Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH3:34])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[C:15]([OH:24])[CH:16]=[CH:17][C:18]=3[OH:23])[C:13](=[O:25])[C:12]=2[C:11](NCCNCC(O)C)=[CH:10][CH:9]=1.[C:35]([OH:38])(=[O:37])[CH3:36].C(O)C>CC(C)=O>[C:35]([OH:38])(=[O:37])[CH3:36].[C:35]([OH:38])(=[O:37])[CH3:36].[OH:1][CH:2]([CH3:34])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[C:15]([OH:24])[CH:16]=[CH:17][C:18]=3[OH:23])[C:13](=[O:25])[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CC(O)CNCCNc1ccc(NCCNCC(C)O)c2c1C(=O)c1c(O)ccc(O)c1C2=O
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: CCO
Product: CC(O)CNCCNc1cccc2c1C(=O)c1c(O)ccc(O)c1C2=O

Procedure:
A mixture of 228 mg. of 1,4-bis[2-(2-hydroxypropylamino)ethylamino]-5,8-dihydroxyanthraquinone, 60 mg. of glacial acetic acid, and 10 ml. of ethanol is heated on a steam bath for 10 minutes, cooled, treated with 50 ml. of acetone and cooled to obtain the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])[CH:6]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16]([CH2:17][C:18]([F:20])([F:21])[F:19])=[O:41])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:29])([F:30])[F:28])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(OCC(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(OCC(F)(F)C(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
0.2 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole was dissolved in 10 mL of chloroform, and 0.1g of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous potassium carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.2 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole.
Reaction SMILES: [CH2:1]([CH:4]([C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=1)[C:5](O)=[O:6])[CH:2]=[CH2:3].Cl.[O:23]=[C:24]1[CH2:29][CH2:28][C:27]([NH2:36])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>>[O:23]=[C:24]1[CH2:25][CH2:26][C:27]([NH:36][C:5](=[O:6])[CH:4]([CH2:1][CH:2]=[CH2:3])[C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:29]1
Reactant: C=CCC(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NC1(c2ccccc2)CCC(=O)CC1
Agent: Cl
Product: C=CCC(C(=O)NC1(c2ccccc2)CCC(=O)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Prepared from (RS)-α-(2-propenyl)-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 9) and 4-oxo-1-phenylcyclohexylamine hydrochloride (Description 3) according to the method of Description 11. 1H NMR (400 MHz, CDCl3) δ 7.80 (1H, s), 7.73 (2H, s), 7.35-7.2 (5H, m), 5.80 (1H, br s), 5.75-5.63 (1H, m), 5.13-5.05 (2H, m), 3.56 (1H, dd, J 7, 6 Hz), 2.90-2.80 (21H, m), 2.65-2.55 (1H, m), and 2.52-2.30 (7H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([OH:8])[CH2:7][CH2:6]1)=[O:4].[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1([O:8][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(O)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1(OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 43.6 %

Procedure:
1-Hydroxy-cyclopropanecarboxylic acid methyl ester (Acros; 1.00 g, 8.61 mmol) in 24 mL of THF was stirred with 516 mg (12.9 mmol) of NaH (60% in mineral oil) for 10 min. Benzyl bromide (1.13 mL, 9.37 mmol) and Bu4I (0.32 g, 0.85 mmol) were then added, and the mixture was stirred overnight. The mixture was diluted with EtOAc and washed with saturated NH4Cl. The wash was extracted once with EtOAc, and the combined extracts were washed with brine, dried with Na2SO4, filtered, concentrated, and chromatographed (0–50% EtOAc in hexanes) to provide 774 mg (3.75 mmol) of 1-benzyloxy-cyclopropanecarboxylic acid methyl ester that was dissolved in 14 mL of 1:1 Is EtOH/THF. Sodium hydroxide (1M, 5.63 mL) was added, and the mixture was stirred for 4 h. After concentrating, 5 mL of water was added and the solution was extracted once with Et2O. The aqueous layer was then adjusted to pH 3 with HCl, and the suspension was extracted twice with EtOAc. The extracts were washed with brine, dried with Na2SO4, filtered, and concentrated to provide 723 mg of 1-Benzyloxy-cyclopropanecarboxylic acid. To the above acid (3.76 mmol) in 10 mL of CH2Cl2 was added 2.82 mL (5.64 mmol) of 2M oxalyl chloride in CH2Cl2 and one drop of DMF. After stirring for 15 min, the mixture was concentrated and redissolved in 4 mL of MTBE and 0.15 mL of CH2Cl2 and chilled to 0° C. Ammonium hydroxide (28% in water; 0.78 mL) was added, and the mixture was stirred for 15 min when 1 mL of saturated NaHCO3 was added. The mixture was extracted twice with EtOAc, and the extracts were combined, washed with brine, dried with Na2SO4, filtered, and concentrated to provide 550 mg of 1-benzyloxy-cyclopropanecarboxylic acid amide as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])=[O:7].[H-].[Na+].[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH2:30]Br>CN(C=O)C>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH2:30][N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])[C:6](=[O:7])[C:5]1[CH:17]=[CH:18][CH:19]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: BrCCOC1CCCCO1
Reactant: COc1cccc(C(=O)Nc2ccccc2OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)N(CCOC2CCCCO2)c2ccccc2OC)c1
Reaction time: 0.33 h
Yield: 67 %

Procedure:
In an atmosphere of argon, 3-methoxy-N-(2-methoxyphenyl) benzamide (500 mg, 1.94 mmol) was dissolved in DMF (10 ml) to which was subsequently added sodium hydride (85 mg, 60%, 2.13 mmol) at room temperature, followed by 20 minutes of stirring. After additional 5 minutes of stirring under an ultrasonic irradiation condition at the same temperature, to this was added 2-tetrahydropyranyloxyethyl bromide (446 mg, 2.13 mmol) at room temperature. After 1 hour of stirring at room temperature and subsequent stirring at 70° C. for 6 hours, DMF was removed by evaporation, and the resulting residue was mixed with water (20 ml), extracted with ether and then washed with water and saturated brine. The resulting organic layer was dried on anhydrous magnesium sulfate, the solvent was removed by evaporation and then the resulting orange oily residue was purified by subjecting it to a silica gel column chromatography (ether:hexane=2:1) to obtain 501 mg (67.0%) of the title compound in the form of yellow oil.
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[NH3:16]>>[CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]([C:11]([OH:13])=[O:12])[CH:5]2[C:14](=[NH:16])[OH:15])[CH:2]=[CH2:3]
Reactant: N
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(=N)O
Yield: 60 %

Procedure:
A mixture of 102 g of allyl-bicyclo[2.2.1]-hept-5-ene-2,3-dicarboxylic acid anhydride, prepared according to Example 1 in U.S. Pat. No. 3,105,839, and 68.1 g of 25% aqueous ammonia solution is refluxed with cooling at 95°-102° C. for 70 minutes, while stirring. The water and excess ammonia are then distilled off under reduced pressure (6,133 Pa). When the internal temperature reaches 120° C., 54 ml of aqueous ammonia have been distilled off. An orange-coloured, viscous residue remains, and is distilled under a pressure of 13.3 Pa. 62.07 g of allyl-bicyclo[2.2.1]-hept-5-ene-2,3-dicarboxylic acid imide pass over between 132° and 135° C., corresponding to a yield of 60% of theory. The imide is a yellow oil of refractive index nD20 1.5421 and viscosity η25 345 Pa.s at 25° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][C:13](Cl)=[N:14][CH:15]=3)[N:10]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:46]([O:50][C:51](=[O:60])[NH:52][CH:53]1[CH2:58][CH2:57][CH:56]([NH2:59])[CH2:55][CH2:54]1)([CH3:49])([CH3:48])[CH3:47].O>CN(C=O)C>[C:46]([O:50][C:51](=[O:60])[NH:52][CH:53]1[CH2:54][CH2:55][CH:56]([NH:59][C:13]2[N:12]=[C:11]3[N:10]([C:18]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)[C:16]3=[CH:15][N:14]=2)[CH2:57][CH2:58]1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: Clc1ncc2c(-c3cccc(Br)c3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(Br)c4)nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3n2)CC1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(3-bromo-phenyl)-6-chloro-1-trityl-1H-pyrazolo[3,4-d]pyrimidine (from Example 42 supra) (1.10 g, 2.0 mmol) in DMF (20 mL) was add DIPEA (0.39 g, 2.8 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.60 g, 2.8 mmol). This mixture was stirred at 120° C. for 12 hours. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and the resulting precipitate was collected by filtration. The obtained yellow solid was purified by chromatography (silica gel, MeOH:dichloromethane, 1:100) to give a light solid which was washed with ether (4 mL) to give {4-[3-(3-bromo-phenyl)-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid. (Yield 730 mg, 50.1%).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([CH2:22]CS([O-])(=O)=O)[C@@H:18]([CH2:28]CS([O-])(=O)=O)[C@@H:17]2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(O)C>[CH2:43]([N:50]1[CH2:28][C@@H:18]2[C@H:19]([CH2:20][CH2:21][C@H:16]([O:15][C@@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:42])([F:41])[F:1])[CH:4]=3)[CH3:14])[C@H:17]2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH2:22]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NCc1ccccc1
Reactant: C[C@@H](O[C@H]1CC[C@@H](CCS(=O)(=O)[O-])[C@@H](CCS(=O)(=O)[O-])[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCO
Product: C[C@@H](O[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C

Procedure:
In a pressure tube was placed a solution of crude [(1S,2R,3R,4S)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-diyl]di(methylene) dimethanesulfonate (step H) in ˜20 mL ethanol and 1.2 mL (˜3 equiv.) benzylamine. The pressure tube was sealed and heated at 150° C. in an oil bath for 3 hr. The tube was cooled to RT and opened. The resulting mixture was transferred to a round bottom flask and the solvent removed under vacuum. The residue was diluted with 100 mL EtOAc, washed with 20 mL 5N aq. NaOH, dried over MgSO4 drying agent, filtered and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with EtOAc to give 1.6 g of the title compound. 1H-NMR (CDCl3): δ: 7.35-7.20 (5 H, m), 7.50 (2 H, s), 6.97 (2 H, m), 6.85 (2 H, t, J=8.2 Hz), 4.42 (1 H, t, J=6.0 Hz), 3.75 (2 H, d, J=13.4 Hz), 3.50 (2 H, d, J=13.4 Hz), 3.30 (1 H, m), 2.96 (1 H, m), 2.52 (3 H, m), 2.19 (2 H, m), 1.98 (1 H, m), 1.97 (1 H, m), 1.86 (2 H, m), 1.57 (1 H, m), 1.33 (3 H, t, J=6.0 Hz), 1.30 (1 H, m). MS: (MH)+ 566.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:4][C:5]3[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:11]([OH:13])=O)[C:7](=[O:21])[C:6]=3[O:22][C:23]=2[CH:24]=[CH:25][CH:26]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[Cl:1][C:2]1[C:3]2[CH2:4][C:5]3[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:11]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:13])[C:7](=[O:21])[C:6]=3[O:22][C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccccn1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccccn1)[C@H](CC1CCCCC1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Yield: 17.6 %

Procedure:
A solution of (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (200 mg, 2.1 mmol), commercially available 2-aminopyridine (60 mg, 0.63 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (112 mg, 0.59 mmol), and N-hydroxybenzotriazole (HOBt) (79 mg, 0.59 mmol) in methylene chloride (10 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradiant elution, to afford (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-N-pyridin-2-ylpropionamide (50 mg, 20.8%), as a white solid. 1H NMR (DMSO-d6) δ: 10.87 (s, 1H), 8.28-8.41 (m, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.70-7.86 (m, 1H), 7.20-7.40 (m, 2H), 7.03-7.16 (m, 2H), 5.09 (br. s., 1H), 5.00-5.01 (m, 1H), 4.36-4.37 (m, 1H), 4.43 (d, J=18.6 Hz, 1H), 4.07 (d, J=18.6 Hz, 3H), 3.99-4.15 (m, 1H), 3.75 (s, 2H), 1.49-1.90 (m, 6H), 1.05-1.29 (m, 4H), 0.88-1.02 (m, 2H).
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1)([O-:12])=[O:11]>CC(C)=O>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:21])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: CCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1ccc([N+](=O)[O-])cc1

Procedure:
Following a procedure similar to that described in Example 1 but using 3.39 g. sodium in 200 ml. dry acetone, 20 g. valeramidine hydrochloride, and 21.9 g. 4-nitrophenyl isocyanate in 100 ml. dry acetone, there was obtained after recrystallization from methyl alcohol 10.8 g. of the hydrochloride of 1-(4-nitrophenyl)-3(-pentanimidoyl)urea; m.p. 187°-191°C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH2:46]([C:49]1[S:50][CH:51]=[C:52]([C:54](O)=[O:55])[N:53]=1)[CH2:47][CH3:48].C(N(CC)CC)C>CN(C=O)C>[OH:45][CH2:44][CH2:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[CH2:36][N:33]1[CH2:32][CH2:31][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:54]([C:52]3[N:53]=[C:49]([CH2:46][CH2:47][CH3:48])[S:50][CH:51]=3)=[O:55])[CH2:29]2)[CH2:35][CH2:34]1
Reactant: CCCc1nc(C(=O)O)cs1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.24 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)phenyl)ethanol (example 82, step a) (0.14 g), 2-propylthiazole-4-carboxylic acid (example 87, step c) (0.084 g) and triethylamine (0.27 mL) in DMF (7 mL) at 0° C. The resulting yellow solution was allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL), the organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.14 g.
Reaction SMILES: [NH2:1][C:2](=O)[CH:3]([NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1)[CH3:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17]>C1(C)C=CC=CC=1>[CH3:4][C:3]1[N:5]=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=2)[S:17][C:2]=1[NH2:1]
Reactant: Cc1cc(C(=O)NC(C)C(N)=O)ccn1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: Cc1cc(-c2nc(C)c(N)s2)ccn1
Yield: 47.9 %

Procedure:
A mixture of N-(1-amino-1-oxopropan-2-yl)-2-methylisonicotinamide (1.00 g, 4.83 mmol) and phosphorus pentasulfide (2.15 g, 9.65 mmol) in 10 mL of toluene was allowed to reflux overnight. The mixture was concentrated and the residue was purified by CombiFlash using 0-10% methanol/DCM to give 0.475 g of 4-methyl-2-(2-methylpyridin-4-yl)thiazol-5-amine 22C. LCMS (ES+) m/z 206.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[N:17]=[C:16]([N:18]4[CH:22]=[C:21]([CH2:23][N:24]5[CH2:27][CH:26]([OH:28])[CH2:25]5)[C:20]([CH3:29])=[N:19]4)[CH:15]=[CH:14][N:13]=3)[CH:9]=2)[N:4]([CH3:30])[CH:3]=1.[CH3:31][S:32](O)(=[O:34])=[O:33]>CO>[CH3:31][S:32]([O:28][CH:26]1[CH2:25][N:24]([CH2:23][C:21]2[C:20]([CH3:29])=[N:19][N:18]([C:16]3[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]4[CH:9]=[C:10]5[C:5](=[CH:6][CH:7]=4)[N:4]([CH3:30])[CH:3]=[C:2]5[Cl:1])[N:17]=3)[CH:22]=2)[CH2:27]1)(=[O:34])=[O:33]
Reactant: Cc1nn(-c2ccnc(Nc3ccc4c(c3)c(Cl)cn4C)n2)cc1CN1CC(O)C1
Reactant: CS(=O)(=O)O
Solvent: CO
Product: Cc1nn(-c2ccnc(Nc3ccc4c(c3)c(Cl)cn4C)n2)cc1CN1CC(OS(C)(=O)=O)C1
Temperature: 25 °C
Yield: 54 %

Procedure:
To a slurry of 1-((1-(2-(3-chloro-1-methyl-1H-indol-5-ylamino)pyrimidin-4-yl)-3-methyl-1H-pyrazol-4-yl)methyl)azetidin-3-ol, Compound No. 144 (127 mg, 0.3 mmol) in methanol, was added 1 equivalant of methanesulfonic acid at room temperature. After being stirred at room temperature, the resulting solids were collected by filtration, rinsed with cold methanol and then vacuum dried to give 85 mg (54%) of the desired compound 181 as a pale yellow solid. MS (ESI) m/z 424 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.9 (br s, 1H), 9.98 (s, 1H), 8.66 (s, 1H), 8.53 (d, 1H, J=5.4 Hz), 7.92 (S, 1H), 7.53˜7.51 (m, 3H), 7.19 (d, 1H, J=5.4 Hz), 4.45˜4.50 (m, 1H), 4.32˜4.38 (m, 2H), 4.22˜4.28 (m, 2H), 3.85˜3.91 (m, 2H), 3.79 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=2)[CH:13]=[C:12]([N:21]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH3:22])[N:11]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>ClCCl>[Cl:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=2)[CH:13]=[C:12]([N:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:25][CH:24]=2)[CH3:22])[N:11]=1
Reactant: CN(c1ccc(O)cc1)c1cc2ccc(F)cc2c(Cl)n1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(F)cc3c(Cl)n2)cc1
Yield: 88.4 %

Procedure:
A mixture of ethyl 2-bromopropionate (1.12 g), 4-[N-(1-chloro-7-fluoroisoquinolin-3-yl)-N-methylamino]phenol (1.70 g), anhydrous potassium carbonate (0.86 g) and methyl ethyl ketone (20 ml) was heated under reflux for a period of 3 hours. The mixture was cooled, diluted with dichloromethane, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give an oil which was purified by column chromatography over silica gel (eluant dichloromethane) to give ethyl 2-{4-[N-(1-chloro-7-fluoroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (2.00 g) as a yellow oil. The assigned structure was confirmed by proton magnetic spectroscopy and mass spectrometry. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.29 (3H, t); 1.65 (3H, d); 3.47 (3H, s); 4.27 (2H, q); 4.75 (1H, q); 6.47 (1H, s) 6.85-7.20 (6H, m); 7.30 (1H, d).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])[CH:6]=[CH:5]2
Reactant: Clc1ccc2cc(Br)ccc2n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc2cc(Br)ccc2n1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Dichlorobis(triphenylphosphine)-palladium(II) (0.289 g, 0.412 mmol) was added to a solution of 6-bromo-2-chloroquinoline (1.0 g, 4.1 mmol) and tributyl(1-ethoxyvinyl)stannane (1.79 g, 4.95 mmol) in dioxane (8 mL) and the mixture was stirred at 100° C. for 5 h, desired product was identified by LC-MS. The crude reaction mixture was concentrated and purified by flash silica gel chromatography (eluted with 1:1 hexanes/DCM) to yield product 6-bromo-2-(1-ethoxyvinyl)quinoline (720 mg) as white solid. LC-MS retention time 4.091 min; m/z 279.84 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[C:16](I)=[CH:15][C:14]([S:18][CH3:19])=[CH:13][N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)#[CH:21].O>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:11]3=[N:12][CH:13]=[C:14]([S:18][CH3:19])[CH:15]=[C:16]3[CH:21]=[C:20]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccn1
Reactant: CSc1cnc(NS(=O)(=O)c2ccccc2)c(I)c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: CSc1cnc2c(c1)cc(-c1ccccn1)n2S(=O)(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A suspension of the compound obtained in Example 5 (1) (100 mg), 2-ethynylpyridine (30.4 mg), bis(triphenylphosphine) palladium(II) dichloride (17.3 mg) and cuprous iodide (4.7 mg) in triethylamine (2.5 ml) was stirred in a sealed tube at 100° C. for 1 hour. After completion of the reaction, the reaction suspension was poured into water, extracted with methylene chloride, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=1:1) to obtain 71.9 mg of the desired product as a colorless oil.