Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[OH-].[K+]>C1(C)C=CC=CC=1.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl.[Fe]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:10])[CH3:9]
Reactant: CC(=O)c1ccccc1C
Agent: Cl[Ru]Cl
Agent: [Fe]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: Cc1ccc(C(C)C)cc1
Product: Cc1ccccc1C(C)O
Temperature: 120 °C
Reaction time: 2 h

Procedure:
Dichloro(p-cymene)ruthenium(II) dimer (1.2 mg, 2 μmol, 0.5 mol %) and a chiral ligand (M=Fe, R=i-Pr, Ar=C6H5—, 2.6 μmol, 0.65 mol %) were dissolved in toluene (3 mL) under nitrogen atmosphere, and then heated and stirred for 2 h at 120° C. After the mixture was cooled to room temperature, o-methylacetophenone (0.4 mmol), toluene (2 mL) and an aqueous solution of potassium hydroxide (0.4 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 24 h under H2 (10 atm) at 25° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent:ethyl acetate/petroleum ether=1/5). Accordingly, pure 1-(o-methylphenyl)ethanol was obtained and the ee value (ee=98%) was measured by GC analysis.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[N:28][CH:29]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:28]4[CH:29]=[C:24]([F:23])[CH:25]=[CH:26][C:27]4=[O:30])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cn1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3cc(F)ccc3=O)cc2)cn1)c1ccc(Cl)s1
Temperature: 130 °C
Yield: 9.3 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 (66 mg, 0.15 mmol), 5-fluoro-2-hydroxypyridine (46 mg, 0.40 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and K2CO3 (50 mg, 0.36 mmol) in DMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg, 0.079 mmol). The mixture in a sealed tube was heated at 130° C. overnight. The mixture was then purified by HPLC to give the titled compound (6 mg). MS 429.0 and 431.0 (M+H, Cl pattern).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:24][CH:25]([F:27])[F:26])[C:5]([F:28])=[CH:4][N:3]=1.C(OC([N:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[C:44]([O:49][CH3:50])[CH:43]=2)[CH2:38][CH2:37]1)=O)(C)(C)C>C(OC(O)C)C.Cl>[F:26][CH:25]([F:27])[O:24][C:10]1[CH:11]=[C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]2)[CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[C:5]([F:28])=[CH:4][N:3]=[C:2]([NH:48][C:45]2[CH:46]=[CH:47][C:42]([N:39]3[CH2:38][CH2:37][NH:36][CH2:41][CH2:40]3)=[CH:43][C:44]=2[O:49][CH3:50])[N:7]=1
Reactant: CC(=O)N1CCN(c2ccc(Nc3nc(Cl)ncc3F)c(OC(F)F)c2)CC1
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Agent: CCOC(C)O
Agent: Cl
Product: COc1cc(N2CCNCC2)ccc1Nc1ncc(F)c(Nc2ccc(N3CCN(C(C)=O)CC3)cc2OC(F)F)n1
Temperature: 115 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
1-(4-(4-(2-chloro-5-fluoropyrimidine-4-ylamino)-3-(difluoromethoxy)phenyl)piperazin-1-yl)ethanone (320 mg) and tert-butyl-4-(4-amino-3-methoxyphenyl)piperazin-1-carboxylate (236 mg) were dissolved in 0.08M HCl ethoxyethanol solution (7.7 ml), and stirred at 115° C. overnight. Upon completion of the reaction, the mixture was distilled under reduced pressure to remove the solvent, and the thus obtained oil was diluted with ethyl acetate. The diluted mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, subjected to layer separation, and the extracted organic layer obtained as a result of layer separation was dried with sodium sulfate. The dried organic layer was distilled under reduced pressure to remove the solvent and purified by column chromatography to obtain a target compound (100 mg, 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:38])[N:7]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:8]([C@H:12]([NH:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:13][C:14]#[CH:15])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:46][C:47]1[C:55]([Cl:56])=[CH:54][CH:53]=[CH:52][C:48]=1[C:49](Cl)=[O:50]>ClCCl>[Cl:56][C:55]1[C:47]([F:46])=[C:48]([CH:52]=[CH:53][CH:54]=1)[C:49]([N:16]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C@@H:12]([C:8]1[N:7]([NH:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:6](=[O:38])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)[CH2:13][C:14]#[CH:15])=[O:50]
Reactant: O=C(Cl)c1cccc(Cl)c1F
Reactant: C#CC[C@@H](NCCCNC(=O)OCc1ccccc1)c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC[C@H](c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1)N(CCCNC(=O)OCc1ccccc1)C(=O)c1cccc(Cl)c1F
Yield: 84.9 %

Procedure:
(R)-Benzyl 3-(1-(7-chloro-4-oxo-3-(phenylamino)-3,4-dihydroquinazolin-2-yl)but-3-ynylamino)propylcarbamate (0.28 g, 0.53 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (0.22 mL, 1.60 mmol) was added followed by the addition of 2-fluoro-3-chlorobenzoyl chloride (0.112 g, 0.58 mmol). The reaction was stirred under a nitrogen atmosphere until the reaction was complete (LC/MS) (total of 5 min). The mixture was stirred for an additional 10 min, diluted with dichloromethane (50 mL) and washed with aqueous sodium bicarbonate (5 mL), water (5 ml×2) and brine solution and dried over anhydrous sodium sulfate. The solid was removed by filtration and the solvent removed under vacuum to provide (R)-benzyl 3-(3-chloro-N-(1-(7-chloro-4-oxo-3-(phenylamino)-3,4-dihydroquinazolin-2-yl)but-3-ynyl)-2-fluorobenzamido)propyl-carbamate as an orange solid (0.31 g, 0.45 mmol, 84%). mp 103-105° C. 1H-NMR (DMSO-d6): δ 9.41-8.94 (m, 1H), 8.21-5.62 (m, 16H), 5.35-4.80 (m, 2H), 3.46-1.15 (m, 11H). LC/MS: 686 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:66][NH:67][CH2:68][CH:69]4[CH2:71][CH2:70]4)C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:66][NH:67][CH2:68][CH:69]4[CH2:71][CH2:70]4)[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNCC2CC2)CC1
Product: NC(=O)c1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNCC2CC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=547, obsd.=547).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10](=O)[CH2:11]Cl)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:14]([SH:17])[CH2:15][SH:16].C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([C:10]1[S:16][CH2:15][CH2:14][S:17][CH:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Reactant: SCCS
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=NOC)C1=CSCCS1
Temperature: 19.5 °C
Reaction time: 2.5 h
Yield: 22.3 %

Procedure:
A solution of ethyl 2-methoxyimino-3-oxo-4-chlorobutyrate (41.4 g.) in dried chloroform (100 ml.) was added dropwise over 1 hour at 20° C. to a mixture of ethane-1,2-dithiol (20.6 g.), triethylamine (21 g.) and dried chloroform (60 ml.). After stirring for 2.5 hours at 18 to 21° C., the mixture was adjusted to pH 1.0 with 10% hydrochloric acid. The chloroform layer was separated, washed with water (100 ml.×3), dried over magnesium sulfate and concentrated to dryness under reduced pressure at 40° C. The residue was dissolved in toluene (300 ml.), p-toluenesulfonic acid (3 g.) was added thereto and the resulting mixture was refluxed for 3 hours with removal of water. The reaction mixture was cooled to ambient temperature and an insoluble material was filtered off. The filtrate was concentrated under reduced pressure at 40° C. The residue was dissolved in ethyl acetate (300 ml.). The solution was in turn washed with a saturated aqueous solution of sodium bicarbonate (3 times) and water (twice), dried over magnesium sulfate and concentrated to dryness under reduced pressure at 40° C. to give yellow oil. The oil was subjected to column chromatography on silica gel (1 kg) and eluted with benzene. The eluate was concentrated under reduced pressure at 40° C. The residue was washed with diisopropyl ether and dried to give white crystals of ethyl 2-methoxyimino-2-(2,3-dihydro-1,4-dithiin-5-yl)acetate (syn isomer) (11 g.), mp. 65° to 67° C.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.Cl[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][N:29]=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[C:32]([C:31]1[CH:34]=[CH:35][C:28]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=2)=[N:29][CH:30]=1)#[N:33]
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 6-chloronicotinonitrile as starting materials and by an operation similar to that of Example 303-3 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=50:1) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OCCO
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C1CCC2(CC1)OCCO2

Procedure:
4-oxocyclohexane carboxylic acid ethyl ester 9 (52.8 g, 0.31 mole, Merck, Order No. 814249), ethylene glycol (67.4 g, 1.08 mol) and p-toluenesulfonic acid (0.7 g) in toluene (160 ml) were stirred for 20 hours at RT, and the reaction solution was poured into diethyl ether (300 ml) and washed with water, sodium hydrogen carbonate solution and sodium chloride solution. The solution was dried (Na2SO4), concentrated by evaporation in vacuo, and the remaining colorless liquid was processed further without purification.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11](=[O:35])[C@H:12]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:13][C:14]1[CH:23]=[CH:22][C:17]2[NH:18][C:19](=[O:21])[O:20][C:16]=2[CH:15]=1>C(O)(=O)C>[CH3:9][O:10][C:11](=[O:35])[C@H:12]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[CH2:13][C:14]1[C:23]([Cl:1])=[CH:22][C:17]2[NH:18][C:19](=[O:21])[O:20][C:16]=2[CH:15]=1
Reactant: COC(=O)[C@@H](Cc1ccc2[nH]c(=O)oc2c1)NC(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: COC(=O)[C@@H](Cc1cc2oc(=O)[nH]c2cc1Cl)NC(=O)OCc1ccccc1
Temperature: 100 °C
Yield: 31.6 %

Procedure:
N-Chlorosuccinimide (315 mg, 2.36 mmol) was added to a solution of (R)-2-benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid methyl ester (700 mg, 1.89 mmol) in acetic acid (50 mL) at room temperature. The mixture was heated at 100° C. for 16 h. After it was cooled down to room temperature, solvents were removed in vacuo. The residue was subjected to silica gel chromatography using ethyl acetate/hexanes (4:6) then (1:1) as eluent to afford the title compound as an off-yellow solid (242 mg, 32%). The structure of the product was confirmed by 2D NMR. 1H-NMR (CD3COCD3, 500 MHz) δ 10.47 (s, 1H), 7.36-7.28 (m, 6H), 7.20 (s, 1H), 6.80 (d, J=8.5 Hz, 1H), 5.05 (d, J=12.5 Hz, 1H), 5.00 (d, J=12.5 Hz, 1H), 4.65-4.60 (m, 1H), 3.73 (s, 3H), 3.43 (dd, J=14.0, 5.0 Hz, 1H), 3.08 (dd, J=14.0, 10.5 Hz, 1H); 13C-NMR (CD3COCD3, 125 MHz) δ 172.2, 156.5, 154.5, 143.1, 137.5, 130.8, 129.0, 128.9, 128.7, 128.2, 128.0, 112.8, 110.9, 66.3, 54.3, 52.1, 35.8; Mass spec. 405 (MH+).
Reaction SMILES: Cl[C:2]1([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1.[CH3:21][NH2:22].C(OCC)(=O)C.O>O1CCCC1>[OH:20][C:17]1[CH:18]=[CH:19][C:14]([C:2]2([NH:22][CH3:21])[C:7](=[O:8])[N:6]([CH3:9])[C:5]3[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=3[S:3]2)=[CH:15][CH:16]=1
Reactant: CN1C(=O)C(Cl)(c2ccc(O)cc2)Sc2ccccc21
Reactant: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CNC1(c2ccc(O)cc2)Sc2ccccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a stirred suspension of 2-chloro-3,4-dihydro-2-(4-hydroxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (11.5 g, compound No. 2) in tetrahydrofuran (40 ml), 40% aqueous methylamine solution (14.6 ml) is added. The mixture is stirred for 2 hours at room temperature, and poured into a mixture of ethyl acetate and water. The organic layer is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give 10.1 g (89.8%) of the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH:5]=[O:6])[CH3:2].CO[CH:10]=[CH:11][C:12](=[CH2:18])[O:13][Si](C)(C)C>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:3][C:4]([CH:5]1[CH2:18][C:12](=[O:13])[CH:11]=[CH:10][O:6]1)=[O:7])[CH3:2]
Reactant: C=C(C=COC)O[Si](C)(C)C
Reactant: CCOC(=O)C=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: CCOC(=O)C1CC(=O)C=CO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75 %

Procedure:
A solution of glyoxylic acid ethyl ester, polymer form (2.02 g, 8.9 mmol) and (3-methoxy-1 methylene-allyloxy)trimethylsilane (1.9 ml, 8.9 mmol, Danishefsky's diene) in benzene (12 ml) was placed under nitrogen. Zinc chloride (0.5 N in tetrahydrofuran, 8.9 ml, 4.45 mmol) was added and the reaction stirred at ambient temperature for 72 hours. The mixture was concentrated in vacuo, diluted with ethyl acetate (100 ml) and washed with 1 N hydrochloric acid (20 ml), saturated sodium bicarbonate (20 ml), and brine (20 ml). The organic layer was dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of ethyl acetate/hexane (1:2) as eluent. Pure fractions were collected and the solvent evaporated in vacuo which afforded 1.2 g (75%) of 4-oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[C:18]2[C:9](=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[CH:13][CH:12]=[N:11]3)[N:8]=[C:7]([CH3:19])[CH:6]=1>CO>[CH3:19][C:7]1[CH:6]=[C:5]([S:2][CH3:1])[C:18]2[C:9](=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[CH:13][CH:12]=[N:11]3)[N:8]=1
Reactant: Cc1cc(Cl)c2ccc3cccnc3c2n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSc1cc(C)nc2c1ccc1cccnc12
Temperature: 25 °C
Yield: 84 %

Procedure:
Solid sodium methanethiolate (3.30 g, 47.7 mmol) was added to a 100 mL round-bottomed flask containing a solution of 4-chloro-2-methyl-[1,10]phenanthroline (intermediate obtained previously), (2.10 g, 9.4 mmol) in methanol (50 mL). The reaction mixture was refluxed for 18 hours and allowed to cool down to room temperature afterwards. The solvent was removed in a rotary evaporator and the residue was treated with methylene choride (100 mL) and saturated NaHCO3 (100 mL) and transferred to a separatory funnel. The organic layer was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The solid residue was treated with ethyl ether, filtered and dried, yielding 1.90 g of a light brown solid (84%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([C:26]#[N:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.C(O)(=O)C(O)=O.[H][H]>[C].[Pd].C(O)C>[C:26]([C:13]([C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:27]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
The procedure of Example 1 was followed except that the autoclave was charged with 3.9 g of 79% pure (S)-1-benzyl-3-(1-cyano-1,1-diphenylmethyl)-pyrrolidine, 3.1 ml of ethanol, 786 mg of oxalic acid and 158 mg of moist 5% palladium-carbon (water content 52% by weight) and that hydrogen was introduced thereinto and the autoclave was heated to thereby raise the temperature to 60° C. and the pressure to 203 kPa and the reaction was allowed to proceed for 3.5 hours. (S)-3-(1-Cyano-1,1-diphenylmethyl)-pyrrolidine was obtained in a yield of 70 mole percent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[N:25]1[CH:26]=[CH:27][C:22]([NH:21][C:16]2[CH:17]=[N:18][CH:19]=[C:14]([NH:13][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[N:15]=2)=[CH:23][CH:24]=1
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Reactant: Nc1ccncc1
Product: COc1cc(Nc2cncc(Nc3ccncc3)n2)cc(OC)c1OC
Yield: 10 %

Procedure:
Using Method R, with 200 mg of 2-(3,4,5-trimethoxyphenylamino)-6-chloropyrazine (all amounts scaled accordingly) and 4-aminopyridine, 25 mg of title compound were obtained. Yield: 10%. 1H NMR (250 MHz, DMSO-d6) δ 3.64 (s, 3 H), 3.68 (s, 6 H), 6.83 (s, 2 H), 7.55 (d, 2 H, J=6.3 Hz), 7.62 (s, 1 H), 7.69 (s, 1 H), 8.25 (d, 2 H, J=6.3 Hz), 9.23 (s, 1 H), 9.66 (s, 1 H). 13C NMR (62.5 MHz, DMSO-d6) δ 55.66, 60.14, 97.52, 112.07, 122.57, 123.96, 132.67, 136.40, 147.39, 148.88, 149.83, 150.18, 152.93. m/z 354.2 [(M+H)+ calcd for C18H19N5O3 353.2].
Reaction SMILES: [CH3:1][N:2]([CH3:47])[C:3]([C:5]1[N:6](S(C2C=CC(C)=CC=2)(=O)=O)[N:7]=[C:8]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[CH:17][N:16](S(C4C=CC(C)=CC=4)(=O)=O)[C:13]3=[N:14][CH:15]=2)[CH:9]=1)=[O:4].CN(C)C=O.[OH-].[K+].C(O)(=O)C>CO.O>[CH3:1][N:2]([CH3:47])[C:3]([C:5]1[NH:6][N:7]=[C:8]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[CH:17][NH:16][C:13]3=[N:14][CH:15]=2)[CH:9]=1)=[O:4]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(C(=O)N(C)C)n(S(=O)(=O)c4ccc(C)cc4)n3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc(C(=O)N(C)C)[nH]n3)cc12
Reaction time: 3 h
Yield: 25.4 %

Procedure:
5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-(toluene-4-sulfonyl)-2H-pyrazole-3-carboxylic acid dimethylamide (90 mg, 0.174 mmol) was dissolved in methanol (0.5 mL) and dimethylformamide (0.5 mL) and 50% w/v aqueous potassium hydroxide (0.5 mL) was added. After 3 hours, acetic acid (0.5 mL) was added and the mixture diluted with water. The solids were collected by filtration and the material purified by preparative HPLC to afford 5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2H-pyrazole-3-carboxylic acid dimethylamide (16.0 mg, 25.4%) 1H-NMR (500 MHz, dimethylsulfoxide-d6, 70° C.) δ 3.06-3.15 (s, 6H), 3.83 (s, 3H), 6.98 (br s, 1H), 7.07 (t, J=7.5 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.31 (Br t, J=8.5 Hz, 1H), 7.60 (br d, J=6.0 Hz, 1H), 7.71 (Br s, 1H), 8.39 (br s, 1H), 8.67 (br s, 1H). MS: m/z 362 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:23]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])=[CH:4][C:5]([N:8](S(C(F)(F)F)(=O)=O)[S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[N:6][CH:7]=1.O.[OH-].[Li+].[Cl-].[NH4+].FC(F)(F)C(O)=O>O1CCCC1.O.CCOCC.C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[C:3]([CH:23]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)(=[O:33])=[O:34])[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])=[CH:4][C:5]([NH:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:11])=[O:10])=[N:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1cc(N(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)ncc1Cl
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1cc(NS(=O)(=O)C(F)(F)F)ncc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.2 %

Procedure:
To a solution of N-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]-N-(trifluoromethylsulfonyl)trifluoromethanesulfonamide (77 mg, 0.111 mmol) in a mixture of tetrahydrofuran (5 ml) and water (1 ml) was added lithium hydroxide monohydrate (5.0 mg, 0.111 mmol). The resulting mixture was stirred at room temperature for 5 hours. To the reaction mixture was added a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate (=2:1) eluate containing 0.5% trifluoroacetic acid was concentrated under reduced pressure. To the residue thus obtained was added ether, and the solid thus precipitated was collected by filtration to give the title compound (39 mg, 0.069 mmol, 63%) as a white powder.