Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][C:22]1[N:27]=[C:26]([C:28]2[C:36]3[C:31](=[N:32][C:33]([Cl:37])=[N:34][CH:35]=3)[NH:30][N:29]=2)[CH:25]=[CH:24][CH:23]=1.CCN(CC)CC.O>CN(C=O)C>[Br:21][C:22]1[N:27]=[C:26]([C:28]2[C:36]3[C:31](=[N:32][C:33]([Cl:37])=[N:34][CH:35]=3)[N:30]([C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:29]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Clc1ncc2c(-c3cccc(Br)n3)n[nH]c2n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncc2c(-c3cccc(Br)n3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of trityl chloride (8.5 g, 30.5 mmol) in DMF (80 mL) was added dropwise to the solution of 3-(6-bromo-pyridin-2-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidine (from Example 30 supra) (8.0 g, 25.7 mmol) and Et3N (12 mL, 83.2 mmol) in DMF (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours then poured into water and extracted with ethyl acetate. The organic solution was dried with anhydrous Na2SO4. After filtration and concentration, the residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate, 20:1) to give 3-(6-bromo-pyridin-2-yl)-6-chloro-1-trityl-1H-pyrazolo[3,4-d]pyrimidine as a white powder. (Yield 3.8 g, 27%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:21][C:22]([F:44])([F:43])[C:23]1[CH:24]=[C:25]([S:29]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]2[CH2:38][S:39](Cl)(=[O:41])=[O:40])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[CH2:13][CH2:12][N:11]([S:39]([CH2:38][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][N:32]3[S:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:44])([F:21])[F:43])[CH:24]=3)(=[O:31])=[O:30])(=[O:40])=[O:41])[CH2:10][CH2:9]2)[CH2:6][CH2:7]1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: O=S(=O)(Cl)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCC(N2CCN(S(=O)(=O)CC3CCCCN3S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
1-(1-Methyl-4-piperidinyl)piperazine (1.126 mmol) was dissolved in methylene chloride (7 ml), the solution was cooled in an ice bath and triethylamine (2.8 mmol) and (1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-2-yl)methanesulfonic acid chloride (dissolved in methylene chloride (3 ml)) were added. The mixture was stirred for 16 h, during which it was allowed to warm slowly to room temperature. The reaction mixture was diluted with methylene chloride and washed with water and the organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with methylene chloride/methanol (19:1). Yield: 30%. MS, Rt=2.4 min, m/z=553.0 [MH]+
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:43])([F:42])[S:5]([N:8]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:33][CH3:34])=[CH:30][CH:31]=3)[CH:26]=[C:25]([CH3:35])[C:24]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:18][CH:17]=1)S(C(F)(F)F)(=O)=O)(=[O:7])=[O:6].Cl>C(Cl)Cl>[F:42][C:4]([F:3])([F:43])[S:5]([NH:8][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:33][CH3:34])=[CH:30][CH:31]=3)[CH:26]=[C:25]([CH3:35])[C:24]=2[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:18][CH:17]=1)(=[O:6])=[O:7]
Reactant: COc1ccc2c(Oc3ccc(N(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NS(=O)(=O)C(F)(F)F)cc3)c(-c3ccccc3)c(C)cc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.3 %

Procedure:
1 N Sodium Hydroxide (2 mL) was added to a solution of 30 (94 mg, 0.15 mmol, 1 equiv) in CH2Cl2 (2 mL) and the reaction mixture was stirred at RT for 3 days. The reaction was then acidified to pH 2 with 1 N HCl and the product extracted into CH2Cl2 (100 mL). The organic layer was washed with saturated aqueous NaHCO3 (2×50 mL), dried over MgSO4, filtered and concentrated to dryness. The residue was purified by silica gel flash column chomatography (20% EtOAc in hexanes) to provide 31 (47 mg, 64%) as a yellow oil. 1HNMR (400 MHz, DMSO-d6): δ 11.52 (br s, 1H), 7.69 (m, 1H), 7.57 (m, 1H), 7.34-7.21 (m, 4H), 7.15 (m, 2H), 7.07 (m, 1H), 6.99 (m, 2H), 6.59 (m, 2H), 3.86 (s, 3H), 2.16 (s, 3H). MS m/z 486.1 (M−H)−.
Reaction SMILES: [F:1][C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.Cl>C1COCC1.C(Cl)Cl>[F:1][C:2]1[C:10]2[CH:9]=[C:8]([B:16]([OH:21])[OH:17])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1cccc2sccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: OB(O)c1cc2c(F)cccc2s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of 4-fluorobenzo[b]thiophene (80.4 mg, 0.528 mmol) in anhydrous THF (1 mL) was added n-butyllithium (0.363 mL, 0.581 mmol) dropwise. The reaction mixture was stirred at −78° C. for 60 minutes. A solution of triisopropyl borate (0.146 mL, 0.634 mmol) was added. The reaction mixture was stirred at −78° C. for 30 minutes and was then allowed to warm to room temperature over a 2 hour period. TLC showed completion of reaction. 1N HCl (100 mL) and DCM (50 mL) were added to the reaction mixture. The aqueous and organic layers were separated. The aqueous layer was concentrated to 50 mL, yielding a solid precipitate that was filtered and dried to give the title compound as off-white, needle-shaped crystals. The product was used without further purification.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[N:6]=[CH:7][N:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:11]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:10][C:9]=12)=[NH:4].[S:28]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=O)=[CH:34][CH:33]=1)(=[O:31])(=[O:30])[NH2:29]>>[F:17][C:14]([F:15])([F:16])[C:13]1[N:8]2[CH:7]=[N:6][C:5]([C:3]3[N:4]=[C:36]([C:35]4[CH:34]=[CH:33][C:32]([S:28]([NH2:29])(=[O:31])=[O:30])=[CH:40][CH:39]=4)[O:1][N:2]=3)=[C:9]2[N:10]=[C:11]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH:12]=1
Reactant: N=C(NO)c1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Product: NS(=O)(=O)c1ccc(-c2nc(-c3ncn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)no2)cc1

Procedure:
The title compound was prepared from N-hydroxy-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxamidine (example B.3) (195 mg, 0.5 mmol) and commercially available 4-sulfamoyl-benzoic acid (101 mg, 0.5 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (dichloromethane) as a yellow solid (61 mg, 22%). MS (ISP) 555.3 [(M+H)+]; mp 303° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C[O-].[Na+].CO.[CH3:13][O:14][C:15]1[CH:55]=[CH:54][C:18]([CH2:19][O:20][C:21]([C:23]2[N:28]3[C:29](=[O:51])[C@@H:30]([NH:31][C:32](=[O:50])[C:33]([C:37]4[N:38]=[C:39]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[S:40][CH:41]=4)=[N:34][O:35][CH3:36])[C@H:27]3[S:26][CH2:25][C:24]=2[CH2:52]Cl)=[O:22])=[CH:17][CH:16]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]([C:23]2[N:28]3[C:29](=[O:51])[C@@H:30]([NH:31][C:32](=[O:50])[C:33]([C:37]4[N:38]=[C:39]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[S:40][CH:41]=4)=[N:34][O:35][CH3:36])[C@H:27]3[S:26][CH2:25][C:24]=2[CH2:52][S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[O:22])=[CH:54][CH:55]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(CCl)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: Sc1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(CSc3ccncc3)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Reaction time: 0.17 h
Yield: 97.4 %

Procedure:
To a solution of 4-mercaptopyridine (222 mg; 2 Eq.) in N,N-dimethylformamide (10 ml) keeping at 0° C. is added a solution of sodium methoxide in methanol (1.5 Eq.). To this mixture is added 7β-[2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (2) (652 mg; 1 mMol.), and the mixture is stirred for 10 minutes. The reaction mixture is diluted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel chromatography (toluene:ethyl acetate) to give 7β-[2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-methoxyiminoacetamido]-3-(4-pyridyl)thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (3) (708 mg).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH:14]=[CH2:15])=[CH:6][C:7]3[CH2:11][O:10][C:9](=[O:12])[C:8]=3[CH:13]=2)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:24])C=1>ClCCl.C(=O)(O)[O-].[Na+]>[CH:1]1([C:4]2[C:5]([CH:14]3[CH2:15][O:24]3)=[CH:6][C:7]3[CH2:11][O:10][C:9](=[O:12])[C:8]=3[CH:13]=2)[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1cc2c(cc1C1CC1)C(=O)OC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1OCc2cc(C3CO3)c(C3CC3)cc21
Reaction time: 12 h

Procedure:
6-Cyclopropyl-5-vinyl-2-benzofuran-1(3H)-one (0.45 g, 2.25 mmol) was dissolved in dichloromethane (10 mL) and treated with meta-chloro perbenzoic acid (1 g, 6.3 mmol) at 0° C. and stirred for 12 h. TLC indicated completion of the reaction; the mixture was diluted with saturated sodium bicarbonate solution and extracted with dichloromethane (2×). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The epoxide was purified by silica gel column chromatography (hexanes/EtOAc=1/1) to give 6-Cyclopropyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one. The oxirane was further resolved over a chiral column giving two isomers:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:19]=[C:18]([CH:20]2[CH2:23][O:22][CH2:21]2)[CH:17]=[C:16]([F:24])[C:15]=1B1OC(C)(C)C(C)(C)O1>>[F:13][C:14]1[CH:19]=[C:18]([CH:20]2[CH2:23][O:22][CH2:21]2)[CH:17]=[C:16]([F:24])[C:15]=1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: COC(=O)c1ccc(F)c(Br)n1
Reactant: CC1(C)OB(c2c(F)cc(C3COC3)cc2F)OC1(C)C
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(C3COC3)cc2F)n1
Yield: 47 %

Procedure:
Method 1 was followed using methyl 6-bromo-5-fluoropicolinate (1.2 equiv.) and 2-(2,6-difluoro-4-(oxetan-3-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 equiv.) at 80° C. for 15 min in microwave to give methyl 6-(2,6-difluoro-4-(oxetan-3-yl)phenyl)-5-fluoropicolinate in 47% yield. LC/MS=324.0 (MH+), Rt=0.75 min.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH3:16][C:17]1[CH:18]=[C:19]([O:23][CH2:24][CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=1>>[CH2:24]([O:23][C:19]1[CH:20]=[CH:21][C:22]([CH:9]=[O:10])=[C:17]([CH3:16])[CH:18]=1)[CH:25]=[CH2:26]
Reactant: C=CCOc1cccc(C)c1
Reactant: CN(C=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: C=CCOc1ccc(C=O)c(C)c1
Temperature: 70 °C
Reaction time: 0.42 h
Yield: 81 %

Procedure:
N-methyl formanilide 19.4 ml (158 mmole), was chilled to 13° C., where it began to solidify. Phosphorus oxychloride, 13.7 ml (147 mmole), was added with stirring, under nitrogen. After 25 minutes, the temperature was 45° C. and the reaction had again begun to solidify. The compound of Step A, 14 g (95 mmole), was added and the mixture was stirred and heated in a 70° C. oil bath. The reaction exothermed to 95° C. Stirring was continued under nitrogen for 30 minutes. The bath was removed and when the temperature reached 350, the mixture was dissolved in chloroform. Ice was added and the layers were separated and washed once with water, twice with saturated sodium bicarbonate, once again with water and once with brine. The organic layer was chromatographed on 450 ml silica, eluting with chloroform to give 13.54 g (81%) of subtitled product which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([C:11]([O:13]CC)=[O:12])=[CH:8][C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:6][C:5]=2[N:4]([CH:22]([CH3:24])[CH3:23])[N:3]=1.[OH-].[Na+].Cl>C1COCC1.C(O)C.O>[Br:1][C:2]1[C:10]2[C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:6][C:5]=2[N:4]([CH:22]([CH3:24])[CH3:23])[N:3]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)nc2c1c(Br)nn2C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)n1nc(Br)c2c(C(=O)O)cc(-c3ccccc3)nc21
Temperature: 55 °C
Reaction time: 3 h

Procedure:
Ethyl 3-bromo-1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (112 mg, 0.288 mmol) was suspended in THF (0.5 mL) and ethanol (1.5 mL), followed by addition of 3N NaOH (150 μl, 0.433 mmol). The reaction mixture was stirred at 55° C. for 3 hours, and then allowed to cool to room temperature. The reaction mixture was diluted with water (1.5 mL), cooled in an ice bath, and acidified with 1N HCl in a dropwise manner. The mixture was extracted with EtOAc. The organic layer was separated and concentrated in vacuo to afford a solid that dried on the high vacuum 3 hours. The product was collected as a pale yellow solid (93.6 mg, 90%). LCMS E-S (M+H)=360.0/362.2. 1H NMR (400 MHz, MeOD) 68.22 (dd, J=1.52, 8.08 Hz, 2H), 8.05 (s, 1H), 7.48-7.59 (m, 3H), 5.47 (quin, J=6.76 Hz, 1H), 1.63 (d, J=6.82 Hz, 6H)
Reaction SMILES: [CH2:1]([C:3]([OH:8])([CH2:6][CH3:7])[C:4]#[CH:5])[CH3:2].C[Li].[CH3:11][S:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>C1COCC1.CCCCCC>[CH2:4]([C:3]([OH:8])([CH2:6][CH3:7])[C:1]#[C:2][CH:17]([C:16]1[CH:19]=[CH:20][C:13]([S:12][CH3:11])=[CH:14][CH:15]=1)[OH:18])[CH3:5]
Reactant: C#CC(O)(CC)CC
Reactant: CSc1ccc(C=O)cc1
Agent: [Li]C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(O)(C#CC(O)c1ccc(SC)cc1)CC
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-ethyl-1-pentyn-3-ol (7.7 ml) in 300 ml anhydrous THF, was added dropwise 100 ml of 1.4 M methyllithium in hexane at −78° C. under argon. The mixture was further stirred for 30 minutes, followed by dropwise addition of 4-(methylthio)benzaldehyde (9.3 ml). The reaction mixture was stirred for another 12 hours, during which the cold bath was removed such that the reaction temperature reached room temperature slowly. Then the reaction was quenched by adding dilute aqueous HCl. The solvent was removed in vacuo and the resulting residue was extracted with brine and dichloromethane (150 ml×3). The organic layer was concentrated under reduced pressure and the resulting crude product was purified by recrystallization from hexane and ethylacetate (4:1) to give 11.8 g of 4-ethyl-1-{4-(methylthio)phenyl}-2-hexyn-1,4-diol as a low-melting solid. mp: 64-65° C. NMR: δ1.04 (t, J=7.5 Hz, 6H), 1.70 (q, J=7.5 Hz, 4H), 2.49 (s, 3H), 5.47 (s, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H). IR (cm−1): 3368, 2970, 2207, 1637, 1589, 1262, 1093.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:13]=2)=[O:9])[CH:5]=[C:4]([C:39]2[O:40][CH:41]=[CH:42][CH:43]=2)[N:3]=1.Cl.O1CCOCC1>CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[N:13]=2)=[O:9])[CH:5]=[C:4]([C:39]2[O:40][CH:41]=[CH:42][CH:43]=2)[N:3]=1
Reactant: Nc1nc(C(=O)NCc2cccc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc(-c2ccco2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1nc(C(=O)NCc2cccc(CO)n2)cc(-c2ccco2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 61 %

Procedure:
A solution of 2-amino-6-(2-furyl)-N-(6-(triphenylmethoxymethyl)pyridin-2-ylmethyl)pyrimidine-4-carboxamide (3.41 g, 6 mmol) in MeOH (50 mL) was treated with 4-M HCl in dioxane (7.5 mL, 30 mmol), stirred at room temperature for 20 h and concentrated in vacuo. The residue was diluted with water (50 mL) basified with 5-M NaOH, extracted with EtOAc (2×25 mL) and the combined organic phase washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (1.19 g, 61%) as a cream solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]#[N:20])[CH2:14][CH2:13]2)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.C(O[C:24](OCC)(OCC)[CH2:25][CH3:26])C>C(O)(=O)C.CO>[CH2:25]([C:26]1[N:11]([C@H:12]2[CH2:13][CH2:14][C@H:15]([CH2:18][C:19]#[N:20])[CH2:16][CH2:17]2)[C:3]2=[C:4]3[S:10][CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]2[N:1]=1)[CH3:24]
Reactant: N#CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Reactant: CCOC(CC)(OCC)OCC
Solvent: CO
Solvent: CC(=O)O
Product: CCc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)CC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of {trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetonitrile (20.1 mg, 0.0702 mmol) and 1,1,1-triethoxypropane (0.0428 mL, 0.213 mmol) in acetic acid (0.2 mL) was stirred at 120° C. for 30 min. The mixture was diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (13 mg, 57%). LCMS calculated for C18H21N4S (M+H)+: m/z=325.1. Found: 325.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([N:7]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].Cl.[CH2:31]([C:35]1[O:36][C:37]2[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=2[C:39]=1[CH2:40][NH2:41])[CH2:32][CH2:33][CH3:34].C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:29])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:41][CH2:40][C:39]2[C:38]3[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=3[O:36][C:35]=2[CH2:31][CH2:32][CH2:33][CH3:34])=[O:26])=[CH:27][CH:28]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)=[O:6])[CH3:2]
Reactant: CCCCc1oc2ccccc2c1CN
Reactant: CCOC(=O)C(=O)N(Cc1ccc(C(=O)O)cc1)Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCc1oc2ccccc2c1CNC(=O)c1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)C(=O)OCC)cc1
Yield: 33 %

Procedure:
The same procedure as employed in the preparation of Example 1 (step d) but using 4-({[ethoxy(oxo)acetyl][4-(trifluoromethyl)benzyl]amino}methyl)benzoic acid and [(2-butyl-1-benzofuran-3-yl)methyl]amine hydrochloride, HOBT and TEA in DCM gave the title compound as a white solid (33%). 1H NMR (CDCl3, 300 MHz) δ 7.66 (m, 2H), 7.51 (m, 3H), 7.35-7.18 (m, 7H), 6.05 (br s, 1H), 4.64 (s, 2H), 4.44 (s, 2H), 4.29 (m, 4H), 2.78 (m, 2H), 1.66 (m, 2H), 1.46 (m, 2H), 1.24 (m, 3H), 0.88 (m, 3H). M−(LC/MS(ESI)): 593; M+(LC/MS(ESI)): 595. HPLC (Condition A), Rt: 6.38 min (HPLC purity: 99.6%).
Reaction SMILES: Cl.[CH2:2]([NH:5][N:6]=[CH:7][C:8]1[CH:32]=[CH:31][C:11]([C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH:22]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:21][CH2:20][C:19]=3[CH:30]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:3][CH3:4].C(O)C.[OH-].[Na+]>C(O)(=O)C>[CH2:2]([NH:5][N:6]=[CH:7][C:8]1[CH:32]=[CH:31][C:11]([C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH:22]([CH2:24][C:25]([OH:27])=[O:26])[CH2:21][CH2:20][C:19]=3[CH:30]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:3][CH3:4]
Reactant: CCCNN=Cc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)OCC)O3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCNN=Cc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)O)O3)cc1

Procedure:
0.25 g (0.54 mmol) of the ester from Example 81 were stirred at room temperature overnight with 5 ml ethanol and 0.7 ml 2 N aqueous sodium hydroxide. The mixture was brought to pH 4 with 2 N acetic acid, and the precipitate of the acid (338) was filtered with suction, washed successively with water and with acetone, and dried in vacuo. Yield: 0.16 g (74%) of a pale yellow powder, m.p. 241-242° C. (dec.).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9](O)=[O:10]>>[CH:1]1([NH:4][C:9](=[O:10])[C:8]2[CH:12]=[CH:13][C:14]([F:15])=[C:6]([F:5])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(F)c(F)c1
Product: O=C(NC1CC1)c1ccc(F)c(F)c1
Yield: 89 %

Procedure:
Using cyclopropylamine and 3,4-difluorobenzoic acid in the general procedure for coupling of amines to carboxylic acids, the title compound was obtained (89% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.52-0.63 (m, 2 H) 0.63-0.74 (m, 2 H) 2.83 (tq, J=7.42, 3.98 Hz, 1 H) 7.52 (dt, J=10.55, 8.37 Hz, 1 H) 7.66-7.75 (m, 1 H) 7.85 (ddd, J=11.68, 7.89, 2.15 Hz, 1 H) 8.42-8.60 (m, 1 H). ESI-MS: m/z 198.1 (M+H)+. mp=104.1-108.4° C.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[C:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)#[N:18]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[NH:18])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: N#Cc1cccnc1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(NC(=N)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (6 g, 28.8 mmol) in toluene (150 ml) at 0° C., trimethylaluminum (2M solution in toluene, 21.6 ml, 43.2 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 3-cyanopyridine (6 g, 57.6 mmol) in toluene (150 ml) was added over 10 minutes and the reaction mixture was heated to 90°-95° C. After 24 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol and later methanol. The combined filtrates were concentrated and the resulting yellowish solid was stirred with ethyl acetate (1000 ml) and filtered. The pale yellow amidine (4.5 g, 34%) was used in the next reaction without further purification: mp (DSC) 265° C. Anal Calc'd. for C13H14N3SO2Cl.0.5H2O: C, 48.67, H, 4.71, N, 13.10. Found: C, 48.34, H, 4.26, N, 12.77.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([NH2:18])[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.Br[CH2:26][CH2:27][O:28][CH2:29][CH2:30]Br.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C)C(=O)C>[CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:18]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: Cc1c(O[C@@H]2CCC[C@H](N)C2)ccc2c1cnn2C1CCCCO1
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1c(O[C@H]2CCC[C@@H](N3CCOCC3)C2)ccc2c1cnn2C1CCCCO1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
Under nitrogen, the cis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexanamine (90 mg, 0.273 mmol) obtained in Example 724 was dissolved in N,N-dimethylacetamide (2 ml), followed by adding thereto bis(2-bromoethyl) ether (34 μl, 0.273 mmol) and potassium carbonate (94 mg, 0.683 mmol), and the resulting mixture was stirred at 80° C. for 6 hours. The reaction solution was cooled to room temperature and a 1N-aqueous sodium hydroxide solution was added thereto, followed by extraction with chloroform (three times). The combined chloroform layer was washed with a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: acetonitrile/aqueous ammonia=100/0, 100/1) to obtain 4-methyl-5-[(cis-3-morpholin-4-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole (83 mg, yield 76.0%) as light-yellow tar.