Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:20]([OH:22])=O)[CH:11]=3)=[O:5])[CH2:3][CH2:2]1.[CH3:27][C:28]1([NH2:32])[CH2:31][CH2:30][CH2:29]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:20]([NH:32][C:28]2([CH3:27])[CH2:31][CH2:30][CH2:29]2)=[O:22])[CH:11]=3)=[O:5])[CH2:2][CH2:3]1
Reactant: CC1(N)CCC1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2(C)CCC2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 47.8 %

Procedure:
A mixture of 3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylbenzoic acid (41.0 mg, 0.118 mmol), 1-methylcyclobutylamine (22.5 mg, 0.264 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (81.1 mg, 0.156 mmol), N,N-diisopropylethylamine (64 uL, 0.37 mmol), 4-dimethylaminopyridine (2.89 mg, 0.0237 mmol), and N,N-dimethylformamide (2.0 mL, 26 mmol) was stirred at 50° C. for 15 hours. The reaction mixture was poured into ethyl acetate and washed with water and brine, filtered through a plug of silica gel, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 23.3 mg (78%) of 3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methyl-N-(1-methylcyclobutyl)benzamide. LCMS (ESI): RT (min)=5.083, M+H=414.2, method=E; 1H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 9.19 (s, 1H), 8.51 (s, 1H), 8.35 (s, 1H), 8.04 (s, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.82 (s, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.73 (dd, J=8.5, 1.5 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 2.40-2.29 (m, 5H), 2.13-2.04 (m, 1H), 2.03-1.92 (m, 2H), 1.86-1.75 (m, 2H), 1.47 (s, 3H), 0.91-0.80 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([O:17][CH3:18])=[CH:4][C:3]=1[C:19]1[CH:20]=[N:21][NH:22][CH:23]=1.Cl[C:25]1[N:30]=[N:29][C:28]([N:31]([CH3:42])[CH:32]2[CH2:37][C:36]([CH3:39])([CH3:38])[NH:35][C:34]([CH3:41])([CH3:40])[CH2:33]2)=[CH:27][CH:26]=1>>[Cl:1][C:2]1[C:3]([C:19]2[CH:23]=[N:22][NH:21][CH:20]=2)=[CH:4][C:5]([O:17][CH3:18])=[C:6]([C:25]2[N:30]=[N:29][C:28]([N:31]([CH3:42])[CH:32]3[CH2:37][C:36]([CH3:38])([CH3:39])[NH:35][C:34]([CH3:41])([CH3:40])[CH2:33]3)=[CH:27][CH:26]=2)[CH:7]=1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: COc1cc(-c2cn[nH]c2)c(Cl)cc1B1OC(C)(C)C(C)(C)O1
Product: COc1cc(-c2cn[nH]c2)c(Cl)cc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Yield: 86.7 %

Procedure:
Following standard GENERAL METHOD 1-4 for Suzuki coupling using 4-(2-chloro-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (118 mg, 0.35 mmol) and 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Intermediate 1-1,100 mg, 0.35 mmol) afforded 6-(5-chloro-2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (138 mg) MS [M+H+]=455.0.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:17]3[CH:18]=[CH:19][S:20][C:16]=3[C:15]3[CH:14]=[CH:13][C:12]([C:21]([OH:23])=O)=[CH:11][C:10]=3[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][S:25]([NH2:28])(=[O:27])=[O:26].CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:24][S:25]([NH:28][C:21]([C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[S:20][CH:19]=[CH:18][C:17]=3[C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:9][C:10]=2[CH:11]=1)=[O:23])(=[O:27])=[O:26]
Reactant: O=C(O)c1ccc2c(c1)nc(Nc1ccccc1)c1ccsc12
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)NC(=O)c1ccc2c(c1)nc(Nc1ccccc1)c1ccsc12
Reaction time: 5 h
Yield: 80.6 %

Procedure:
4-(phenylamino)thieno[3,2-c]quinoline-7-carboxylic acid (6 mg) was reacted with methyl sulfonamide (120 mg), EDCI (80 mg) and DMAP (20 mg) in anhydrous DMF (0.5 ml). After 5 hours, water was added and the solution subjected to preparative HPLC. Genevac evaporation provided N-(methylsulfonyl)-4-(phenylamino)thieno[3,2-c]quinoline-7-carboxamide as a solid (6 mg, 81% yield). LCMS (ES): 95% pure, m/z 398 [M+1]+.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:26]1SC2CCC(C)CC=2C=1C(OCC)=O.C1(S(Cl)(=O)=O)C=CC=CC=1>>[CH3:26][CH:18]1[CH2:17][CH2:16][C:14]2[S:15][C:11]([NH:10][S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])=[C:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]=2[CH2:19]1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Reactant: CCOC(=O)c1c(N)sc2c1CC(C)CC2
Agent: O=S(=O)(Cl)c1ccccc1
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CC(C)CC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-5-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (prepared according to Pinkerton et al., Bioorg. Med. Chem. Lett., 2007, 17, 3562-3569) and benzenesulphonyl chloride.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[Cl:12][C:13]1[CH:14]=[C:15]([C:22]([CH3:32])([CH3:31])[CH2:23][C:24]2([C:27]([F:30])([F:29])[F:28])[CH2:26][O:25]2)[C:16]2[O:20][CH2:19][CH2:18][C:17]=2[CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([C:22]([CH3:32])([CH3:31])[CH2:23][C:24]([CH2:26][N:1]2[C:9]3[C:4](=[N:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)([OH:25])[C:27]([F:28])([F:29])[F:30])[C:16]2[O:20][CH2:19][CH2:18][C:17]=2[CH:21]=1
Reactant: c1cnc2cc[nH]c2c1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cc(Cl)cc2c1OCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(CC(O)(Cn1ccc2ncccc21)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
A solution of 1H-pyrrolo[3,2-b]pyridine (33.0 mg, 0.279 mmol) in 4 mL of DMF was treated with NaH (60% in mineral oil, 16.8 mg, 0.419 mmol) at room temperature. After 30 minutes, 5-chloro-7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-2,3-dihydrobenzofuran (188 mg, 0.558 mmol) was added and the resulting mixture was stirred overnight. The reaction was then diluted with 5 mL of ethyl acetate and quenched with 5 mL of saturated ammonium chloride solution. The aqueous layer was extracted with 5 mL of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with diethyl ether to afford 55.0 mg (45% yield) of the title product as white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[CH2:23][OH:24])[N:9]([CH3:25])[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1>ClCCl>[C:26]([O:24][CH2:23][C:17]1[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=1[N:10]1[N:9]([CH3:25])[CH2:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=2)[C:11]1=[O:15])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CN1Cc2cc(C(C)(C)C)ccc2C(=O)N1c1cccc(Cl)c1CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCc1c(Cl)cccc1N1C(=O)c2ccc(C(C)(C)C)cc2CN1C
Temperature: 45 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
In a 100 mL round-bottomed flask, 6-tert-butyl-2-(3-chloro-2-(hydroxymethyl)phenyl)-3-methyl-3,4-dihydrophthalazin-1(2H)-one (500 mg, 1.39 mmol, Eq: 1.00), acetic anhydride (711 mg, 657 μl, 6.97 mmol, Eq: 5) and pyridine (331 mg, 338 μl, 4.18 mmol, Eq: 3) were combined with dichloromethane (10.0 ml) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 8 h. Cooled to room temperature and stirred for 48 h. The crude reaction mixture was concentrated in vacuo to a tan oil. The crude material was purified by flash chromatography (silica gel, 20%-30% ethyl acetate/hexanes gradient) to give 2-(6-tert-butyl-3-methyl-1-oxo-3,4-dihydrophthalazin-2(1H)-yl)-6-chlorobenzyl acetate (489 mg, 88%): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 9H) 2.03 (s, 3H) 2.62 (s, 3H) 4.45 (s, 2H) 5.33 (s, 2H) 7.23 (d, J=1.51 Hz, 1H) 7.35-7.39 (m, 2H) 7.43-7.52 (m, 2H) 8.03 (d, J=8.31 Hz, 1H).
Reaction SMILES: [CH2:1]([C@H:8]([N:24]([CH2:39][C:40]1[CH:45]=[CH:44][C:43](Br)=[CH:42][CH:41]=1)[C:25](=[O:38])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:47]1[CH:52]=[CH:51][CH:50]=[C:49](B(O)O)[CH:48]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(C)C>C1(C)C=CC=CC=1.O>[CH2:1]([C@H:8]([N:24]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:49]2[CH:48]=[N:47][CH:52]=[CH:51][CH:50]=2)=[CH:42][CH:41]=1)[C:25](=[O:38])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C([C@H](Cc1ccccc1)N(Cc1ccc(Br)cc1)C(=O)C=Cc1ccc(C(F)(F)F)cc1)N1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: O=C([C@H](Cc1ccccc1)N(Cc1ccc(-c2cccnc2)cc1)C(=O)C=Cc1ccc(C(F)(F)F)cc1)N1CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
In an inert atmosphere, N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-(4-bromo-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide (60 mg, 0.087 mmol) was dissolved in toluene (0.5 mL) followed by the addition of 3-pyridineboronic acid (11 mg, 0.087 mmol), 2M potassium carbonate solution (0.5 mL) and iso-propanol (0.5 mL). The mixture was degassed with argon for 5 min and heated to 100° C. followed by the addition of tetrakis-(triphenylphosphine)palladium (3 mg, 0.003 mmol). The mixture was stirred for 3 h at 110° C., cooled to rt again and water (1 mL) was added. The product was extracted with EtOAc (3×3 mL). The combined organic layers were evaporated to dryness and the residue was purified by prep. HPLC to give 21 mg (35%) of N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-(4-pyridin-3-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide. LC-MS: tR=0.85 min; [M+H]+=689.68.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>CN(C)C1C=CN=CC=1.ClCCl>[N:5]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7][CH:2]=[C:3]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1=CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 40 h
Yield: 46 %

Procedure:
To a cold (0° C.) solution of 1-tert-butyl 3-methyl 4-hydroxy-1,3-piperidine-dicarboxylate (1,64 g, 6.32 mmol), 4-dimethylaminopyridine (16.0 mg, 0.13 mmol), and triethylamine (2.64 mL, 19.0 mmol) in dichloromethane (25 mL) was added dropwise trifluoroacetic anhydride (1.12 mL, 7.91 mmol). The reaction mixture was stirred at room temperature for 40 hrs. The reaction was quenched with 10% K2CO3 solution, extracted with CHCl3. The separated organic phase was washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate=5:1) to give 1-tert-butyl 3-methyl 5,6-dihydro-1,3(2H)-pyridinedicarboxylate as a pale yellow oil. (707.4 mg, yield 46%)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.[Cl:6][C:7]1[CH:26]=[CH:25][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[C:9]([F:27])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:6].[Cl:6][C:7]1[CH:26]=[CH:25][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:4][CH2:3][O:2][CH3:1])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[C:9]([F:27])[CH:8]=1
Reactant: COCCBr
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Product: Cl
Temperature: 60 °C
Reaction time: 10 h
Yield: 122.1 %

Procedure:
2-Bromoethyl methyl ether (712 μl, 7.56 mmol) was added dropwise to a solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (2.2 g, 6.88 mmol) and potassium carbonate (2.84 g, 20.6 mmol) in DMF (110 ml). The mixture was stirred for 10 hours at 60° C. then for 2 days at ambient temperature, the solvent was removed by evaporation and the crude product purified by flash chromatography eluting with ethyl acetate/petroleum ether (4/1). The resulting solid was dissolved in hot ethanol and ethanolic hydrogen chloride was added. After cooling, the resulting solid was collected by filtration, washed with ethanol and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methoxyethoxy)quinazoline hydrochloride (1.74 g, 62%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])[CH:5]=[N:6][CH:7]=1.CC(C)([O-])C.[K+].[C:21](=[S:23])=[S:22].[CH3:24]I>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:21]([S:23][CH3:24])=[S:22])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])[CH:5]=[N:6][CH:7]=1
Reactant: S=C=S
Reactant: CI
Reactant: O=C1CCCCC1c1cncc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CSC(=S)C1(c2cncc(Br)c2)CCCCC1=O
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(5-bromopyrid-3-yl)cyclohexanone (1.28 g, 5.05 mmol) in dry tetrahydrofuran (35 ml) at -40° C. was added portionwise with stirring potassium tert. butoxide (0.61 g, 5.4 mmol). The reaction mixture was stirred for 1 hour at -40° C. and a solution of carbon disulphide (0.5 ml) in dry tetrahydrofuran (5 ml) was added and the reaction mixture allowed to warm up to -20° C. over 20 minutes. A solution of methyl iodide (1.03 g) in dry tetrahydrofuran (5 ml) was added dropwise and the solution stirred at room temperature for 6 hours. The reaction mixture was concentrated in vacuo, treated with water (25 ml) and extracted with dichloromethane (2×25 ml). The extract was washed with water, dried over magnesium sulphate and concentrated to give 2-(5-bromopyrid-3-yl)-2-methylthiothiocarbonylcyclohexanone as an orange oil 1.33 g. NMR (CDCl3) 1.6-2.1(m,4H); 2.26-2.35(m,2H); 2.6 (s,3H); 2.65-2.9(m.1H); 3.4-3.5(m,1H), 7.84-7.86(dd,1H); 8.54-8.6(dd,2H).
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH:10]=O.[CH2:14]([O:16][CH2:17][CH3:18])[CH3:15]>O1CCCC1.O>[CH2:14]([O:16][C:17](=[O:2])[CH:18]=[CH:10][CH:9]([O:8][CH3:7])[O:12][CH3:13])[CH3:15]
Reactant: O=C([O-])[O-]
Reactant: CCOCC
Reactant: COC(C=O)OC
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=CC(OC)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Add potassium carbonate (16.5 g, 120 mmol) to a solution of dimethoxy acetaldehyde (60% wt. in water) (15 mL, 100 mmol) and triethyl phosphonoacetate (20 mL, 100 mmol) in 210 mL tetrahydrofuran and 30 mL water. Stir the mixture at room temperature for 4 hours. Pour the reaction mixture into diethyl ether (200 mL) and wash with saturated aqueous sodium chloride. Dry the organic phase over sodium sulfate and concentrate under reduced pressure to provide the desired compound as a yellow oil (15.8 g, 90%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C[Si](Cl)(C)C>CCCCO>[N:23]1([C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:2]3[N:3]=[C:4]([N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=3)=[CH:22][CH:21]=2)[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]1.[N:11]1([C:4]2[C:5]3[CH:10]=[CH:9][NH:8][C:6]=3[N:7]=[C:2]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:24][CH2:25][N:26]([C:29](=[O:31])[CH3:30])[CH2:27][CH2:28]4)=[CH:21][CH:22]=3)[N:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Clc1nc(N2CCCC2)c2cc[nH]c2n1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCCC4)c4cc[nH]c4n3)cc2)CC1
Product: c1cc2c(N3CCCC3)nc(Nc3ccc(N4CCNCC4)cc3)nc2[nH]1

Procedure:
A mixture of 2-chloro-4-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (116 mg, 0.521 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (200 mg, 0.913 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in n-BuOH (5 mL) was stirred at 120° C. for 20 h. n-BuOH was removed in vacuo. The residue was purified by HPLC to give N-(4-(piperazin-1-yl)phenyl)-4-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (3 mg) (MS 364.5 (M+H)) and 1-(4-(4-(4-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (30 mg) (MS 406.5 (M+H)).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21](C)[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl.O1CC[CH2:36][CH2:35]1>O>[CH:20]1([NH:19][N:16]2[C:17](=[O:18])[C:12]([C:4]3[NH:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[S:2](=[O:28])(=[O:1])[N:3]=3)=[C:13]([OH:27])[C:14]3[S:26][CH:25]=[CH:24][C:15]2=3)[CH2:21][CH2:22][CH2:36][CH2:35]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: C1CCOC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1NC1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.040 g, 0.09 mmol) in tetrahydrofuran (3 mL) and methanol (0.008 mL, 0.19 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.07 mL, 0.14 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid a pH of approximately 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 98:2 dichloromethane/methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54 (m, 6 H) 1.74 (m, 2 H) 3.75 (m, 1 H) 5.77 (d, J=3.68 Hz, 1 H) 7.12 (d, J=5.15 Hz, 1 H) 7.19 (d, J=7.72 Hz, 1 H) 7.26 (t, J=7.17 Hz, 1 H) 7.54 (m, 1 H) 7.64 (d, J=7.72 Hz, 1 H) 7.74 (d, J=5.52 Hz, 1 H) 15.91 (s, 1 H). MS (ESI−) m/z 429 (M−H)−.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCc1c(C)nc2cc(C)nn2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCCCCCc1c(C)nc2cc(C)nn2c1Cl

Procedure:
190 g of the condensate obtained from (a), in 550 ml of phosphorus oxytrichloride, are refluxed for 1.5 hours, after which the excess phosphorus oxytrichloride is evaporated under reduced pressure and the residue is stirred with 500 ml of CH2Cl2 and 500 ml of ice water. The organic phase is separated off, washed with three times 100 ml of ice water, dried over sodium sulfate and filtered, the solvent is evaporated under reduced pressure, and 179 g of 7-chloro-2,5-dimethyl-6-n-octylpyrazolo-[1,5-a]pyrimidine are isolated as a viscous mass.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14](Br)[CH:13]=1)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].[C:20]1(B(O)O)[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1>>[C:1]([O:4][CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([C:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=2)[CH:13]=1)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: OB(O)C1=CCCCC1
Reactant: CC(=O)OCC(COC(C)=O)c1ccc(N)c(Br)c1
Product: CC(=O)OCC(COC(C)=O)c1ccc(N)c(C2=CCCCC2)c1

Procedure:
The title compound was prepared according to the Suzuki coupling procedure of Example 1, step (e) using acetic acid 3-acetoxy-2-(4-amino-3-bromo-phenyl)-propyl ester (as prepared above) and cyclohex-1-enyl boronic acid: Mass spectrum, (ESI, m/z): Calcd. for C19H25NO4, 332.1 (M+H). found 332.1.
Reaction SMILES: O=[Ce:2]=O.[C:4](=[O:7])([O-])[O-:5].[Ce+3].[C:9](=[O:12])([O-])[O-:10].[C:13](=[O:16])([O-])[O-:14].[Ce+3]>C(O)(=O)C>[C:4]([O-:5])(=[O:7])[CH3:9].[Ce+3:2].[C:9]([O-:10])(=[O:12])[CH3:13].[C:13]([O-:14])(=[O:16])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: O=[Ce]=O
Agent: [Ce+3]
Solvent: CC(=O)O
Product: CC(=O)[O-]

Procedure:
High surface area ceria was first prepared following traditional procedures. Five grams of cerium carbonate was slowly mixed with 4.5 ml of glacial acetic acid to produce cerium acetate. The sample was dried in a vacuum over at 100° C., the calcined in air at 425° C. to produce cerium oxide. The ceria was coated with a layer of Al2O3 to act as a template by mixing 2 g of the ceria with 40 ml of a 0.01M Al2O3 sol (diluted from a 20 wt % sol), stirring overnight, then filtering, washing, drying, and calcining in air at 500° C. as above. The zeolite precursor solution was prepared by mixing a solution containing NaOH, dissolved Al foil, and H2O with tetraethylorthosilicate (TEOS) and tetrapropylammonium hydroxide (TPAOH) such that the molar concentrations in the final solution was 4:0.06:571:6:1 NaOH:Al:H2O:TEOS:TPAOH. The solution was stirred at room temperature overnight, then approximately 40 ml was added to 2 g of the Al2O3 coated ceria in an autoclave. The autoclave was heated to 175° C. for 6 hrs under autogenic pressure. After rapid cooling, the sample was filtered, washed, dried, then calcined for 6 hrs in air at 500° C. to remove residual organic compounds. Copper was exchanged with the zeolite film/ceria following the methods listed above for CeO2/Cu-ZSM-5. The final catalyst will be referred to as “Cu-ZSM-5/CeO2”.
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C@H:24]2[CH2:28][CH2:27][CH2:26][C@@H:25]2[C:29]2[N:33]([CH2:34][CH3:35])[N:32]=[CH:31][CH:30]=2)=[CH:18][C:17]=1[F:36])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:22][C:20]1[C:19]([O:23][C@H:24]2[CH2:28][CH2:27][CH2:26][C@@H:25]2[C:29]2[N:33]([CH2:34][CH3:35])[N:32]=[CH:31][CH:30]=2)=[CH:18][C:17]([F:36])=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:15])=[O:14])[CH:21]=1
Reactant: CCn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(C(=O)OC(C)(C)C)c2cscn2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2cscn2)cc1Cl
Yield: 69.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the tert-butyl[(5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}phenyl)sulfonyl](1,3-thiazol-4-yl)carbamic acid (125 mg, 0.213 mmol) prepared in Example 12b, trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (70.0 mg, 68%) as a colorless solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][CH2:10][NH2:11].[C:12]([N:14]=[C:15](SC)SC)#[N:13].[CH2:20]([NH2:23])[C:21]#[CH:22]>>[C:12]([NH:14][C:15]([NH:23][CH2:20][C:21]#[CH:22])=[N:11][CH2:10][CH2:9][CH2:8][S:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)#[N:13]
Reactant: C#CCN
Reactant: NCCCSCc1nccs1
Reactant: CSC(=NC#N)SC
Product: C#CCNC(=NCCCSCc1nccs1)NC#N

Procedure:
Reaction of 3-[(thiazol-2-yl)methylthio]propylamine with dimethyl cyanodithioimidocarbonate and treatment of the product with excess propargylamine yields the title compound.