Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[C:14]([C:16]([O:18]CC)=[O:17])[CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].CO>O>[CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc2c(c1)NCc1ccccc1O2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)NCc1ccccc1O2
Yield: 92 %

Procedure:
A mixture of ethyl 10,11-dihydrodibenz[b,f][1,4]oxazepine-8-carboxylate (5.4 g), potassium hydroxide (1.1 g), methanol (70 ml) and water (5 ml) was refluxed for 3 hours. After distilling off the solvents under reduced pressure, the residue was dissolved in distilled water (20 ml). The solution was washed with ethyl acetate and acidified with diluted hydrochloric acid. The separated crystals were collected by filtration and then recrystallized from methanol to give 10,11-dihydrodibenz[b,f][1,4]oxazepine-8-carboxylic acid.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]([CH2:9][CH2:10][C@@H:11]([OH:19])[CH2:12][C@@H:13]([OH:18])[CH2:14][C:15]([OH:17])=[O:16])[C:7]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[C:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:5]=1[C:33]([NH:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:34])[CH3:3].[CH3:42][CH2:43][O:44][C:45]([C:47]1[CH:52]([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][C:58]=2[Cl:59])[C:51]([C:60]([O:62][CH3:63])=[O:61])=[C:50]([CH3:64])[NH:49][C:48]=1[CH2:65][O:66][CH2:67][CH2:68][NH2:69])=[O:46].[C:70](=[O:73])([OH:72])[O-:71].[K+]>CN(C)C=O>[CH3:63][O:62][C:60]([C:51]1[CH:52]([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][C:58]=2[Cl:59])[C:47]([C:45]([O:44][CH2:43][CH3:42])=[O:46])=[C:48]([CH2:65][O:66][CH2:67][CH2:68][NH:69][CH2:1][C:2]2[O:73][C:70](=[O:72])[O:71][C:4]=2[CH2:5][O:16][C:15](=[O:17])[CH2:14][CH:13]([OH:18])[CH2:12][CH:11]([OH:19])[CH2:10][CH2:9][N:8]2[C:4]([CH:2]([CH3:1])[CH3:3])=[C:5]([C:33](=[O:34])[NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:6]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:7]2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[NH:49][C:50]=1[CH3:64])=[O:61]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)O
Reactant: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(COCCNCc2oc(=O)oc2COC(=O)CC(O)CC(O)CCn2c(-c3ccc(F)cc3)c(-c3ccccc3)c(C(=O)Nc3ccccc3)c2C(C)C)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 4,5-bis(bromomethyl)-1,3-dioxol-2-one (10 g, 36.8 mmol) in ethyl acetate (10 ml) is added dropwise to a mixture of atorvastatin (7.45 g, 12.9 mmol), potassium bicarbonate (3 g) and sodium iodide (0.05 g) in ethyl acetate (60 ml) and N,N-dimethylformamide (20 ml) at 5° C. and the mixture is stirred at room temperature for 8 h. Cold water (30 ml) is added with stirring and the organic phase is separated, washed with 5% aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography on silica gel to yield the 5-bromomethyl-2-oxo-1,3-dioxol-4-yl)methyl ester of atorvastatin. A mixture of the 5-bromomethyl-2-oxo-1,3-dioxol-4-yl)methyl ester of atorvastatin (7.7 g, 10 mmol), amlodipine (5.25 g, 10 mmol) and potassium bicarbonate (1 g, 10 mmol) in N,N-dimethylformamide (50 ml) is stirred at 0° C. for 8 h. The solvent is removed in vacuo and the residue is dissolved in chloroform. The chloroform solution is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the title compound of Example One.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[C:8]([CH2:14][NH:15][CH:16]=O)=[N:9][CH:10]=[C:11]([F:13])[CH:12]=1>C1(C)C=CC=CC=1>[F:13][C:11]1[CH:12]=[C:7]([F:6])[C:8]2[N:9]([CH:16]=[N:15][CH:14]=2)[CH:10]=1
Reactant: O=CNCc1ncc(F)cc1F
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1cc(F)c2cncn2c1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 45 %

Procedure:
In a round-bottomed flask, N-(3,5-difluoro-pyridin-2-ylmethyl)-formamide (crude from Step 2) was dissolved in toluene (14 ml) and phosphorus oxychloride (0.65 ml, 7.0 mmol) was added. The reaction mixture was stirred at 100° C. in an oil bath for 3.5 h then cooled to 0° C. and carefully quenched with ice. Aqueous 25% ammonium hydroxide was added until pH=˜9. The mixture was diluted with water and extracted with dichloromethane (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient 0-60% EtOAc) to give 319 mg (45%, 2 steps) of 6,8-difluoro-imidazo[1,5-a]pyridine as a yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.36 (d, J=3.0 Hz, 1H), 7.84 (d, J=3.4 Hz, 1H), 7.65 (s, 1H), 6.39-6.57 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C@@:16]([CH3:31])([S:27]([CH3:30])(=[O:29])=[O:28])[C:17]([NH:19][O:20]C3CCCCO3)=[O:18])[C:10](=[O:32])[CH:9]=2)=[C:4]([F:33])[C:3]=1[F:34].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C@@:16]([CH3:31])([S:27]([CH3:30])(=[O:28])=[O:29])[C:17]([NH:19][OH:20])=[O:18])[C:10](=[O:32])[CH:9]=2)=[C:4]([F:33])[C:3]=1[F:34]
Reactant: C[C@@](CCn1ccc(-c2ccc(Cl)c(F)c2F)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: O
Product: C[C@@](CCn1ccc(-c2ccc(Cl)c(F)c2F)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a heterogeneous mixture of (2R)-4-[4-(4-chloro-2,3-difluorophenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (14500 mg, 26.94 mmol) in Ethanol (50 mL) and water (100 mL) was added a solution of PPTS (pyridinium p-touluenesulfonate) (7090 mg, 27.9 mmol). The mixture was stirred overnight at 70° C. and a solid formed. The solid was collected via filtration and dried to furnish the title compound as a white solid (5.7 g, 46.9%). The filtrate was concentrated to half the volume and more desired product formed and was collected via filtration to provide additional title compound (3.3 g, 27.1%). LCMS m/z 435.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (s, 3H) 2.06-2.20 (m, 1H) 2.36-2.45 (m, 1H) 3.08 (s, 3H) 3.67-3.81 (m, 1H) 4.10 (ddd, J=12.20, 11.32, 4.78 Hz, 1H) 6.47 (dt, J=7.17, 1.98 Hz, 1H) 6.57-6.62 (m, 1H) 7.39-7.47 (m, 1H) 7.49-7.57 (m, 1H) 7.77 (d, J=7.22 Hz, 1H) 9.23 (br. s., 1H) 11.08 (s, 1H) 19F NMR (376 MHz, DMSO-d6) δ ppm −138.08 (dd, J=22.56, 7.52 Hz) −139.09 (dd, J=22.56, 7.52 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:37]([O:38][CH3:39])=[CH:36][C:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH:33]([OH:35])[CH3:34])[CH2:30][CH2:31][C:25]=2[CH:24]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:22][C:23]2[C:37]([O:38][CH3:39])=[CH:36][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][CH:33]([OH:35])[CH3:34])[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CC(C)O)CC2
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CC(C)O)CC2
Yield: 62 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide and 1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol. The product was isolated as off-white needles (60 mg, 62%). mp: 183-185° C., MS (ESI+): 561 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.35 (s, 1H), 8.55 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.03 (s, 1H), 7.91 (d, J=8 Hz, 1H), 7.58 (t, 1H), 7.53 (s, 1H), 7.26 (m, 1H), 6.68 (s, 1H), 3.89 (s, 3H), 3.89 (m, 1H), 2.86-2.52 (m, 15H), 1.18 (d, J=6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](Cl)=[O:4].[CH3:14][NH:15][C@H:16]1[CH2:35][N:20]2[C:21]3[C:26]([C:27]([CH2:28][C:29]([O:31]CCC)=[O:30])=[C:19]2[CH2:18][CH2:17]1)=[CH:25][CH:24]=[CH:23][CH:22]=3>>[CH3:1][C:2]([CH3:13])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([N:15]([CH3:14])[C@H:16]1[CH2:35][N:20]2[C:21]3[C:26]([C:27]([CH2:28][C:29]([OH:31])=[O:30])=[C:19]2[CH2:18][CH2:17]1)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:4]
Reactant: CC(C)(Cc1ccccc1)C(=O)Cl
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)C(C)(C)Cc1ccccc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from 2,2-dimethyl-3-phenylpropanoyl chloride and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 419.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=O)[CH:10]=[CH:9][C:7](=O)[C:5]=2[CH:6]=1.C1(=O)OC(=O)C2=CC=CC=C12>>[CH:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:7]=2)[CH:3]=[CH:2][CH:1]=1
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: O=C1OC(=O)c2ccccc21
Product: c1ccc2ccccc2c1

Procedure:
In a process for separation of naphthoquinone from an aqueous slurry prepared by contacting, with an aqueous medium, a reaction mixture gas containing naphthoquinone and phthalic anhydride formed by a catalytic vapor phase oxidation of naphthalene, an improvement characterized in that naphthoquinone having a purity of higher than 95% in a form of a solution or a powder is separated by adjusting the pH of said aqueous slurry to 1.2 to 5 and extracting naphthoquinone with a straight or branched chain saturated hydrocarbon or cyclic saturated hydrocarbon at 60° to 110° C. under the condition of substantially dissolving phthalic acid in the aqueous phase and leaving resinous materials separated as a bottom phase and separating a solvent solution of naphthoquinone.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH:15]2[C:21]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=3[S:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[CH2:16]2)[CH2:7]1)=[O:5])C.[OH-:31].[Na+].C([OH:35])C>>[C:4]([OH:3])(=[O:5])[C:6]([OH:35])=[O:31].[Cl:26][C:23]1[CH:24]=[CH:25][C:20]2[S:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[CH2:16][CH:15]([O:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:21]=2[CH:22]=1
Reactant: CCOC(=O)C1CCCN(CCOC2Cc3ccccc3Sc3ccc(Cl)cc32)C1
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Product: O=C(O)C(=O)O
Product: O=C(O)C1CCCN(CCOC2Cc3ccccc3Sc3ccc(Cl)cc32)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62 %

Procedure:
The above ester (5.4 g, 12.1 mmol) was dissolved in ethanol (50 ml), 5 N sodium hydroxide (5 ml) was added, and the mixture was stirred at room temperature for 20 h. Ethanol was evaporated in vacuo, water (50 ml) and acetic acid (7 ml) were added, and the mixture was extracted with dichloromethane (100 ml). The organic phase was dried (MgSO4) and the solvent was evaporated in vacuo. The residue was dissolved in acetone and treated with oxalic acid to give 3.8 g (62%) of the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH3:6])[CH2:3][OH:4].[C:7]1(=O)[O:12][C:10](=[O:11])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12>C(O)(C)C>[C:7]1(=[O:12])[N:1]([CH:2]([CH2:5][CH3:6])[CH2:3][OH:4])[C:10](=[O:11])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12
Reactant: CCC(N)CO
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(C)O
Product: CCC(CO)N1C(=O)c2ccccc2C1=O
Yield: 87 %

Procedure:
17.83 Gms. (0.2 mole) of 2-aminobutan-1-ol was added, with stirring, to a suspension of 29.62 gms. (0.2 mole) of phthalic anhydride in 90 mls. of isopropanol. The resulting mixture was refluxed for 18 hours. Thereafter, the isopropanol was distilled off under reduced pressure and the residue was distilled to give 38.1 gms. (yield 87%) of 2-phthalimidobutan-1-ol as a colourless viscous oil. (boiling point = 170° to 172°C./1 mm. Hg.)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[CH:4][C:3]=1[C@:16]1([CH3:27])[C:21]([F:23])([F:22])[CH2:20][C@:19]([F:25])([CH3:24])[C:18](=[S:26])[NH:17]1.C(O)(C(F)(F)F)=O>ClCCl.C1(C)C=CC=CC=1>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@@:16]2([CH3:27])[NH:17][C:18](=[S:26])[C@@:19]([F:25])([CH3:24])[CH2:20][C:21]2([F:23])[F:22])[CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c([C@@]2(C)NC(=S)[C@](C)(F)CC2(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@@]1(F)CC(F)(F)[C@@](C)(c2cc(N)ccc2F)NC1=S
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 95.3 %

Procedure:
tert-butyl (4-fluoro-3-((2R,5R)-3,3,5-trifluoro-2,5-dimethyl-6-thioxopiperidin-2-yl)phenyl)carbamate (816 mg, 2.01 mmol) was dissolved in dichloromethane (9.2 mL). The solution was cooled to 0° C. and TFA (4.6 mL, 59.5 mmol) was added. The solution was stirred at 0° C. for 1 h 20 min. The reaction was diluted with toluene (15 mL) and concentrated to approx. 10 mL under reduced pressure. The residue was diluted with ethyl acetate (50 mL) and washed with saturated aqueous NaHCO3 (25 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure to afford (3R,6R)-6-(5-amino-2-fluorophenyl)-3,5,5-trifluoro-3,6-dimethylpiperidine-2-thione (587 mg, (50% purity), 47.7% yield). The material was used in the next reaction step without further purification.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:22])([F:21])[CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)C(C)C)(C)C.[CH3:32][C:33]1[CH:38]=[C:37]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)=[C:41]([CH3:52])[CH:40]=2)[CH:36]=[C:35]([CH3:53])[N:34]=1>ClCCl>[CH3:53][C:35]1[CH:36]=[C:37]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][N:46]3[CH2:51][CH2:50][N:49]([C:5]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:11])[CH2:48][CH2:47]3)=[C:41]([CH3:52])[CH:40]=2)[CH:38]=[C:33]([CH3:32])[N:34]=1
Reactant: Cc1cc(-c2ccc(CN3CCNCC3)c(C)c2)cc(C)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC(C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(-c2ccc(CN3CCN(C(=O)OC(C(F)(F)F)C(F)(F)F)CC3)c(C)c2)cc(C)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 137.6 %

Procedure:
A 25 mL round-bottom flask maintained with an inert atmosphere of nitrogen was charged with triphosgene (46.0 mg, 0.150 mmol, 0.35 equiv), 1,1,1,3,3,3-hexafluoropropan-2-ol (111 mg, 0.660 mmol, 1.50 equiv) and dichloromethane (3 mL). N,N-diisopropylethylamine (170 mg, 1.32 mmol, 2.99 equiv) was added dropwise at 0° C. The resulting solution was stirred for 2 h at 0° C. 1-[[4-(2,6-Dimethylpyridin-4-yl)-2-methylphenyl]methyl]piperazine (130 mg, 0.440 mmol, 1.00 equiv) in dichloromethane (2 mL) was added dropwise at 0° C. The resulting solution was stirred for 3 h at 0° C. The reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with brine (2×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (300 mg) was purified by preparative HPLC using the following gradient conditions: 30% CH3CN/70% Phase A increasing to 70% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 30% CH3CN over 0.1 min, and holding at 30% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 101 mg (47% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[4-(2,6-dimethylpyridin-4-yl)-2-methylphenyl]methyl]piperazine-1-carboxylate as yellow oil. 1H NMR 400 MHz (CDCl3) δ 7.42-7.45 (m, 2H), 7.35-7.37 (m, 1H), 7.21 (s, 2H), 5.75-5.81 (m, 1H), 3.56-3.58 (m, 6H), 3.62 (s, 6H), 2.48-2.53 (m, 4H), 2.46 (s, 3H). LCMS (ESI, m/z): 490 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:18]1([NH:24][C:25]([C:27]2[S:28][C:29]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:31]=2)=[O:26])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.O>CS(C)=O>[N:18]1([NH:24][C:25]([C:27]2[S:28][C:29]([C:32]([NH:34][N:35]=[C:15]([C:12]3[C:13]([OH:14])=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[S:10][CH:11]=3)[CH3:17])=[O:33])=[CH:30][CH:31]=2)=[O:26])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: NNC(=O)c1ccc(C(=O)NN2CCOCC2)s1
Solvent: O
Solvent: CS(C)=O
Product: CC(=NNC(=O)c1ccc(C(=O)NN2CCOCC2)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Yield: 74.1 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (29 mg, 0.1 mmol) in dimethyl sulfoxide (4.0 mL) was heated with 5-(hydrazinocarbonyl)thiophene-2-carboxylic acid morpholin-4-ylamide (27 mg, 0.1 mmol) prepared in Reference Synthetic Example 11 at 100° C. for 20 hours and allowed to cool to room temperature 2 mL of water was added, and the precipitated solid was collected by filtration, washed with chloroform and dried Synthesis was carried out in the same manner as in Reference Synthetic Example by using to give 40 mg of the desired product (yield 73%).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:18]=[N:17][CH:16]=[CH:15][C:9]=3/[C:10](=[N:13]/[OH:14])/[C:11](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+:23].[F:24][CH:25]([F:40])[C:26]1[C:30]([CH:31]=O)=[C:29]([CH3:33])[N:28]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[N:27]=1.C(O)(=O)C>>[F:24][CH:25]([F:40])[C:26]1[C:30]([C:31]2[N:13]([OH:14])[C:10]3[C:9]4[CH:15]=[CH:16][N:17]=[CH:18][C:8]=4[NH:7][C:6]4[N:1]=[CH:2][CH:3]=[CH:4][C:5]=4[C:11]=3[N:23]=2)=[C:29]([CH3:33])[N:28]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[N:27]=1
Reactant: Cc1c(C=O)c(C(F)F)nn1C1CCCCO1
Reactant: [NH4+]
Reactant: O=c1/c(=N\O)c2ccncc2[nH]c2ncccc12
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1c(-c2nc3c(n2O)-c2ccncc2Nc2ncccc2-3)c(C(F)F)nn1C1CCCCO1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of (6Z)-5H-dipyrido[2,3-b:4′,3′-f]azepine-5,6(11H)-dione 6-oxime (1.00 g, 4.16 mmol), ammonium acetate (6.00 g, 77.8 mmol) and 3-(difluoromethyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde (2.50 g, 8.19 mmol) in acetic acid (6.0 mL, 0.106 mol) was stirred at 80° C. for 2 h. The reaction was partitioned between dichloromethane/isopropanol (5:1) and water and the organic extract was washed with NaHCO3, brine, dried (MgSO4) and concentrated in vacuo. The residue was used in the next reaction without purification. Mass spec: (EI) m/z=466 (M+1).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.Br[C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]([CH2:32][N:33]([CH:41]1[CH2:43][CH2:42]1)[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=N[N:22]2[CH2:27][CH2:28][CH2:29][O:30][CH3:31]>ClCCCl.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>[CH:41]1([N:33]([CH2:32][C:20]2[C:19]3[C:23](=[CH:24][CH:25]=[CH:26][C:18]=3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:22]([CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:1]=2)[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:43][CH2:42]1
Reactant: OB(O)c1ccccc1
Reactant: COCCCn1nc(CN(C(=O)OC(C)(C)C)C2CC2)c2c(Br)cccc21
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: ClCCCl
Solvent: O
Product: COCCCn1cc(CN(C(=O)OC(C)(C)C)C2CC2)c2c(-c3ccccc3)cccc21
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 98.1 %

Procedure:
Potassium carbonate (276 mg), phenylboronic acid (122 mg), dichlorobis(triphenylphosphine)palladium(II) (175 mg) and water (132 μl) were added to a solution of tert-butyl {[4-bromo-1-(3-methoxypropyl)-1H-indazol-3-yl]methyl}cyclopropylcarbamate (218 mg) in 1,2-dichloroethane (11 ml) and the mixture was stirred under argon atmosphere at 80° C. for 1.5 hours. The reaction mixture was cooled to room temperature, poured into ice water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=20/1 to 7/3) to give tert-butyl cyclopropyl{[1-(3-methoxypropyl)-4-phenyl-1H-indol-3-yl]methyl}carbamate (212 mg) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[C:21](C#N)[CH:22]=1)[O:6][C:7]1[C:8]([F:19])=[C:9]([CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])#[N:2].C(C1C=C(C=C(C(F)F)C=1)OC1C(F)=C(CC(O)=O)C=CC=1OC)#N.CN1C2C(C(OC)=O)C(OC(C3C=CC(F)=CC=3)C3C=CC(F)=CC=3)CC1CC2.[Cl:79]C1C=C(C=C(O)C=1)C#N>>[Cl:79][C:21]1[CH:20]=[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH:22]=1)[O:6][C:7]1[C:8]([F:19])=[C:9]([CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(CC(=O)O)c(F)c1Oc1cc(C#N)cc(C#N)c1
Reactant: N#Cc1cc(O)cc(Cl)c1
Agent: COC(=O)C1C(OC(c2ccc(F)cc2)c2ccc(F)cc2)CC2CCC1N2C
Agent: COc1ccc(CC(=O)O)c(F)c1Oc1cc(C#N)cc(C(F)F)c1
Product: COc1ccc(CC(=O)O)c(F)c1Oc1cc(Cl)cc(C#N)c1

Procedure:
[3-(3,5-Dicyano-phenoxy)-2-fluoro-4-methoxy-phenyl]-acetic acid (R-45) and [3-(3-cyano-5-difluoromethyl-phenoxy)-2-fluoro-4-methoxy-phenyl]-acetic acid (R-46) can be prepared similarly except R-10 and R-26 respectively are used in place of 3-chloro-5-hydroxy-benzonitrile.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:11])=[CH:5][C:4]=1[Cl:32].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1.ClCCl>[Cl:32][C:4]1[CH:5]=[C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[O:11])[CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][S:34]([CH3:33])(=[O:36])=[O:35]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CN)c(Cl)c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CNS(C)(=O)=O)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.6 %

Procedure:
To a stirred solution of 2-(4-(aminomethyl)-3-chlorophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (90 mg, 0.195 mmol) in pyridine, cooled to 0° C., were added methanesulfonyl chloride (90 mg). The resulting reaction mixture was stirred for 15 h at room temperature. The mixture dissolved in dichloromethane and washed with 1N HCl. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(3-Chloro-4-(methylsulfonamidomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (example 77) (87 mg) was obtained as 83% yield. 1H NMR (300 MHz, CDCl3) 7.77 (d, 1H, J=8.04 Hz, Ar), 7.58 (d, 1H J=8.07 Hz, Ar), 7.39 (d, 1H, J=7.86 Hz, Ar), 7.28 (m, 4H, Ar), 7.13 (m, 2H, Ar), 5.59 (t, 1H, NH), 4.82 (t, 1H, NH), 4.47 (d, 2H, J=6.03 Hz, CH2), 4.37 (d, 2H, J=6.39, CH2), 3.44 (q, 1H, CH), 2.88 (s, 3H, mesyl), 2.38 (s, 3H, methyl), 1.44 (d, 3H, J=7.14 Hz, CH3)