Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]=O)=[CH:2]1.Cl.[NH2:13][OH:14]>N1C=CC=CC=1.C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]=[N:13][OH:14])=[CH:2]1
Reactant: O=Cc1csc2ccccc12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=Cc1csc2ccccc12
Yield: 98.6 %

Procedure:
Benzothiophene-3-carbaldehyde (4.0 g, 24.6 mmol) was dissolved in a mixture of pyridine (25 ml) and ethanol (25 ml). Hydroxylamine hydrochloride (3.4 g, 49.2 mmol) was added, while stirring. The mixture was stirred for 30 minutes at RT and then heated under reflux for eight hours. A red-brown solution formed. For working up, the solution was concentrated and the residue was freed from residual pyridine by distillation with ethanol (3×50 ml). Water (50 ml) was added to the oily residue and the mixture was stirred vigorously overnight. The pink solid present was filtered off with suction, washed with water and dried in vacuo. 4.3 g benzothiophene-3-carbaldehyde oxime were obtained (m.p. 87-89° C.).
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)O1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Nc1ncc(-c2cn[nH]c2)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole gives the compound “A34”;
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[C:17]([O:26][CH3:27])(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH2:20].C(O)(=O)C>O>[CH3:27][O:26][C:17]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[N:20]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=2[CH:1]=[C:2]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:25]
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccccc1-n1c(-c2ccccc2)cc2c1CCCC2

Procedure:
A solution of 10.8 g. (0.05 mole) of 2-phenacylcyclohexanone, 7.55 g. (0.05 mole) of methyl anthranilate, and 30 ml. of glacial acetic acid was heated under reflux for 7 hours, cooled, and diluted with water. The layers were separated, and the aqueous phase was extracted with ether. The combined organic phase was washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to an oil. Chromatography on silica gel with toluene as the eluent gave 2.91 g. (18%) of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:32])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29](O)=[O:30])[CH2:24]2)[O:12]1.[O:33]1[CH2:36][CH:35]([C:37]2[CH:38]=[C:39]([NH2:44])[C:40]([NH2:43])=[CH:41][CH:42]=2)[CH2:34]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>C(Cl)Cl>[NH2:43][C:40]1[CH:41]=[CH:42][C:37]([CH:35]2[CH2:34][O:33][CH2:36]2)=[CH:38][C:39]=1[NH:44][C:29](=[O:30])[CH2:28][CH2:27][CH:25]1[CH2:26][CH:23]([N:22]([CH2:21][C@@H:13]2[C@@H:14]3[C@@H:15]([O:16][C:17]([CH3:20])([CH3:19])[O:18]3)[C@H:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[NH2:1])[O:12]2)[CH3:32])[CH2:24]1
Reactant: Nc1ccc(C2COC2)cc1N
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)Nc2cc(C3COC3)ccc2N)C1
Temperature: 15 °C
Reaction time: 5.25 h
Yield: 82 %

Procedure:
A suspension of the above crude 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanoic acid and 4-(oxetan-3-yl)benzene-1,2-diamine (0.135 g, 0.822 mmol) in methylene chloride (8.0 mL) was treated with N,N-diisopropylethylamine (0.716 mL, 4.11 mmol) and cooled to −5° C. (ice/brine). N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate [HATU] (0.469 g, 1.23 mmol) was added and the reaction mixture was stirred for 5.25 h, warming to 15° C.; HPLC/LC MS indicated complete conversion. The reaction mixture was concentrated in vacuo and diluted with CH2Cl2 (15 mL) and water (7.5 mL). The separated aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford a brown-purple semi-opaque oil/foam. Purification by column chromatography (2×8 cm silica; 0-5% 7 N methanolic NH3/CH2Cl2) afforded both amide regioisomers of the title compound (0.45 g, 82%) as a semi-opaque pink foam: MS (ESI+) for C30H40N8O5 m/z 593.3 (M+H)+; MS (ESI−) for C30H40N8O5 m/z 591.3 (M−H)− and 637.4 (M+HCO2)−; HPLC purity 90% (ret. time, 2.097 min).
Reaction SMILES: FC(F)(F)C1C=CC=CC=1C(Cl)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][N:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.[F:36][C:37]([F:50])([F:49])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]([N:46]=[C:47]=[S:48])=[O:45]>C1(C)C=CC=CC=1.C(O)C>[F:49][C:37]([F:36])([F:50])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]([N:46]=[C:47]=[S:48])=[O:45].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][N:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:47]([NH:46][C:44](=[O:45])[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[C:37]([F:36])([F:50])[F:49])=[S:48])=[CH:31][CH:30]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccccc1C(F)(F)F
Agent: O=C(N=C=S)c1ccccc1C(F)(F)F
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C(F)(F)F)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
2-(Trifluoromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-(trifluoromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-(trifluoromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (49 mg, yield 56%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[O:14]=[C:15]1[N:21]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C@@H:31]([C:42](O)=[O:43])[CH2:32][C:33]3[CH:38]=[C:37]([Br:39])[C:36]([OH:40])=[C:35]([Br:41])[CH:34]=3)=[O:29])[CH2:24][CH2:23]2)[CH2:20][CH2:19][C:18]2[CH:45]=[CH:46][CH:47]=[CH:48][C:17]=2[NH:16]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[O:14]=[C:15]1[N:21]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C@H:31]([CH2:32][C:33]3[CH:34]=[C:35]([Br:41])[C:36]([OH:40])=[C:37]([Br:39])[CH:38]=3)[C:42]([N:11]3[CH2:12][CH2:13][CH:8]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH2:9][CH2:10]3)=[O:43])=[O:29])[CH2:24][CH2:23]2)[CH2:20][CH2:19][C:18]2[CH:45]=[CH:46][CH:47]=[CH:48][C:17]=2[NH:16]1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: O=C(O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Br)c(O)c(Br)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere 55 mg (0.30 mmol) 1-methyl-4-piperidin-4-yl-piperazine was added to a solution of 151 mg (0.25 mmol) of (R)-1-carboxy-2-(3,5-dibromo-4-hydroxy-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 104 mg (0.27 mmol) HATU and 47 μL (0.27 mmol) ethyldiisopropylamine in 5 mL DMF and the reaction mixture was stirred for 3 h at RT. The reaction solution was evaporated down i.vac. and the residue was purified by chromatography (silica gel, DCM/MeOH/NH3 80:20:2).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1.[CH3:13][NH2:14]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:14][CH3:13])=[O:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CN
Reactant: CCc1cc(Br)ccc1C(=O)Cl
Solvent: ClCCl
Product: CCc1cc(Br)ccc1C(=O)NC
Reaction time: 3 h

Procedure:
To a solution of 4-bromo-2-ethyl-benzoyl chloride (1.00 g, 4.04 mmol) in CH2Cl2 (20 mL) was added methylamine (0.70 mL, 40% solution in water, 8.08 mmol). The mixture was stirred for 3 hours, at which time the volatiles were removed in vacuo. The residue was dissolved in EtOAc, washed with H2O, dried over MgSO4, and concentrated to a brown oil (0.857 g, 88%). 1H NMR (300 MHz, CDCl3): δ 1.21 (t, J=7.4 Hz, 3H), 2.75 (q, J=7.5 Hz, 2H), 2.97 (d, J=4.9 Hz, 3H), 5.74 (s, 1H), 7.17 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.39 (s, 1H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:11]([CH3:22])=[C:12]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=1>C(#N)C.C(OCC)(=O)C>[NH2:9][C:10]1[C:11]([CH3:22])=[C:12]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)CCc1cccc(N)c1C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(Cl)c(N)c1C
Reaction time: 0.5 h

Procedure:
At RT, 1.38 g (10.3 mmol) of N-chlorosuccinimide were added to a solution of 2.0 g (10.3 mmol) of methyl 3-(3-amino-2-methylphenyl)propanoate in 10 ml of acetonitrile. The reaction mixture was stirred for 30 min and then diluted with ethyl acetate. The mixture was washed successively with sat. sodium bicarbonate solution and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product gave, after chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1), 279 mg of the target product (11.8% of theory).
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9](=[N:22][NH2:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:10]1([C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:22][NH:23][C:2]2[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ncccc1Br
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ncccc1NN=C(c1ccccc1)c1ccccc1
Temperature: 120 °C
Yield: 75 %

Procedure:
3-Bromo-2-methyl-pyridine (1.0 g, 5.80 mmol) in 15 mL dry toluene was treated with benzophenone hydrazone (1.25 g, 6.39 mmol), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (170 mg, 0.29 mmol), sodium tert-butoxide (835 mg, 8.70 mmol), and Pd(II)(OAc)2 (67 mg, 0.30 mmol). Heated to 120° C. in the microwave for five minutes. Extracted using EtOAc/H2O (3×100 mL EtOAc, 1×100 mL H2O, 1×100 mL brine). Dried using Na2SO4 and then purified by flash chromatography (silica, 10-50% EtOAc/Hexane) to afford 3-(2-(diphenylmethylene)hydrazinyl)-2-methylpyridine (1.25 g, 4.35 mmol, 75%). 1H NMR (300 MHz, DMSO-d6) δ 7.95 (d, 1H), 7.85 (d, 1H), 7.70-7.53 (m, 6H), 7.45-7.34 (m, 5H), 7.20 (d, 1H), 2.07 (s, 3H); LC-MS (ESI) m/z 288 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:11]([CH2:14][C:15](=[O:17])[CH3:16])(=[O:13])[CH3:12].N1CCCCC1>C1CCCCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:14]([C:15](=[O:17])[CH3:16])[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1
Reactant: CC(=O)CC(C)=O
Reactant: COc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: C1CCCCC1
Product: COc1ccc(C=C(C(C)=O)C(C)=O)cc1
Reaction time: 8 h
Yield: 70 %

Procedure:
3-(4-methoxybenzylidene)-2,4-pentanedione was prepared by the condensation of 4-methoxy benzaldehyde with acetyl acetone in the presence of piperidine and cyclohexane as the reaction medium at reflux temperature under continuous azeotropic water removal. The reaction takes about eight hours to complete. The reaction product was purified by crystallization with methanol and yields about 70% 3-(4-methoxybenzylidene)-2,4-pentanedione (hereinafter “Compound 3”) with a purity, as determined by GC, of about 99.6%. Compound 3 is an off-white free-flowing powder having a melting point of 82-84° C. with a λmax at 319 nm.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[Li]CCCC.[C:15](Cl)(=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=C>C1COCC1>[O:5]=[C:3]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: C=CCCCCCCCCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCCCCCCCC(=O)CC(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A stirred solution of monoethyl malonate (5.3 g, 40 mmol) in anhydrous THF (150 mL) was cooled to −78° C. under an argon atmosphere, and n-BuLi (2.5 M, 32 mL, 80 mmol) was added drop-wise via an air-tight syringe. After the addition, the temperature was raised to 0° C., and the stirring was continued for 1 hour. The reaction mixture was then re-cooled to −78° C., and 10-undecenoyl chloride (25 mmol) was added drop-wise via an air-tight syringe. The mixture was stirred for one hour at −78° C., 30 minutes at 0° C., and 30 minutes at room temperature. The solvent was removed under reduced pressure, and the residue was re-dissolved in 50 mL ethyl acetate. The solution was washed with 1 M HCl (100 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL). The organic layer was dried over MgSO4 and concentrated to give (1) (6.270 g). The crude product was used for the next reaction without further purification. 1H NMR (400 MHz, CDCl3) δ 1.28-1.40 (m, 13H), 1.58 (m, 2H), 2.03 (m, 2H), 2.53 (t, J=7 Hz, 2H), 3.43 (s, 2H), 4.21 (q, J=7 Hz, 2H), 4.97 (m, 2H), 5.80 (m, 1H).
Reaction SMILES: [CH:1]1([CH2:10][C:11](Cl)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:14]1[CH2:21][S:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17].C1(CC(Cl)=O)C2C(=CC=CC=2)CC1>>[CH:1]1([CH2:10][C:11]([CH:19]2[S:20][CH2:21][NH:14][C@@H:15]2[C:16]([OH:18])=[O:17])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(Cl)CC1C=Cc2ccccc21
Reactant: O=C(O)[C@@H]1CSCN1
Agent: O=C(Cl)CC1CCc2ccccc21
Product: O=C(CC1C=Cc2ccccc21)C1SCN[C@@H]1C(=O)O
Yield: 44 %

Procedure:
Colorless crystals of 3-(2-indenylacetyl)-L-thioproline were prepared in the same manner as Reference Example 10, except that 2-indenylacetyl chloride and L-thioproline were used instead of 2-indanylacetyl chloride and L-piperidin-2-ylcarboxylic acid, respectively (yield: 44%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:24])[C:4]1[C:5]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1c(O)cccc1OCCCCNC(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(OCCCCNC(=O)OC(C)(C)C)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-tert-butoxycarbonylaminobutoxy)-6-hydroxybenzoic acid methyl ester (1.5 g, 4.4 mmol) in DMF (20 mL) is added benzyl bromide (0.56 mL, 4.6 mmol) and K2CO3 (1.8 g, 13.0 mmol). The suspension is stirred at RT for 3 h then is poured into water and extracted with EtOAc. The organic layer is washed with water and brine, and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue purified by flash chromatography eluting with hexanes/EtOAc (5:1 to 1:1) to afford the title compound as a colorless liquid: 1H NMR (CDCl3) δ 7.38-7.19 (m, 6H), 6.57-6.51 (dd, J=8.34, 12.63 Hz, 2H), 5.10 (s, 1H), 4.60 (s, 1H), 4.00 (t, J=6.06 Hz, 2H), 3.88 (s, 3H), 3.18-3.13 (m, 2H), 1.81-1.75 (m, 2H), 1.66-1.59 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH3:16])[CH2:13][CH:14]=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[C:17]([O:21][C:22]([N:24]1[CH2:31][CH:30]2[O:32][CH:26]([CH2:27][NH:28][CH2:29]2)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCl>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH:26]2[O:32][CH:30]([CH2:29][N:28]([CH2:14][CH2:13][N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[CH3:16])[CH2:27]2)[CH2:31]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: CN(CC=O)S(=O)(=O)c1ccc(C#N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(CCN1CC2CN(C(=O)OC(C)(C)C)CC(C1)O2)S(=O)(=O)c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of step (ii) product 4-Cyano-N-methyl-N-(2-oxo-ethyl)-benzenesulfonamide (4.97 g), and 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (4.95 g; see WO 01/28992) and acetic acid (1.7 ml) in dry dichloromethane (50 ml) was stirred at RT for 3 h and then cooled to 0° C. NaBH3CN (1.96 g, 0.0312 mol) was added and stirring continued at RT overnight under nitrogen atmosphere. The reaction mixture was quenched with water, extracted with dichloromethane, washed with water and brine and dried over sodium sulfate. Solvent evaporated under reduced pressure and the residue was purified by column chromatography over silica gel using 28% ethyl acetate in petroleum ether eluent to give the sub-title compound (2.2 g) as a liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[N:15]O)[CH:6]=[CH:7][CH:8]=1.[OH2:17]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[NH:15][C:10](=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O
Reactant: COc1cccc(C2CCCCC2=NO)c1
Product: COc1cccc(C2CCCCC(=O)N2)c1
Temperature: 117.5 °C
Reaction time: 0.33 h

Procedure:
2-(3-Methoxyphenyl)-cyclohexanone oxime, as described above in Step B, (0.62 g, 2.8 mmol) and polyphosphoric acid (20 g) were combined and heated at 115-120° C. with stirring for 20 min. The dark mixture was poured into ice (100 g) with stirring, diluted with H2O (200 mL), then extracted with CHCl3 (5×100 mL), the organic layers combined, washed with brine, dried (MgSO4), filtered, and concentrated to dryness to give the title compound after SiO2 chromatography (CHCl3:MeOH, 100:1 to 20:1).
Reaction SMILES: [F:1][C:2]([F:10])=[CH:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].N1C=CC=CC=1.[CH3:17][OH:18]>>[CH3:17][O:18][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]=[C:2]([F:10])[F:1]
Reactant: CO
Reactant: O=C(Cl)CCCC=C(F)F
Solvent: c1ccncc1
Product: COC(=O)CCCC=C(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
42.1 g of 6,6-difluorohex-5-enoic acid chloride are added slowly at 10° to 17.6 g of pyridine in 200 ml of methanol. The mixture is then stirred at room temperature for 5 hours. The excess methanol is evaporated off in a rotary evaporator and the residue is taken up in tert-butyl methyl ether and washed with water. The organic phase is dried over sodium sulfate and concentrated to dryness by evaporation. The residue is distilled at 60 mbar. The title compound is obtained in the form of a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]#[N:21])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:22])[CH:5]=1.Br[C:25]1[CH:26]=[N:27][N:28]([CH2:30][CH3:31])[CH:29]=1>>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]#[N:21])=[CH:17][CH:18]=3)[N:13]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][CH3:31])[CH:29]=3)[C:12]=2[CH3:22])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(C#N)ccc23)c1
Reactant: CCn1cc(Br)cn1
Product: CCn1cc(-n2c(C)c(Sc3cccc(C(=O)OC)c3)c3ccc(C#N)cc32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-cyano-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH2:15])(C)(C)C.CCN(C(C)C)C(C)C.Cl[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28]>C1COCC1>[CH2:30]([O:29][C:27](=[O:28])[NH:15][C:9]1[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=1[NH2:7])[CH:31]=[CH2:32]
Reactant: C=CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CCOC(=O)Nc1cc(F)ccc1N
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(2-Amino-4-fluoro-phenyl)-carbamic acid tert-butyl ester (5.0 g, 22 mmol, 1 equiv.) was added to a solution of DIPEA (3.62 ml, 22 mmol, 1 equiv.) in THF (80 ml). The mixture was cooled to 0° C. and allyl chloroformate (2.36 ml, 22 mmol, 1 equiv.) in THF added. The mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the crude extracted from ethylacetate and aq. NaHCO3. The residue was taken up in DCM and trifluoroacetic acid (1:1) for 2 hours. The product was obtained after evaporation of the organic solvents.