Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:24])[O:22][CH3:23])[CH3:19])[N:11]=2)[CH2:6][NH:5][C:4]([CH:7]2[CH2:9][CH2:8]2)=[N:3]1.[Cl:25][C:26]1[CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[C:29]([F:33])=[C:30]([CH:32]=1)[NH2:31].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:31][C:30]1[C:29]([F:33])=[C:28]([C:6]2[N:5]=[C:4]([CH:7]3[CH2:9][CH2:8]3)[NH:3][C:2]=2[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:24])[O:22][CH3:23])[CH3:19])[N:11]=2)[CH:27]=[C:26]([Cl:25])[CH:32]=1
Reactant: CC1(C)OB(c2cc(Cl)cc(N)c2F)OC1(C)C
Reactant: COC(=O)N[C@@H](C)CNc1nccc(C2(Br)CNC(C3CC3)=N2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: COCCOC
Product: COC(=O)N[C@@H](C)CNc1nccc(-c2[nH]c(C3CC3)nc2-c2cc(Cl)cc(N)c2F)n1
Temperature: 25 °C

Procedure:
To a solution of (S)-methyl 1-(4-(4-bromo-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (I-1b, 0.59 g, 1.5 mmol) in DME (15 mL) was added a solution of 5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (SM-5, (˜12 mL, 0.25 M solution in dioxane; 3.0 mmol) and aqueous Na2CO3 solution (6 mL, 2.0 M, 12.0 mL). The resulting mixture was sparged with nitrogen, and Pd(PPh3)4 (87 mg, 0.075 mmol) was added. The reaction mixture was sealed and subjected to microwave irradiation at 120° C. for about 20 minutes. The reaction was allowed to cool to room temperature and partitioned upon standing. The layers were separated and the organic portion was concentrated, dissolved in EtOAc (150 mL), washed with water (50 mL), followed by extraction with aqueous 0.01 M HCl solution (2×100 mL) and aqueous 0.02 M HCl solution (2×100 mL). The combined acidic aqueous portions were neutralized with saturated aqueous NaHCO3 solution, and extracted with EtOAc (2×225 mL). The combined organic portions were washed with brine, dried (Na2SO4), and concentrated to yield (S)-methyl 1-(4-(4-(3-amino-5-chloro-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (530 mg) which was carried forward without further purification. LCMS (m/z) 460.2 (MH+), tR=0.57 minute.
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][CH:4]=[C:5]([C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([OH:19])[CH:12]=1)=[O:7].CN(C)C=O.Cl[CH2:37][C:38]#[CH:39].[H-].[Na+]>O>[F:1][CH:2]([F:30])[O:3][CH:4]=[C:5]([C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:39][C:38]#[CH:37])[CH:12]=1)=[O:7]
Reactant: COc1ccc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)cc1O
Reactant: C#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.6 %

Procedure:
417 mg (1.00 mmol) of 3-difluoromethoxy-N-[2-(3-hydroxy-4-methoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide, 5 ml of anhydrous N,N-dimethylformamide, 74 mg (1.00 mmol) of 3-chloropropyne and 50 mg (1.25 mmol) of 60% sodium hydride were mixed and stirred at room temperature for 3 hours. Water was added to to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid, saturated aqueous sodium bicarbonate solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 162 mg of 3-difluoromethoxy-N-[2-{4-methoxy-3-(2-propynyloxy)phenyl}ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (the present compound 1299).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].[F:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[C:24]([F:27])[C:25]=1[F:26].[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8](=[O:11])[C:22]1[CH:21]=[C:20]([F:19])[C:25]([F:26])=[C:24]([F:27])[CH:23]=1)[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1cc([Mg]Br)cc(F)c1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CCC(=O)c1cc(F)c(F)c(F)c1)NC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 5 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (CAS No. 128811-48-3; 4.1 g) in tetrahydrofuran (100 mL), 3,4,5-trifluorophenylmagnesium bromide (0.35 M solution in diethyl ether; 55 mL) was added dropwise at −40° C. over 20 minutes, and the reaction solution was stirred at −40° C. for five hours. Saturated aqueous ammonium chloride and ethyl acetate were added to the solution. The reaction solution was heated to room temperature, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane->heptane:ethyl acetate=1:1) to obtain 4.8 g of ethyl (R)-2-tert-butoxycarbonylamino-5-oxo-5-(3,4,5-trifluorophenyl)pentanoate. A solution of 4 N hydrochloric acid in ethyl acetate (30 mL) was added to a solution of the resulting ethyl(R)-2-tert-butoxycarbonylamino-5-oxo-5-(3,4,5-trifluorophenyl)pentanoate in ethyl acetate (30 mL), and the solution was stirred for 15 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. 10% palladium-carbon (100 mg) was added to a solution of the residue in ethyl acetate (50 mL), and the reaction solution was stirred in a hydrogen stream at 1 atm for six hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 2.91 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [C:1]1([C@H:7]2[O:12][CH2:11][C@H:10](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([O-:27])(=[S:26])[CH3:25].[K+].C1(C)C=CC=CC=1>CN(C)C(=O)C>[C:24]([S:26][C@H:10]1[CH2:9][O:8][C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:12][CH2:11]1)(=[O:27])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H](c3ccccc3)OC2)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CC(=O)S[C@H]1CO[C@@H](c2ccccc2)OC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
A mixture of 30 g (90 mmol) of trans-2-phenyl-5-(p-toluenesulfonyloxy)-1,3-dioxane (prepared as described in Tetrahedron, 48, 5941-5950), 15.3 g (134 mmol) of potassium thioacetate, 240 ml of toluene and 60 ml of N,N-dimethylacetamide was stirred at 100° C. for 3 hours and then at 110-120° C. for 7 hours. After cooling, the reaction mixture was partitioned between toluene and water. The organic layer was then washed with water, dried over anhydrous magnesium sulfate and concentrated. The resulting oily residue was purified by chromatography on a silica el (200 g) column using, a 1:4 mixture of ethyl acetate and hexane as the eluant to afford the crude title compound as a solid. This solid was recrystallized from a mixture of ethyl acetate and hexane to afford 10 g (yield 47%) of the title compound as brown needle-like crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:20]1[CH2:29][C@H:28]([OH:30])[CH2:27][C@H:21]1[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[F:31][C:32]([F:52])([F:51])[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]([F:46])([F:45])[F:44])=[CH:37][C:36]=1[S:47](Cl)(=[O:49])=[O:48]>>[F:52][C:32]([F:31])([F:51])[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]([F:44])([F:45])[F:46])=[CH:37][C:36]=1[S:47]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[C:5]([N:20]2[CH2:29][C@H:28]([OH:30])[CH2:27][C@H:21]2[C:22]([N:24]([CH3:25])[CH3:26])=[O:23])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[C:6]1=[O:11])(=[O:49])=[O:48]
Reactant: COc1ccccc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: COc1ccccc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)N(S(=O)(=O)c2cc(OCC(F)(F)F)ccc2OCC(F)(F)F)c2ccc(Cl)cc21
Yield: 66.8 %

Procedure:
With 100 mg of (4R)-1-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-L-prolinamide (levorotatory isomer), which is the compound described in Preparation 3.2 (Isomer B) of the brochure Publication No. WO01/55130, and 89 mg of 2,5-bis (2,2,2-trifluoroethoxy)benzene sulfonyl chloride as starting materials, 119 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=[CH:5][N:4]=1.[OH-].[NH4+].[CH:19](O)=[O:20]>>[CH:19]([NH:1][CH2:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:20]
Reactant: COC(=O)CCCCc1cccnc1CN
Reactant: O=CO
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)CCCCc1cccnc1CNC=O

Procedure:
A solution of 0.1 g of 2-aminomethyl-3-(4-methoxycarbonylbutyl)pyridine in 0.6 ml of formic acid is heated at 90° for 18 hours. The mixture is cooled to 0°, made basic with saturated ammonium hydroxide solution and extracted with methylene chloride (4×10 ml). Drying, filtration and evaporation of the extracts yields 2-(N-formylaminomethyl)-3-(4-methoxycarbonylbutyl)pyridine, melting at 43°-45° C. which is redissolved in 1 ml of toluene and heated at 90° for 17 hours with 75 mg of phosphorus oxychloride. Evaporation of excess phosphorus oxychloride with toluene, basification at 0° with saturated ammonium hydroxide solution, extraction with methylene chloride (4×15 ml) and drying over sodium sulfate yields an oil, which is chromatographed (silica gel, ethyl acetate) to yield as an oil, 8-(4-methoxycarbonylbutyl)imidazo[1,5-a]pyridine; Rf 0.29;NMR (CDCl3) 3.70 (s, 3H), 6.50 (d, 2H), 7.43 (s, 1H), 7.83 (t, 1H), 8.22 (s, 1H); IR (CH2Cl2) 1725 cm-1.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][NH:7][C:8](=[O:40])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)C.[Li+].[OH-]>C1COCC1.CO>[C:22]1([C:19]2[CH:18]=[CH:17][C:16]([CH:15]([NH:28][C:29]([NH:31][C:32]3[CH:33]=[C:34]([Cl:39])[CH:35]=[C:36]([Cl:38])[CH:37]=3)=[O:30])[C:12]3[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])=[O:40])=[CH:10][CH:11]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(NC(=O)Nc2cc(Cl)cc(Cl)c2)c2ccc(C3=CCCCC3)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)c1ccc(C(NC(=O)Nc2cc(Cl)cc(Cl)c2)c2ccc(C3=CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The propionic acid ethyl ester prepared in step D was dissolved in THF (6 mL) and MeOH (3 mL). A solution of 2 M LiOH (3 mL) was then added and the reaction was stirred at room temperature for 30 minutes. The solvents were evaporated under reduced pressure. The residue was taken up in ethyl acetate and washed with 1 N HCl (2×), brine (2×), dried over MgSO4, filtered, and concentrated to a syrup. Addition of hexane followed by trituration precipitated the title compound (270 mg, 0.48 mmol) as a cream colored solid.
Reaction SMILES: [N:1]1[C:11]2[C:10]3[S:12][C:13]([CH:15](Br)[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])=[O:17])=[CH:14][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:26]([NH2:28])=O>O>[N:1]1[C:11]2[C:10]3[S:12][C:13]([C:15]4[N:28]=[CH:26][O:17][C:16]=4[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])=[CH:14][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NC=O
Reactant: O=C(c1ccccc1Cl)C(Br)c1cc2c(s1)-c1ncccc1OCC2
Solvent: O
Product: Clc1ccccc1-c1ocnc1-c1cc2c(s1)-c1ncccc1OCC2
Yield: 17.5 %

Procedure:
6,7-Dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl-(2-chlorophenyl)-2-bromoethanone from Example 37 (65.0 mg, 0.150 mmol) was suspended in formamide (2 mL, 50 mmol). The reaction was microwaved on 300 watts at 130° C. for 20 minutes. Water was added and the product was extracted with ethylacetate. The organic layer was washed with water twice and brine, dried over MgSO4, and evaporated to dryness. The crude product was purified on silica gel column, eluting with 25% of ethylacetate in hexane to give 129 (yield 10 mg, 18%). MS (ESI+) 381.1
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[C:12]([F:35])=[C:13]([C:28]2[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=O)(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[NH2:48][CH2:49][CH2:50][OH:51]>CN(C)C=O.O>[F:35][C:12]1[C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:15][N:14]([S:16]([C:19]2[CH:27]=[CH:26][CH:25]=[C:21]([C:22]([NH:48][CH2:49][CH2:50][OH:51])=[O:24])[CH:20]=2)(=[O:18])=[O:17])[C:13]=1[C:28]1[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: NCCO
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(C(=O)O)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cn(S(=O)(=O)c2cccc(C(=O)NCCO)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Yield: 35.6 %

Procedure:
To a solution of 3-{[4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-3-fluoro-2-(2-fluoropyridin-3-yl)-1H-pyrrol-1-yl]sulfonyl}benzoic acid (300 mg) in dimethylformamide (1.5 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (136 mg), then a solution of 2-aminoethanol (40 mg) in dimethylformamide (0.5 mL) at room temperature, and the mixture was stirred for 2 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound as a pale-yellow oil (yield 116 mg, 36%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=1)[CH:7]=[C:6]([C:22]([O:24]CC)=[O:23])[C:5]2=[O:27].Br>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[N:8]([C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[CH:7]=[C:6]([C:22]([OH:24])=[O:23])[C:5]2=[O:27]
Reactant: CCOC(=O)c1cn(-c2ccc(OC)cc2)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Product: O=C(O)c1cn(-c2ccc(O)cc2)c2c(F)c(F)c(F)cc2c1=O
Temperature: 120 °C
Yield: 79.1 %

Procedure:
A mixture of ethyl 6,7,8-trifluro-1-(4-methoxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.37 g) and 47% hydrobromic acid (4 ml) is heated at 120° C. for 3 hours. After cooling, the precipitated crystals are separated by filtration, washed with water and further with a mixture of ethanol and ether to give 6,7,8-trifluoro-1-(4-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.26 g), m.p. >300° C., white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH:10]=[CH:9]1>C(CN)O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12]([NH:13][CH2:14][CH2:15][OH:21])[C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Solvent: NCCO
Product: Cc1ccccc1-n1ccc2c(NCCO)nc3c(OC(F)(F)F)cccc3c21
Yield: 144 %

Procedure:
1-(2-Methylphenyl)-4-chloro-6-trifluoromethoxypyrrolo[3,2-c]quinoline(377 mg, 1.0 mmol) was dissolved in ethanolamine(10 ml) in the pressure tube, then reacted at the same condition of Step 3 in the Example 6 to obtain 289 mg of desired compound as solid in 72% of yield.
Reaction SMILES: C[Al](C)C.[I:5][C:6]1[N:15]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:9]2=[N:10][CH:11]=[C:12]([NH2:14])[CH:13]=[C:8]2[CH:7]=1.[F:25][C:26]1[C:35]([N:36]([S:43]([CH2:46][CH2:47][CH3:48])(=[O:45])=[O:44])[S:37]([CH2:40][CH2:41][CH3:42])(=[O:39])=[O:38])=[CH:34][CH:33]=[C:32]([F:49])[C:27]=1[C:28](OC)=[O:29]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:25][C:26]1[C:35]([N:36]([S:37]([CH2:40][CH2:41][CH3:42])(=[O:39])=[O:38])[S:43]([CH2:46][CH2:47][CH3:48])(=[O:44])=[O:45])=[CH:34][CH:33]=[C:32]([F:49])[C:27]=1[C:28]([NH:14][C:12]1[CH:13]=[C:8]2[CH:7]=[C:6]([I:5])[N:15]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:17])=[O:18])[C:9]2=[N:10][CH:11]=1)=[O:29]
Reactant: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)OC)c1F)S(=O)(=O)CCC
Reactant: Nc1cnc2c(c1)cc(I)n2S(=O)(=O)c1ccccc1
Agent: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(I)n3S(=O)(=O)c2ccccc2)c1F)S(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.8 %

Procedure:
Trimethylaluminum (0.51 mL, 1.01 mmol, 2.0M solution in toluene) was added dropwise via a syringe to a cold (0° C.) suspension of 2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amine (0.135 g, 0.338 mmol) in toluene (10 mL). The cold bath was removed and the mixture was stirred at room temperature for 20 minutes. Methyl 2,6-difluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate (0.149 g, 0.372 mmol) was added, and the reaction mixture was heated to 90° C. under N2 for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL) 30% Aqueous potassium sodium tartrate solution (50 mL) was carefully added, and the resulting emulsion was stirred at room temperature for 30 minutes. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1), hexanes/ethyl acetate (2:1) to give 2,6-difluoro-N-(2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(N-(propylsulfonyl)propylsulfonamido)benzamide (0.225 g, 87%) as a foam.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH:5]([O:16][CH:17]1[CH2:20][NH:19][CH2:18]1)[C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1.[C:27]([N:31]=[C:32]=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH:5]([O:16][CH:17]1[CH2:20][N:19]([C:32]([NH:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH2:18]1)[C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccc(S(C)(=O)=O)cc2)c2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.9 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-(methylsulfonyl)benzhydryloxy]azetidine (171) (222 mg, 0.58 mmol) in anhydrous DCM (7 mL) was added molecular sieves and tert-butyl isocyanate (68 μL, 0.58 mmol). After shaking at ambient temperature for 16 h, the mixture was poured onto a DCM-wet SCX-2 cartridge (2 g). Elution with DCM (24 mL) and evaporation afforded the desired product as a pale yellow solid (188 mg, 67%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]#[N:19])[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.O.[NH4+].[Cl-]>CCO.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]#[N:19])[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CCS(=O)(=O)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#CC1(c2ccc(N)cc2)CCS(=O)(=O)CC1
Temperature: 50 °C
Yield: 62 %

Procedure:
A suspension of 4-(4-nitro-phenyl)-1,1-dioxo-hexahydro-1λ6-thiopyran-4-carbonitrile (205 mg, 0.731 mmol, as prepared in the previous step) in EtOH (5 mL) and water (5 mL) was treated with solid NH4Cl (204 mg, 3.66 mmol) and Fe powder (392 mg, 7.31 mmol) and heated to 50° C. for 1.5 h. The cooled mixture was filtered through Celite, and the filter cake was washed with MeOH. The solvents were evaporated in vacuo. The residue was diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded the title compound (114 mg, 62%) as a pale yellow solid. Mass spectrum (ESI, m/z): Calcd. for C12H14N2O2S, 251.1 (M+H). found 251.2.
Reaction SMILES: C([O-])(=O)C.[K+].[F:6][C:7]([F:18])([F:17])[CH:8](C(F)(F)F)[C:9]([O:11][CH3:12])=[O:10]>O>[F:6][C:7]([F:18])([F:17])[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(C(F)(F)F)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)CC(F)(F)F
Yield: 76.1 %

Procedure:
A solution of 150 g (1.5 mol) of potassium acetate in 500 ml of water was added dropwise to a solution of 105 g (0.5 mol) of methyl 2-(trifluoromethyl)-3,3,3-trifluoropropionate as above produced in 250 ml of water and the mixture was refluxed for 5 hours. After separation of the oily layer, extraction was made from the water layer that was left with use of methylene chloride and the solution of extracts and separated oily layer were joined and dried. After methylene chloride was removed by evaporation under atmospheric pressure, purification was made by distillation to give methyl 3,3,3-trifluoropropionate (TFPE) (54.07 g, 76%). Its analysis gave the following data:
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.O.[NH2:24][NH2:25]>C(O)C>[CH:15]1([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:21]=[CH:22][C:2]([NH:24][NH2:25])=[N:3][CH:4]=3)=[CH:10][CH:11]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(Nc1ccc(C2CCCCC2)cc1)c1ccc(Cl)nc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ccc(C(=O)Nc2ccc(C3CCCCC3)cc2)cn1
Yield: 99 %

Procedure:
6-Chloro-N-(4-cyclohexylphenyl)nicotinamide (0.40 g) and hydrazine monohydrate (3 mL) were suspended in ethanol (6 mL), and the suspension was heated to reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained solid was then collected by filtration and washed with an ethyl acetate-ethanol mixed solvent. The solid was dried under reduced pressure to obtain the title compound (0.39 g) as a white solid (yield: 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH3:25]>>[CH3:36][N:34]([CH3:35])[C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:26]([CH2:24][CH3:25])[C:21](=[O:23])[CH2:20][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[S:10]([C:13]2[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:11])=[O:12])=[CH:29][CH:30]=1
Reactant: CCNCc1ccc(N(C)C)cc1
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Product: CCN(Cc1ccc(N(C)C)cc1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with (4-ethylaminomethyl-phenyl)-dimethyl-amine