Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.[CH2:6]=[CH:7][CH2:8][CH:9]([OH:13])[CH2:10][CH:11]=[CH2:12].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>O>[O:13]([CH:9]([CH2:10][CH:11]=[CH2:12])[CH2:8][CH:7]=[CH2:6])[Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCC(O)CC=C
Agent: c1c[nH]cn1
Solvent: O
Product: C=CCC(CC=C)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Yield: 30 %

Procedure:
There were supplied 6.5 g of imidazole manufactured by Wako Pure Chemical Industries, Ltd. to a 100 mL-two neck flask, and thereto, 50 mL of anhydrous N,N-dimethylformaide manufactured by Wako Pure Chemical Industries, Ltd., and 5.78 mL of 1,6-heptadien-4-ol manufactured by Aldrich Chemical Company were added. The obtained mixture was cooled down to 0° C. To the mixture, 6.5 g of tert-butyldimethylsilyl chloride manufactured by Tokyo Chemical Industry Co., Ltd. were added, and the resultant mixture was stirred for 12 hours at a room temperature. Then, an excess amount of water was added thereto, thereby terminating the reaction. A product contained in the reaction mixture was extracted with hexane, and the obtained organic extract was dried over anhydrous sodium sulfate manufactured by Nacalai Tesque, Inc. The dried hexane solution was distilled in vacuo, thereby obtaining 2.88 g (yield: 30%) of 4-(tert-butyldimethylsiloxy)-1,6-heptadiene as clear colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:26]=[CH:27][CH:28]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23]([OH:25])=O)[S:22][C:15]=12)=[O:8].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.Cl.[NH2:73][CH2:74][CH2:75][CH2:76][NH:77][CH2:78][C:79]([O:81][CH3:82])=[O:80]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:26]=[CH:27][CH:28]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23]([NH:73][CH2:74][CH2:75][CH2:76][NH:77][CH2:78][C:79]([O:81][CH3:82])=[O:80])=[O:25])[S:22][C:15]=12)=[O:8]
Reactant: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc3cc(C(=O)O)sc23)c1
Reactant: COC(=O)CNCCCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CNCCCNC(=O)c1cc2nccc(Oc3cccc(NC(=O)c4occc4C)c3)c2s1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred, cooled (0° C.) solution of 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylic acid (150 mg, 0.38 mmol) in anhydrous DMF (10 ml) were added PyBOP (218 mg, 0.42 mmol) and N,N-diisopropylethylamine (245 mg, 1.9 mmol). The mixture was stirred at 0° C. for 10 minutes, followed by addition of methyl [(3-aminopropyl)amino]acetate dihydrochloride (100 mg, 0.46 mmol). Stirring was continued at 0° C. for another 40 minutes. The mixture was diluted with ethyl acetate (100 ml), washed with brine (4×100 ml), dried over Na2SO4, and concentrated to give the crude, which was purified by silica gel chromatography eluting with 5-8% methanol in chloroform to give methyl [(3-{[(7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridin-2-yl)carbonyl]amino}propyl)amino]acetate as light beige solid. Yield: 98 mg, 49%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH2:3][CH2:2]1.[CH3:20][N:21]([CH3:31])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26].CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH3:20][N:21]([CH3:31])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:14][C:12]1[S:13][C:9]([C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:8])=[C:10]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:11]=1)=[O:26]
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1cccc(C(=O)Nc2nc(-c3ccco3)c(C(=O)C3CCOCC3)s2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
Compound 454 (125 mg, 0.450 mmol) was dissolved in DMF (2 mL), and 3-(dimethylamino)benzoic acid (296 mg, 1.80 mmol), EDC hydrochloride (344 mg, 1.80 mmol) and 1-hydroxybenzotriazole monohydrate (276 mg, 1.80 mmol) were added thereto, followed by stirring at 80° C. for 2 hours. The reaction mixture was poured into water (200 mL), followed by extraction with chloroform. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=19:1), followed by reslurrying with methanol to afford the entitled Compound 464 (78.5 mg, 41%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]2[O:7][C@H:8]([C@H:10]([OH:13])[CH2:11][OH:12])[CH2:9][C@H:4]2[O:3]1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:12][CH2:11][C@H:10]([C@H:8]2[O:7][C@@H:5]3[O:6][C:2]([CH3:14])([CH3:1])[O:3][C@@H:4]3[CH2:9]2)[OH:13])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)O[C@H]2O[C@H]([C@H](O)CO)C[C@H]2O1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@@H]2C[C@H]3OC(C)(C)O[C@H]3O2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74 %

Procedure:
To a solution of (1R)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]ethane-1,2-diol (100 g, 490 mmol) in dry pyridine (1000 mL) was added p-toluenesulfonyl chloride (139 g, 735 mmol) at 0° C. After being stirred at room temperature for 12 hours, the resulted solution was quenched by water (100 mL) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:10 to 1:3 EtOAc in petroleum ether) to afford 130 g of [(2R)-2-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-2-hydroxy-ethyl] 4-methylbenzenesulfonate (compound 6a) as a slight yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:6]=[C:7](F)[C:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=O)=[N:9][CH:10]=1.CCO.C(N(CC)C(C)C)(C)C.[NH2:39][NH2:40]>CCOC(C)=O>[F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[NH:40][N:39]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[C:8]2=[N:9][CH:10]=1
Reactant: COc1ccccc1C(=O)c1ncc(Oc2ccc(F)cc2F)cc1F
Reactant: NN
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccccc1-c1n[nH]c2cc(Oc3ccc(F)cc3F)cnc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 5.7 %

Procedure:
[5-(2,4-Difluoro-phenoxy)-3-fluoro-pyridin-2-yl]-(2-methoxy-phenyl)-methanone (560 mg, 1.5 mmol) was added to 17 mL of EtOH and the reaction mixture was heated until all solid had dissolved. The reaction mixture was cooled, and (N,N-diisopropyl)ethylamine (0.21 mL, 2.3 mmol) and hydrazine (0.1 mL, 3.1 mmol) were added. The reaction mixture was stirred for four hours at room temperature, and then was taken up in 60 mL of EtOAc, washed four times with 20 mL of water, dried (MgSO4). The organic solvent was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography 40 mm×7.5 cm) with 4: to 1:1 hexanes/EtOAc to yield 0.03 g of 6-(2,4-difluoro-phenoxy)-3-(2-methoxy-phenyl)-1H-pyrazolo[4,3-b]pyridine. Mass Spec. M+H=354. Mp: 143.2-144.9° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].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>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1ccc(Br)nc1
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: COCCOC
Product: Fc1ccc(-c2ccc(Br)cn2)cc1
Yield: 88.4 %

Procedure:
To a degassed mixture of 2,5-dibromopyridine (500 mg, 2.11 mmol) and 4-fluorobenzeneboronic acid (444 mg, 3.17 mmol) in ethylene glycol dimethyl ether (4.2 ml) and 2M aqueous sodium carbonate (2.1 ml) was added tetrakis(triphenylphosphine)palladium(0) (98 mg, 0.08 mmol). This mixture was heated at reflux for 14 h. After cooling the crude reaction was partitioned between water and dichloromethane. The organics were dried over anhydrous magnesium sulfate, filtered and adsorbed onto silica. Purification by chromatography on silica gel, eluting with a mixture of 4% diethyl ether in isohexane, gave 5-bromo-2-(4-fluorophenyl)pyridine (470 mg) as a white solid: δH (360 MHz, CDCl3) 7.30 (1H, d, J 7), 7.12-7.19 (2H, m), 7.57 (1H, d, J 8), 7.86 (1H, dd, J 2 and 8), 7.92-7.98 (2H, m), 8.72 (1H, d, J 2), m/z (ES+) 251, 252, 253, 254 (M++H).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([OH:20])=[O:19])[NH:15]2)=[CH:11][CH:10]=1)([O-:8])=[O:7].[C:21](=O)(O)[O-].[Na+]>CO>[N+:6]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[NH:15]2)=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: O=C(O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Temperature: 25 °C
Yield: 81 %

Procedure:
Sulfuric acid (1 mL, 18.76 mmol) was added to a suspension of 6-nitro-1H-indole-2-carboxylic acid (0.5 g, 2.425 mmol) in methanol (5 mL). The mixture was heated to reflux for 2 h. The reaction mixture was cooled to RT, poured into ice/water, neutralized with sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were combined, dried over sodium sulfate, and concentrated to give the title compound (0.433 g, 81%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 9.31 (s, 1H), 8.41 (s, 1H), 8.05 (dd, 1H), 7.79 (d, 1H), 7.29 (s, 1H), 3.70-4.24 (m, 3H). MS: m/z 221 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:5]2[N:6]=[C:7]([CH3:14])[CH:8]=[C:9]([NH:10][CH2:11][CH2:12][NH2:13])[N:4]2[N:3]=1.[C:16]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:16]1([NH:13][CH2:12][CH2:11][NH:10][C:9]2[N:4]3[N:3]=[C:2]([CH3:1])[CH:15]=[C:5]3[N:6]=[C:7]([CH3:14])[CH:8]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1cc(NCCN)n2nc(C)cc2n1
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(NCCNC2CCCC2)n2nc(C)cc2n1
Reaction time: 1 h
Yield: 128 %

Procedure:
To a stirred solution of N-(2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl)-ethane-1,2-diamine (3.2 g, 16 mmol) and cyclopentanone (2.7 mL, 30 mmol) in methanol (30 mL)/acetic acid (3 mL) was added sodium cyanoborohydride (0.94 g, 15 mmol), portionwise. After stirring 1 hour the reaction was concentrated under reduced pressure and then extracted from saturated aqueous sodium bicarbonate with ethyl acetate. The combined extracts were dried (Na2SO4), concentrated under reduced pressure to give the crude product as a brown oil (5.6 g): +APcI MS (M+1)+ 274; 1H NMR (CDCl3) δ: 6.11 (s, 1H), 6.76 (s, 1H), 3.21 (t, 2H), 3.21 (m, 1H ), 3.04 (t, 1H), 2.42 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1.[F:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26](F)[CH:27]=1>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH:19][C:26]3[CH:25]=[N:24][CH:23]=[C:22]([F:21])[CH:27]=3)=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1
Reactant: Fc1cncc(F)c1
Reactant: COCCn1ccc(NC(=O)c2nc(C)ccc2N)n1
Product: COCCn1ccc(NC(=O)c2nc(C)ccc2Nc2cncc(F)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid [1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-amide in accordance with the general method of example, step using 3,5-Difluoropyridine instead of 3-bromopyridineto yield the final compound as a off-white solid, MS (ISP): m/e=371.3 (M+H+).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:18]=[C:13]3[C:12]([C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>CCO.CCOC(C)=O.[Cl-].[Na+].O>[CH2:19]([C:17]1[CH:18]=[C:13]2[C:12]([C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cc4ccccc4)cc23)cn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(-c2c[nH]c3ncc(Cc4ccccc4)cc23)cn1
Temperature: 90 °C
Yield: 73.7 %

Procedure:
A mixture of benzyl derivative 38 (36 mg, 0.08 mmol) and 10% NaOH solution (0.80 mL) in EtOH (2.5 mL) was heated at 90° C. After 1 h the mixture was cooled to r.t., diluted with AcOEt and saturated brine and partitioned. The aqueous layer was extracted with AcOEt (3×). The combined organic extracts were dried (MgSO4), concentrated and the residue was purified by LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—MeCN (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 39 (17 mg, 70%). 1H NMR (400 MHz; CDCl3) δ 3.97 (s, 3H), 4.12 (s, 2H), 7.19-7.36 (m, 6H), 7.58 (s, 1H), 7.71 (s, 1H), 7.86 (brs, 1H), 8.24 (m, 1H), 8.79 (brs, 1H). MS (CI) m/z 289 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: CC(C)C(=O)Cl
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 117.6 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.250 g, 0.678 mmol), isobutyryl chloride (0.108 g, 1.01 mmol), TEA (2.0 mL), and dry THF (5 mL) to afford 0.350 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.14 (d, J=6.6 Hz, 6H), 2.41-2.43 (m, 1H), 4.30 (d, J=6.3 Hz, 2H), 7.43 (d, J=8.1 Hz, 1H), 7.61-7.64 (m, 2H), 7.86 (d, J=9.3 Hz, 2H), 8.20 (d, J=8.4 Hz, 2H), 8.38 (m, 1H), 12.69 (s, 1H); MS (m/z): 43924 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:28])[CH2:18][CH2:17][C:16]([CH2:26][NH2:27])([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:27][CH2:26][C:16]1([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:28])[CH2:14][CH2:15]1)=[O:6]
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Reactant: O=C(O)c1c(F)cccc1Cl
Product: O=C(NCC1(c2ccc(F)nc2)CCC(F)(F)CC1)c1c(F)cccc1Cl

Procedure:
From 2-chloro-6-fluorobenzoic acid and C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=401.1, tR (minutes, Method C)=1.07
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.[Cl:21]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[S:3][C:4]([Cl:21])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:14])=[O:15])=[CH:9][CH:8]=2)[N:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2csc(N)n2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2nc(N)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-(2-aminothiazol-4-yl)-N-tert-butylbenzenesulfonamide (7.56 g, 24.3 mmol) in DMF (100 mL) at 0° C. was added 1-chloropyrrolidine-2,5-dione (3.30 g, 24.7 mmol). The reaction mixture was warmed to room temperature, stirred for 6 h, and poured into water (500 mL). The solid was collected by filtration, washed with water, and dried under high vacuum to give 4-(2-amino-5-chlorothiazol-4-yl)-N-tert-butylbenzenesulfonamide.
Reaction SMILES: C([N:8]1[CH2:15][CH:14]2[CH2:16][CH:10]([CH2:11][N:12]([CH:17]([CH3:19])[CH3:18])[CH2:13]2)[CH2:9]1)C1C=CC=CC=1.[OH-].[Na+]>CO.O.[Pd]>[CH:17]([N:12]1[CH2:13][CH:14]2[CH2:16][CH:10]([CH2:9][NH:8][CH2:15]2)[CH2:11]1)([CH3:19])[CH3:18]
Reactant: CC(C)N1CC2CC(CN(Cc3ccccc3)C2)C1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N1CC2CNCC(C2)C1
Temperature: 25 °C

Procedure:
A 200-mL, three-necked, round-bottomed flask was equipped with a magnetic stirrer, a heating mantle, a condenser with a N2 inlet, and two glass stoppers. To a stirred mixture of amine (30) (5.53 g, 21.4 mmol) and 10% Pd/C (0.64 g, 30 mg/mmol of amine) in CH3OH (80 mL) was added anhydrous HCO2NH4 (3.37 g, 53.5 mmol) in one portion. Stirring the mixture at reflux under N2 for 30 min, cooling the new mixture to RT, and filtering through a celite pad was followed by concentration of the resulting solution to give a viscous oil. The oil was then dissolved in H2O (80 mL) and the pH was adjusted to ~12 by the addition of 10% NaOH. Combined extracts (CH2Cl2, 4×40 mL) of the aqueous solution were dried, filtered, and concentrated (rotary evaporator then vacuum pump, 10 min, RT/0.2 mm Hg) to give amine (31) as a light oil (3.35 g, 93.0%) which was used without further purification. IR (film) cm-1 3315 (N--H), 2965, 2900, 2850, 2790, 2760, 2725 (C--H); 1H NMR (DCCl3) δ1.01 (d, 6H, CH3, J=6.7 Hz), 1.60-1.67 [m, 3H, H(1,5) and H(9)], 2.53-2.59 [m, 3H, ring protons and CH(CH3)2 ], 2.90-3.06 [m, 6H, ring protons], 3.56 (bs, 1H, N--H); 13C NMR (DCCl3) ppm 18.12 (CH3), 30.04 [C(1,5)], 33.62 [C(9)], 52.86 [C(6,8)], 54.59 [CH(CH3)2 ], 54.65 [C(2,4)].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[CH2:10]([CH:12]([C:18](OCC)=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:11]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:18]([CH:12]([CH2:10][CH3:11])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:19])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CCOC(=O)C(CC)C(=O)OCC
Product: CCOC(=O)C(CC)C(=O)Nc1cc(F)cc(F)c1

Procedure:
Prepared according to Procedure A using 3,5-difluoroaniline (5.60 g, 43.4 mmol) and diethyl 2-ethylmalonate to give ethyl 2-(3,5-difluorophenylcarbamoyl)butanoate. Mass Spectrum (ESI) m/e=272.0 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1.[C:18](Cl)(=[O:20])[CH3:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:18]([O:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: COC(=O)CCCCCCC1=CC(O)CC1=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)CCCCCCC1=CC(OC(C)=O)CC1=O
Reaction time: 8 h
Yield: 97.9 %

Procedure:
4-Hydroxy-2-(6-methoxycarbonylhexyl)-2-cyclopentenone (24 g) was dissolved in chloroform (200 ml), followed by addition of acetyl chloride (7.9 g) thereto. Triethylamine [10.1 g) was dropwise added thereto while stirring at 0° to 10° C. After completion of the addition, stirring was continued at 25° C. for 8 hours. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-acetoxy-2-(6-methoxycarbonylhexyl)-2-cyclopentenone (27.6 g). Yield, 98%.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:21]=[CH:22][C:23]4[C:27]([C:28]([O:30]C)=[O:29])=[C:26]([CH3:32])[S:25][C:24]=4[CH:33]=3)[CH:11]=2)=[O:9])[CH2:4]1.O[Li].O.Cl>C1COCC1.CO.O.O>[CH3:1][O:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:21]=[CH:22][C:23]4[C:27]([C:28]([OH:30])=[O:29])=[C:26]([CH3:32])[S:25][C:24]=4[CH:33]=3)[CH:11]=2)=[O:9])[CH2:4]1
Reactant: COC(=O)c1c(C)sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](OC)C5)sc34)ccc12
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)sc5c4)c3s2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.3 %

Procedure:
To a solution of methyl 6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylate 11b (258 mg, 0.535 mmole) in a mixture of THF/MeOH/H2O (3:2:1, 6 ml) was added LiOH.H2O (224 mg, 5.35 mmole). The reaction was stirred 24 hours at ambient temperature. The mixture was diluted with H2O (10 ml) and acidified to pH 1 with 1 M HCl. The precipitate was collected by vacuum filtration, rinsed with MeOH, and dried at 50° C. under vacuum to afford 116 mg (45%) of a pale brown solid. 1H NMR (DMSO-d6) δ 8.58 (1H, d, J=5.4 Hz), 8.44 (1H, d, J=8.9 Hz), 8.07 (1H, s), 8.00 (1H, d, J=24 Hz), 7.39 (1H, dd, J=2.4, 8.9 Hz), 6.78 (1H, d, J=5.4 Hz), 4.10–3.81 (3H, m), 3.69–3.54 (4H, m), 3.27, 3.24 (3H, s), 2.81 (3H, s).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:15])=[N+:2]=[N-:3].[H-].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>CN(C)C=O.C1(C)C=CC=CC=1>[N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH2:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:5]1=[O:15])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1CCc2ccccc2NC1=O
Reactant: O=C(CBr)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC1CCc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-azido-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (8.7 g, 0.043 mol), in dry dimethylformamide (75 ml) was added during 30 min to a stirred suspension of sodium hydride [from a 60% mineral oil dispersion (1.9 g) washed with petroleum ether (3×150 ml)] in dry dimethylformamide (250 ml) maintained at 0° C. under a nitrogen atmosphere. Stirring was continued for an additional 1.5 hours, then benzyl bromoacetate (10.8 g; 0.047 mol) in dry dimethylformamide (75 ml) was added during 45 minutes, the temperature being maintained at 0°. The reaction mixture is then allowed to warm to room temperature while stirring for an additional 18 hours. The dimethylformamide was removed under reduced pressure and the residue partitioned between water (500 ml) and dichloromethane (500 ml). The aqueous phase was extracted with additional dichloromethane (3×500 ml). The combined extracts were dried over sodium sulfate and the solvent was removed under reduced pressure to give the crude ester-azide as an oil. This material was dissolved in toluene (500 ml) and silica gel (48 g) was added. Filtration and removal of the solvent under reduced pressure gave 3-azido-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, as an oil, used without further purification in the next synthetic step.