mixture was applied to an SCX-2 cartridge (70 g), washing with methanol then eluting basic components with 0.4-2 M NH3 in MeOH. Product containing fractions were combined and concentrated in vacuo. The residue was purified by FCC, using 0-15% MeOH in EtOAc, to give the title compound as a brown gum (481 mg, 56%). LCMS (Method 3): Rt 2.12 min, m/z 251 [MH+].