Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:10]#[N:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[SH-:13].[Na+]>CCO>[C:1]1([C:7]2([C:10](=[S:13])[NH2:11])[CH2:8][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [SH-]
Reactant: N#CC1(c2ccccc2)CC1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=S)C1(c2ccccc2)CC1
Temperature: -20 °C

Procedure:
1-Phenylcyclopropanenitrile (1-1, 10.0 g, 69.8 mmol) and sodium hydrosulfide hydrate (0.98 g, 17.5 mmol) were mixed in a 350 mL glass bomb and dissolved in 50 mL anhydrous EtOH. The resulting solution was cooled to −20° C. and a stream of H2S was bubbled through the mixture for 30 min. The bomb was sealed and heated to 90° C. for 2 days. The dark mixture was cooled to −25° C. and N2 was bubbled through for 1 h. The reaction mixture was diluted with H2O (50 mL) and extracted with Et2O (3×50 mL). The combined organic layers were dried (MgSO4), filtered and concentrated. The crude thioamide was triturated with hexanes to provide pure 1-phenylcyclopropanecarbothioamide (1-2) as a white solid.
Reaction SMILES: CC[O-].[Na+].O=[C:6]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:14]([O:16]CC)=O.[NH2:19][C:20]([NH2:22])=[S:21].Cl>CCO>[SH:21][C:20]1[N:19]=[C:14]([OH:16])[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:6]=2[N:22]=1
Reactant: CCOC(=O)C1CCCCCCC1=O
Reactant: NC(N)=S
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(S)nc2c1CCCCCC2
Yield: 63.2 %

Procedure:
700 mg of NaOEt (10 mmol; 1.0 equiv) was added to 6 mL of abs. EtOH. To this solution was added, with stirring, 2 g of ethyl 2-keto-cyclooctylcarboxylate (10 mmol; 1.0 equiv) and 1 g of thiourea (13 mmol; 1.3 equiv). The mixture was refluxed for 6 hours. After cooling, the mixture was poured onto ice and acidified with hydrochloric acid. 1.33 g of 2-mercapto-5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine-4-ol (63% yield) was obtained as a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]#[N:20])[CH:10]=1)=O)(=[O:3])[CH3:2].C[Si]([N:25]=[N+:26]=[N-:27])(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCOC(C)=O>[C:1]([O:4][CH2:5][C:6]1[N:8]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]#[N:20])[CH:10]=2)[N:27]=[N:26][N:25]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)OCC(=O)Nc1cc(C#N)cc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)OCc1nnnn1-c1cc(C#N)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 90.7 %

Procedure:
To a solution of 2-{[3-cyano-5-(trifluoromethyl)phenyl]amino}-2-oxoethyl acetate (Intermediate 29, 3.38 g, 11.8 mmol) in tetrahydrofuran (100 mL) was added trimethylsilylazide (3.14 mL, 23.6 mmol), triphenylphosphine (6.20 g, 23.6 mmol) then di-isopropylazodicarboxylate (4.60 mL, 23.6 mmol). The reaction was warmed to 50° C. and stirred for 6 hours. The reaction was cooled and diluted with EtOAc (150 mL). The solution was washed with water (100 mL), passed through a hydrophobic frit and the solvent removed under vacuum. The residue was purified by silica chromatography (Biotage SP4, eluting 10% EtOAc in iso-hexane (4 column volumes) then a gradient from 10-35% EtOAc in iso-hexane (over 8 column volumes)) to yield the title compound as a yellow solid (3.33 g)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][CH2:15][CH3:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:17]C(OC(Cl)C)=O>ClC(Cl)C>[ClH:17].[CH:14](=[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH:15]=[CH2:16]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCC=C1CCN(Cc2ccccc2)CC1
Solvent: CC(Cl)Cl
Product: C=CC=C1CCNCC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 110.4 %

Procedure:
There was dissolved 4.5 g (21 mmol) of 1-benzyl-4-propylidenepiperidine in 20 ml of dichloroethane and thereto 2.8 ml (25 mmol) of 1-chloroethyl chloroformate was added dropwise under cooling with ice. The reaction solution was stirred at room temperature for 30 minutes and then refluxed with heating for 30 minutes. The reaction solution was concentrated to 10 ml by removing the solvent under reduced pressure, and thereto was added 60 ml of methanol and the obtained mixture was refluxed with heating for 12 hours. The solvent was removed under reduced pressure to obtain 3.7 g of the titled compound.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][N:26]=4)[CH2:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)[N:13]=2)[CH2:6][CH2:5][O:4][CH2:3]1.O1CCOCC1.C(N(CC)CC)C.[C:44](Cl)(Cl)=[O:45].[NH2:48][C:49]1[CH:53]=[CH:52][O:51][N:50]=1>C1(C)C=CC=CC=1>[O:51]1[CH:52]=[CH:53][C:49]([NH:48][C:44]([NH:18][C:17]2[CH:16]=[CH:15][C:14]([C:12]3[N:13]=[C:8]([N:7]4[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]4[CH3:1])[C:9]4[CH2:24][CH2:23][N:22]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][N:26]=5)[CH2:21][C:10]=4[N:11]=3)=[CH:20][CH:19]=2)=[O:45])=[N:50]1
Reactant: O=C(Cl)Cl
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc2c1CCN(c1ccncn1)C2
Reactant: Nc1ccon1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Nc3ccon3)cc2)nc2c1CCN(c1ccncn1)C2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
(S)-4-(4-(3-methylmorpholino)-7-(pyrimidin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)aniline (0.0700 g, 0.000173 mol) in dry 1,4-Dioxane (1.50 mL, 0.0192 mol) was added Triethylamine (0.0266 mL, 0.000191 mol) followed by 20% Phosgene in toluene (1:4, Phosgene:Toluene, 0.100 mL). The reaction mixture was heated at 50° C. for 1 hour. The reaction mixture was cooled to room temperature and then added 3-aminoisoxazole (0.0770 mL, 0.00104 mol). The reaction mixture was stirred overnight. The reaction mixture was concentrated and purified by HPLC. 1H NMR (500 MHz, DMSO) δ 9.70 (s, 1H), 9.16 (s, 1H), 8.77 (d, J=1.6, 1H), 8.67 (s, 1H), 8.29 (t, J=7.5, 3H), 7.58 (d, J=8.8, 2H), 7.11 (d, J=6.4, 1H), 6.88 (d, J=1.7, 1H), 4.85 (d, J=18.4, 1H), 4.74 (d, J=18.5, 1H), 4.15 (d, J=6.1, 1H), 4.06 (s, 1H), 3.92-3.82 (m, 3H), 3.76-3.54 (m, 4H), 3.48-3.41 (m, 2H), 2.79 (s, 2H), 1.27 (d, J=6.7, 3H). LC/MS-m/z+514.2 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.[S:8]([O:13]CC)([O:10]CC)=[O:9].[C:16]1(C)[CH:21]=CC=C[CH:17]=1>>[CH2:3]([NH:2][S:8](=[O:10])(=[O:9])[O-:13])[CH3:4].[CH3:1][N+:2]1([CH2:17][CH2:16][CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOS(=O)OCC
Reactant: CN1CCCC1=O
Reactant: Cc1ccccc1
Product: CCC[N+]1(C)CCCC1
Product: CCNS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
200 mmol of 1-methylpyrrolidone (Aldrich) in solution in 100 ml of toluene were quaternized with 100 mmol of diethyl sulfite (Aldrich), added slowly at 0° C., with stirring for 24 hours at ambient temperature. After evaporation of the solvent and drying, N-methyl-N-propylpyrrolidinium ethylsulfamate was obtained. 50 mmol of ethylsulfamate were solubilized in 50 ml of acetonitrile, and were reacted with 50 mmol of KBFFST. After stirring for 2 hours, and then filtration, evaporation of the solvent and drying, the N-propane-N-methylpyrrolidinium salt of 3,5-difluorosulfonyl-1,2,4-triazole (PYR13BFST) corresponding to the following formula was obtained:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[O:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>ClCCl>[CH3:37][S:38]([NH:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[O:11])=[CH:4][CH:3]=1)(=[O:40])=[O:39]
Reactant: Nc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Reactant: CS(=O)(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Temperature: 0 °C

Procedure:
To a solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide (40.0 mg, 0.111 mmol) in dichloromethane (1.0 mL) was added DIEA (0.15 mL, 0.89 mmol). The solution was cooled to 0° C., treated with methanesulfonyl chloride (0.021 mL, 0.28 mmol), and gradually allowed to warm to room temperature. The solution was diluted CH2Cl2 (20 mL) and washed with saturated aqueous NH4Cl (3×10 mL), saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated. The crude mixture was diluted with THF (0.5 mL) and a 1 M solution of TBAF in THF (1.0 mL, 1.0 mmol) was added. The solution was warmed at reflux for 6 hours. The solution was cooled to room temperature and quenched with saturated aqueous NH4Cl (15 mL), diluted with ethyl acetate (15 mL), and washed with NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of 0-10% MeOH in CH2Cl2 to afford the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([NH:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[C:16]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:15]=1[CH3:27])(=[O:12])=[O:11].[H-].[Na+].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>CN(C=O)C>[Cl:8][C:7]1[C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[C:3]([S:10]([NH:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[C:16]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[C:15]=2[CH3:27])(=[O:11])=[O:12])[CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Cc1cc(C)c(N2CCCC2)c(C)c1NS(=O)(=O)c1cc(Cl)cc(Cl)c1N
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(N2CCCC2)c(C)c1NS(=O)(=O)c1cc(Cl)cc(Cl)c1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
To a solution of 40 (69 mg, 0.16 mmol) in DMF at 0° C. was added NaH (60% in mineral oil, 14 mg, 0.35 mmol). The mixture was stirred for 10 min at 0° C. before the addition of methanesulfonyl chloride (22 mg, 0.19 mmol). The resulting mixture was then stirred at room temperature overnight. The reaction was quenched with a few drops of dilute HCl and then diluted with EtOAc (60 mL). The organic layer was washed with water (2×30 mL) and brine (30 mL) and the volatiles were removed by evaporation on a rotavap. The residue was purified on a silica gel column (15% to 30% EtOAc in hexanes) to yield the title compounds as an off-white solid (10 mg ESI [M+H+]=506.12).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[Br:15]Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:7]([Br:15])=[N:6][C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: Nc1cnc(Cl)cn1
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Nc1ncc(Cl)nc1Br
Reaction time: 0.5 h

Procedure:
2-Amino-5-chloropyrazine (1.7 g) was dissolved in chloroform (190 ml) and pyridine (1.3 ml) was added under an argon atomosphere. The flask and its contents were protected from light and a solution of bromine (0.7 ml) in chloroform (85 ml) was added over a period of 1 hour. After stirring for 2 hours more bromine (0.07 ml) in chloroform (8.5 ml) was added. After stirring for 30 minutes, pyridine (0.2 ml) was added. The reaction mixture was stirred for a further 30 minutes then washed with water (50 ml) and the organic phase was separated. Volatile material was removed by evaporation and and the residue was purified by chromatography through a bed of silica (90 g), eluting with hexane (200 ml), followed by dichloromethane. Dichloromethane fractions containing the product were evaporated to give 2-amino-3-bromo-5-chloropyrazine (1.68 g); 1H NMR (d6 -DMSO): 6.94 (br s, 2 H), 8.09 (s, 1 H); mass spectrum (+vc CI): 208 (M+H)+.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH2:16][CH2:15][CH2:14][N:13]=1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:24])=[O:23])=[CH:20][CH:19]=1>C(#N)C.C(OCC)C>[ClH:24].[CH3:3][C:4]1[CH:9]=[C:8]([NH:10][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([F:17])=[CH:19][CH:20]=2)[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH2:16][CH2:15][CH2:14][N:13]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1cc(N)ccc1NC1=NCCC1
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: Cc1cc(NC(=O)c2ccc(F)cc2)ccc1NC1=NCCC1

Procedure:
A mixture of 1.0 g (3.8 mmole) of product compound of Example 9 and 30.5 mmole of p-fluorobenzoyl chloride in 40 ml of acetonitrile was stirred at reflux for four hours, after which time thin-layer chromatography on silica gel (9:1 ethanol/concentrated aqueous ammonia) indicated no unreacted starting amine. The reaction mixture was then diluted eight-fold with diethyl ether. The resultant solid was collected and washed with three portions of ether, then dried in a high vacuum over 5A molecular sieves, giving the title compound as the hydrochloride salt. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.CN1CCN(C2C=CC(C(O)=O)=CC=2)CC1.[CH2:34]([O:41][CH2:42][CH2:43][O:44][C:45]1[CH:53]=[C:52]2[C:48]([C:49]([NH2:54])=[N:50][NH:51]2)=[CH:47][CH:46]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>N1C=CC=CC=1>[CH2:34]([O:41][CH2:42][CH2:43][O:44][C:45]1[CH:53]=[C:52]2[C:48]([C:49]([NH:54][C:13](=[O:14])[C:12]3[CH:16]=[CH:17][C:9]([N:6]4[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]4)=[CH:10][CH:11]=3)=[N:50][NH:51]2)=[CH:47][CH:46]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2)CC1
Reactant: Nc1n[nH]c2cc(OCCOCc3ccccc3)ccc12
Agent: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Solvent: c1ccncc1
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4cc(OCCOCc5ccccc5)ccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A stirred suspension of 4-(4-methyl-piperazin-1-yl)-benzoyl chloride hydrochloride, prepared from 4.55 g (20.7 mmol) of 4-(4-methyl-piperazin-1-yl)-benzoic acid as described above in preparation 3, in dry pyridine (50 ml) was treated dropwise, at 0° C., under argon atmosphere, with a solution of 6-(2-benzyloxy-ethoxy)-1H-indazol-3-ylamine (5.31 g, 18.8 mmol) in 80 ml of dry pyridine. The reaction mixture was allowed to warm to r.t. under stirring overnight, then concentrated to 30 ml by rotary evaporation, poured into 500 ml of saturated solution of NaHCO3 and extracted with 300+100 ml of DCM. The organic layers were combined, dried over sodium sulfate and evaporated to dryness. The crude residue was treated with 200 ml of EtOAc and stirred at reflux for 2 h. After cooling to r.t. the solid was filtered, washed with EtOAc and dried in oven at 50° C. under high vacuum to afford 5.23 g (yield: 57%) of the title compound as a white solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[CH2:10][C@@H:11]([CH3:14])[CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].C(#N)C>ClCCl>[CH3:10][C@@H:11]([CH2:12][CH3:13])[CH2:14][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: CC[C@H](C)CBr
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC[C@H](C)COc1ccc(O)cc1
Yield: 47.9 %

Procedure:
A reaction mixture of hydroquinone (18.2 grams); (S)-(+)-1-bromo-2-methylbutane (4.55 grams); anhydrous potassium carbonate (23 grams); and acetonitrile (250 mls.) was allowed to reflux for 40 hours. Flash chromatography using dichloromethane eluant yielded 2.6 grams (48%) of white crystals exhibiting a Fisher-Johns melting point of 44°-45° C. and having the structure ##STR24## confirmed by TLC, NMR, IR and mass spectral analyses.
Reaction SMILES: [C:1]1([C:6]2[C:14]3[C:9](=[C:10]([O:15][CH3:16])[N:11]=[CH:12][CH:13]=3)[N:8]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.O>CO.[Pd]>[CH:1]1([C:6]2[C:14]3[C:9](=[C:10]([O:15][CH3:16])[N:11]=[CH:12][CH:13]=3)[N:8]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:21][CH:22]=3)[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nccc2c(C3=CCCC3)nn(-c3ccc(S(N)(=O)=O)cc3)c12
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COc1nccc2c(C3CCCC3)nn(-c3ccc(S(N)(=O)=O)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 135.6 %

Procedure:
To a solution of 4-(3-(cyclopent-1-en-1-yl)-7-methoxy-1H-pyrazolo[3,4-c]pyridin-1-yl)benzenesulfonamide (22 mg) in methanol (10 mL) was added 10% palladium/carbon (6.32 mg) containing water, and the mixture was stirred overnight under hydrogen atmosphere at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (30 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([NH:10][C:11](=[O:26])[CH:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH3:13])[CH2:9][CH2:8]1.[CH:27]1([CH2:30][O:31][C:32]2[CH:33]=[CH:34][C:35](F)=[C:36]([CH:39]=2)[C:37]#[N:38])[CH2:29][CH2:28]1>CC(N(C)C)=O>[C:37]([C:36]1[CH:39]=[C:32]([O:31][CH2:30][CH:27]2[CH2:29][CH2:28]2)[CH:33]=[CH:34][C:35]=1[N:23]1[CH2:22][CH2:21][CH:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:12]([CH3:13])[C:11]([NH:10][CH:7]3[CH2:8][CH2:9]3)=[O:26])=[CH:15][CH:16]=2)[CH2:25][CH2:24]1)#[N:38]
Reactant: N#Cc1cc(OCC2CC2)ccc1F
Reactant: CC(C(=O)NC1CC1)c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C(=O)NC1CC1)c1ccc(C2CCN(c3ccc(OCC4CC4)cc3C#N)CC2)cc1
Temperature: 150 °C
Reaction time: 6 h

Procedure:
101 mg (0.73 mmol) potassium carbonate are added to a mixture of 80 mg (0.29 mmol) N-cyclopropyl-2-(4-piperidin-4-yl-phenyl)-propionamide (XI.1) and 56 mg (0.29 mmol) 5-cyclopropylmethoxy-2-fluoro-benzonitrile (1.8) in 2 mL DMA. The mixture is stirred for 6 h at 150° C. under microwave irradiation. Subsequently the solvent is removed in vacuo and the residue is purified using reversed phase HPLC (water, 0.3% NH4OH/MeOH) to yield the desired product.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:34]1[CH:39]=[C:38]([F:40])[C:37]([O:41][CH3:42])=[CH:36][C:35]=1[F:43])[CH2:18][N:19]([CH2:32][CH3:33])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[F:43][C:35]1[CH:36]=[C:37]([O:41][CH3:42])[C:38]([F:40])=[CH:39][C:34]=1[C@H:17]([NH:16][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[CH2:18][NH:19][CH2:32][CH3:33]
Reactant: CCN(C[C@@H](N)c1cc(F)c(OC)cc1F)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CCNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1cc(F)c(OC)cc1F

Procedure:
Compound 31 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(2,5-difluoro-4-methoxy-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a pale yellow solid. LC/MS [403 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.03 (d, J=26.0 Hz, 1H), 8.98 (s, 1H), 8.56 (s, 1H), 8.37 (d, J=4.5 Hz, 1H), 8.16 (s, 1H), 7.40 (dd, J=12.1, 7.0 Hz, 1H), 7.09 (dd, J=11.5, 7.3 Hz, 1H), 5.69 (s, 1H), 3.82 (s, 3H), 3.13 (dd, J=12.3, 8.5 Hz, 1H), 2.91 (dd, J=12.4, 5.2 Hz, 1H), 2.63-2.53 (m, 2H), 1.85 (s, 1H), 0.97 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].C([O-])([O-])=O.[K+].[K+].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CCOC(C)=O>[Cl:5][CH2:4][CH2:3][CH2:2][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: ClCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 1-bromo-3-chloropropane (0.79 g, 5.00 mmol) and K2CO3 (1.38 g, 10.00 mmol) in EtOAc (20 mL) was added a solution of morpholine (0.44 g, 5.05 mmol) in EtOAc (20 mL) dropwise at rt under N2. The mixture was stirred at rt overnight, then filtered and concentrated in vacuo to give the crude product for the next step without further purification.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:40]=[C:41]([O:54][CH3:55])[C:42]=1[CH2:43][C@H:44]1[C@:46]([CH3:53])([CH2:47][CH2:48][CH:49]=[C:50]([CH3:52])[CH3:51])[O:45]1)[O:29][Si](C(C)C)(C(C)C)C(C)C.CCCCCC>CCOC(C)=O>[CH3:55][O:54][C:41]1[CH:40]=[C:28]([OH:29])[CH:27]=[C:26]([O:25][CH3:24])[C:42]=1[CH2:43][C@H:44]1[C@:46]([CH3:53])([CH2:47][CH2:48][CH:49]=[C:50]([CH3:52])[CH3:51])[O:45]1
Reactant: COc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1C[C@@H]1O[C@@]1(C)CCC=C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(O)cc(OC)c1C[C@@H]1O[C@@]1(C)CCC=C(C)C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
Tetrabutylammonium fluoride in THF (1 M, 9.0 mL, 9.01 mmol, 1.05 equiv.) was added to a THF (30 mL) solution of 5 (3.97 g, 8.58 mmol, 1 equiv.) in a 100-mL pear-shaped flask. After stirring for 30 min, the reaction was quenched with saturated aqueous NH4Cl and extracted once with hexane and twice with EtOAc. The organic extracts were combined, washed with brine, Na2SO4, filtered, and concentrated in vacuo to a slight yellow oil. Flash column chromatography (400 mL SiO2, 7:3 to 1:1 hexane:EtOAc) afforded 2.20 g (7.18 mmol, 84% yield) of 6 as a clear, colorless oil. TLC Rf 0.5 (1:1 hexane:EtOAc). 1H NMR (500 MHz; CDCl3): δ 6.06 (s, 2H), 5.11 (s, 1H), 4.99 (t, J=7.1 Hz, 1H), 3.76 (s, 6H), 2.97 (dd, J=13.5, 4.6 Hz, 1H), 2.91 (dd, J=7.3, 4.6 Hz, 1H), 2.69 (dd, J=13.5, 7.3 Hz, 1H), 2.07-1.95 (m, 2H), 1.63 (ddd, J=13.9, 9.1, 5.2 Hz, 1H), 1.59 (s, 3H), 1.54 (s, 3H), 1.38 (s, 3H), 1.37-1.33 (m, 1H). 13C NMR (125 MHz; CDCl3): δ 159.3, 156.4, 131.9, 123.8, 106.1, 92.1, 64.1, 62.6, 55.7, 39.1, 25.8, 24.1, 22.3, 17.7, 16.9. IR (NaCl, thin film, cm−1) 3368 (br), 2936, 2840, 1618, 1603, 1475, 1431, 1206, 1134, 999, 816.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[C:15]2[CH:16]=[CH:17][N:18]=[CH:19][C:20]=2[CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([F:32])[F:31])[CH:25]=2)[CH:23]=1)(=[O:13])=[O:12])(C)(C)C.Cl>C(OCC)(=O)C.O1CCOCC1>[NH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[C:15]2[CH:16]=[CH:17][N:18]=[CH:19][C:20]=2[CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([F:32])[F:31])[CH:25]=2)[CH:23]=1)(=[O:13])=[O:12]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cc(-c2cccc(C(F)F)c2)cc2cnccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NCCNS(=O)(=O)c1cc(-c2cccc(C(F)F)c2)cc2cnccc12
Reaction time: 8 h
Yield: 95 %

Procedure:
Suspend {2-[7-(3-difluoromethylpheny)-isoquinoline-5-sulfonylamino]-ethyl}-carbamic acid tert-butyl ester in ethyl acetate (11 mL), and add an excess of 4 M HCl in 1,4-dioxane. Stir overnight, filter the precipitate, wash with dichloromethane, and dry under vacuum to give the desired compound as a white solid (0.092 g, 95% yield): 1H NMR (CD3OD): δ9.92 (s, 1H), 9.10 (d, J=7.0 Hz, 1H), 9.04 (m, 2H), 8.80 (d, J=7.0 Hz, 1H), 8.09 (m, 2H), 7.74 (m, 2H), 6.94 (t, J=52.1 Hz, 1H), 3.25 (m, 2H), 3.15 (m, 2H). Load the product onto ion exchange resin and elute with 1N NH3 in methanol and concentrate to dryness to give the free base. (Used in example 97).