Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([C:11]3[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:18][C:12]=3[C:13](=[O:17])[O:14]2)=[CH:9][CH:8]=1)(=O)=O.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([F:35])[C:33]=1[F:34].[OH-].[NH3+]N>O.C1COCC1.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>[CH2:22]([CH:19]1[CH2:18][C:12]2[C:13](=[O:17])[O:14][C:15]3[C:10]([C:11]=2[CH2:21][CH2:20]1)=[CH:9][CH:8]=[C:7]([C:30]1[CH:29]=[C:28]([F:27])[C:33]([F:34])=[C:32]([F:35])[CH:31]=1)[CH:16]=3)[CH2:23][CH3:24]
Reactant: CCCC1CCc2c(c(=O)oc3cc(OS(=O)(=O)C(F)(F)F)ccc23)C1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N[NH3+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC1CCc2c(c(=O)oc3cc(-c4cc(F)c(F)c(F)c4)ccc23)C1

Procedure:
10 g (25.6 mmol) of 6-oxo-8-propyl-7,8,9,10-tetrahydro-6H-benzo[c]-chromen-3-yl trifluoromethanesulfonate, 4.50 g (25.6 mmol) of 3,4,5-trifluorobenzeneboronic acid, 10.6 g (38.4 mmol) of sodium metaborate octahydrate, 360 mg (0.51 mmol) of bis(triphenylphosphine)palladium chloride and 50 μl of hydrazinium hydroxide are dissolved in 15 ml of water and 250 ml of THF, and the mixture is refluxed overnight. Water is added to the batch, which is extracted three times with dichloromethane. The combined org. phases are dried over sodium sulfate, the solvent is removed under reduced pressure, and the residue is filtered through silica gel and recrystallised, giving 8-propyl-3-(3,4,5-trifluorophenyl)-7,8,9,10-tetrahydrobenzo[c]chromen-6-one.
Reaction SMILES: O.[N:2]([O-:4])=O.[Na+].[C:6]([O:12][CH3:13])(=[O:11])[CH2:7][C:8]([CH3:10])=[O:9].S(OC)(O[CH3:18])(=O)=O>CO>[O:9]=[C:8]([CH3:10])[C:7](=[N:2][O:4][CH3:18])[C:6]([O:12][CH3:13])=[O:11]
Reactant: O=N[O-]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)CC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CON=C(C(C)=O)C(=O)OC

Procedure:
To 200 ml of water were added 38 g of sodium nitrite together with 53 g of methyl acetoacetate. Under ice-cooling and stirring, 200 ml of 4 N-sulfuric acid were added dropwise over a period of about 1 hour. During this period, the temperature of the reaction mixture was maintained at 5°-8° C. The mixture was further stirred within this temperature range for 2.5 hours. Then, it was extracted twice with 300 ml portions of ethyl acetate and the extracts are combined and washed twice with a standard aqueous solution of sodium chloride. Then, a solution of 96.9 g of sodium carbonate in 1 l of water was divided into three portions and the methyl 3-oxo-2-hydroxyiminobutyrate was extracted from the ethyl acetate layer previously obtained (3 times). To the water layer (1 l) were added 200 ml of methanol and, under ice-cooling and stirring, 150 g of dimethyl sulfate were added dropwise over a period of 10 minutes. After the dropwise addition was completed, the mixture was stirred at room temperature for 1.5 hours. It was then extracted twice with 300 ml of ethyl acetate, washed with water and dried. The ethyl acetate layer was distilled off and the residue is cooled with ice, whereupon it solidified. This solid was collected by filtration and rinsed with a small amount of water. By this procedure was obtained methyl 3-oxo-2-methoxyiminobutyrate as white crystals. 52.3 g; m.p. 64.4° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13]C(OC(C)(C)C)=O)[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.OS(O)(=O)=O>CO.O1CCOCC1>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccnc2)c1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cccc(Cn2ccnc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
The title compound from Step B above (7.64 g, 27.95 mmoles) was dissolved in methanol (148 mL) and 10% conc. H2SO4 in dioxane (v/v) (380.8 mL) was added. The solution was stirred at 25° C. for 4 h. The solution was diluted with methanol and BioRad AG® 1-X8 (OH−) resin was added until the pH was basic. The resin was filtered off and washed with methanol. The combined filtrates were evaporated to dryness and the residue was chromatographed on silica gel using 2.5% (10% conc. NH4OH in methanol)-dichloromethane as the eluant to give the title compound (4.36 g, 90%): CIMS: m/z 174.25 (MH+); δH (CDCl3), 3.44 (2H, bs, NH2), 5.02 (2H, s, CH2-Im), 6.39 (1H, s, Im-H5), 6.55 (1H, d, Ar—H4), 6.62 (1H, dd, Ar—H5), 6.91 (1H, s, Im-H4), 7.07 (1H, s, Ar—H2), 7.13 (1H, m, Ar—H6) and 7.54 ppm (1H, s, Im-H2); δC (CDCl3) CH2: 50.8; CH: 113.4, 114.8, 117.2, 119.5, 129.8, 130.0, 137.7; C, 137.6, 147.1.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH3:46])[CH:43]=[N:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH3:46])[CH:43]=[N:42][N:41]=5)=[O:56])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CC)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CC)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-ethyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (0.94 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.53 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred at −78° C. for 1 hour. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethanol:ethyl acetate 1:9), and was recrystalized from ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-ethyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 135) (858.7 mg) as yellow crystals.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:32]>>[ClH:32].[N+:21]([C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)([O-:23])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cccc([N+](=O)[O-])c1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=[N+]([O-])c1cccc(OC[C@@H]2CCCN2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 159 mg sample of the BOC-protected intermediate from step 1b above was dissolved in 10 mL of 1:1 TFA/methylene chloride and stirred at room temperature for 16 hr. The solvents were removed by evaporation, and excess 10% aqueous NaHCO3 was added. The solution was extracted 3× with methylene chloride, the extract was dried over MgSO4 and the solvent was removed. The residue was purified by column chromatography on silica gel, eluting with 10:1 chloroform:methanol. The product was dissolved in ether and treated with HCl/ether. The white precipitate was filtered off, washed with ether, and dried under vacuum to afford 71 mg of the title product. MS: 223 (M+H)+, 240 (M+NH4)+. NMR (D2O) δ: 1.91-2.36 (m, 4H), 3.39-3.46 (m, 2H), 4.14 (dq, 1H, J=3.3, 8 Hz), 4.27 (dd, 1H, J=7.7, 10.6 Hz), 4.50 (dd, 1H, J=3.3, 10.6 Hz), 7.42-7.46 (m, 1H), 7.59 (t, 1H, 8 Hz), 7.87 (t, 1H, 2.5), 7.95 (ddd, 1H, J=1, 2, 3.3 Hz). Anal. Calcd for C11H15ClN2O3 : C, 51.07; H, 5.84; N, 10.83; Found: C, 51.01; H, 5.88; N, 10.63.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH:8]=[CH2:9])([OH:7])[CH2:5][CH2:4][NH:3]1.[F:10][C:11]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].C(=O)([O-])[O-].[Li+].[Li+]>>[F:10][C:11]1[CH:18]=[C:17]([N:3]2[CH2:4][CH2:5][C@@:6]([OH:7])([CH:8]=[CH2:9])[C@@H:2]2[CH3:1])[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C=C[C@]1(O)CCN[C@H]1C
Reactant: N#Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C=C[C@]1(O)CCN(c2ccc(C#N)c(F)c2)[C@H]1C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3R)-2-methyl-3-vinylpyrrolidin-3-ol (554 mg), 2,4-difluorobenzonitrile (300 mg) and lithium carbonate (350 mg), the title compound was obtained as a colorless solid (yield: 177 mg, yield: 50%).
Reaction SMILES: I(O)(=O)(=O)=O.[I:6]I.S(=O)(=O)(O)O.[Cl:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([Cl:21])[C:15]=1[C@H:22]([O:24][C:25]1[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=1)[CH3:23]>C(O)(=O)C.O>[I:6][C:29]1[CH:30]=[C:25]([O:24][C@@H:22]([C:15]2[C:16]([Cl:21])=[CH:17][CH:18]=[C:19]([F:20])[C:14]=2[Cl:13])[CH3:23])[C:26]([NH2:31])=[N:27][CH:28]=1
Reactant: II
Reactant: C[C@@H](Oc1cccnc1N)c1c(Cl)ccc(F)c1Cl
Agent: O=S(=O)(O)O
Agent: [O-][I+3]([O-])([O-])O
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H](Oc1cc(I)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 80 °C
Yield: 120 %

Procedure:
Periodic acid (60 mg, 0.24 mmol), iodine (130 mg, 0.5 mmol), and sulfuric acid (0.03 mL) were added sequentially to a stirred solution of 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-2-amine (0.97 mmol) in a mixture of acetic acid (3 mL) and H2O (0.5 mL). The resulting solution was heated to 80° C. for 5 h. The cooled reaction mixture was quenched with Na2SO3 (80 mg) and basicified with saturated Na2CO3 (2×100 mL) to pH 7. CH2Cl2 (2×50 mL) was added to extract the aqueous solution. The combined organic layers were dried over Na2SO4 then filtered and concentrated under vacuum. The residue was purified by flash chromatography (eluting with 35→40% EtOAc in hexanes) to give the title compound as a yellow oil (254 mg; 0.6 mmol; 61.6% yield); MS (APCI) (M+H)+ 426. 1H NMR (400 MHz, chloroform-D) δ ppm 1.81 (d, J=6.8 Hz, 3H) 4.86 (s, 2H) 5.98 (q, J=6.57 Hz, 1H) 6.96 (d, J=1.5 Hz, 1H) 7.08 (dd, J=9.0, 8.0 Hz, 1H) 7.31 (dd, J=8.8, 4.8 Hz, 1H) 7.78 (d, J=1.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](Br)=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[NH2:1][C:2]1[C:7]2[C:8]([C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=3)=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc2occ(Br)c12
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
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: Nc1ccc(-c2coc3ccnc(N)c23)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 84.2 %

Procedure:
The mixture of 4-amino-3-bromo-furo[3,2-c]pyridine (7) (63 mg, 0.29 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (84 mg, 0.38 mmol), Pd(PPh3)4 (34 mg, 0.029 mmol) and sodium carbonate (0.74 ml, 1.5 mmol) in 3 ml of DME was stirred for 14 hours at 80° C. The solvent was removed, and the resultant residue was purified by chromatography on a silica gel column gel to afford the titled compound (55 mg) 1H NMR (400 MHz, DMSO-d6) ppm 7.82 (d, J=6.1 Hz, 1H), 7.77 (s, 1H), 7.15 (d, J=8.3 Hz, 2H), 6.89 (d, J=5.8 Hz, 1H), 6.69 (d, J=8.3 Hz, 2H), 5.49 (s, 2H), 5.32 (s, 2H). MS: m/z 226 (M+H)+.
Reaction SMILES: [CH2:1]([C@@H:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][C:8]([F:24])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:25])[CH3:2].I[CH2:27][CH3:28].C([C@H]1N(C(=O)C2C=CC(OC)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:27]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([F:24])[CH:7]=2)[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[C@@H:3]([CH2:1][CH3:2])[C:4]1=[O:25])[CH3:28]
Reactant: CCI
Reactant: CC[C@H]1C(=O)Nc2cc(F)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Product: CC[C@H]1C(=O)N(CC)c2cc(F)ccc2N1S(=O)(=O)c1ccc(OC)cc1

Procedure:
(3S)-3-Ethyl-7-fluoro-4-[(4-methoxyphenyl)sulfonyl]-3,4-dihydroquinoxalin-2(1H)-one (see Example 29) was treated with iodoethane according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3S)-1,3-diethyl-7-fluoro-4-[(4-methoxyphenyl)sulfonyl]-3,4-dihydroquinoxalin-2(1H)-one. MS (ESI) m/z 393 ([M+H]+); Anal. Calcd for C19H21FN2O4S: C, 58.15; H, 5.39; N, 7.14. Found: C, 58.36; H, 5.56; N, 7.05.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](C=O)=[CH:7][CH:8]=1.[CH:11]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH:18](Cl)(Cl)Cl>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]=[N:17][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: ClC(Cl)Cl
Reactant: NC1CCCCC1
Reactant: COc1ccc(C=O)cc1
Product: COc1ccccc1C=NC1CCCCC1

Procedure:
A solution of anisaldehyde (21 g) and cyclohexylamine (15 g) in chloroform (100 ml) was stirred at room temperature for 2 hours and evaporated to afford brown syrup (35 g, quantitative).
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]#[CH:26])[CH2:20][C:19]1=[O:27])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:24]([N:21]1[CH2:22][CH2:23][N:18]([CH2:17][C:9]2[NH:8][C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[CH:10]=2)[C:19](=[O:27])[CH2:20]1)[C:25]#[CH:26]
Reactant: C#CCN1CCN(Cc2cc3cnccc3n2C(=O)OC(C)(C)C)C(=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CCN1CCN(Cc2cc3cnccc3[nH]2)C(=O)C1
Reaction time: 6 h
Yield: 65 %

Procedure:
To a solution containing 2-(2-oxo-4-prop-2-ynyl-piperazin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (1.3 g, 3.53 mmol) in CH2Cl2 (100 mL) is added TFA (20 mL) at 0° C. After 6 h, the reaction mixture is concentrated to dryness and then partitioned between aqueous NaHCO3 (500 mL) and CH2Cl2 (200 mL) and the layers are separated. The aqueous phase is extracted four times with CH2Cl2 (100 mL) and the combined organic phase is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue is purified by flash silica gel chromatography (CH2Cl2 to 10% MeOH/CH2Cl2) to provide 616 mg (65%) of the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[O:6][C:7]3[CH:27]=[CH:26][CH:25]=[CH:24][C:8]=3[CH2:9][N:10]([CH2:11][C:12]#[C:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1>[Pd].C1COCC1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[O:6][C:7]3[CH:27]=[CH:26][CH:25]=[CH:24][C:8]=3[CH2:9][N:10]([CH2:11][CH2:12][CH2:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.[CH:24]1[C:8]2[CH2:9][N:10]([CH2:11][CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=3)[C:4]3[CH:3]=[CH:2][CH:29]=[CH:28][C:5]=3[O:6][C:7]=2[CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(C#CCN2Cc3ccccc3Oc3ccc(Cl)cc32)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCCN2Cc3ccccc3Oc3ccc(Cl)cc32)cc1
Product: COC(=O)c1ccc(CCCN2Cc3ccccc3Oc3ccccc32)cc1
Reaction time: 9 h

Procedure:
A mixture of methyl 4-[3-(8-chloro-10,11-dihydrodibenzo[b,f][1,4]oxazepin-10-yl)prop-1-ynyl]benzoate (2.7 g), 10% palladium-on-charcoal catalyst (0.05 g) and THF (100 ml) was stirred under an atmosphere of hydrogen for 9 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography using a 9:1 v/v mixture of methylene chloride and petroleum ether (b.p. 60°-80° C.) as eluent. There were thus obtained in turn methyl 4-[3-(8-chloro-10,11-dihydrodibenzo[b,f][1,4]oxazepin-10-yl)propyl]benzoate (0.6 g) as a gum and methyl 4-[3-(10,11-dihydrodibenzo[b,f][1,4]oxazepin-10-yl)propyl]benzoate (0.18 g) as a gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19](O)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:22])[N:10]1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31].O1CCCCC1[O:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[CH2:44][O:45][NH2:46].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>O.C(OCC)(=O)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:46][O:45][CH2:44][C:43]2[CH:47]=[CH:48][CH:49]=[C:41]([OH:40])[CH:42]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:22])[N:10]1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH:29][S:30]([CH3:33])(=[O:31])=[O:32]
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)O)C1c1ccc(Cl)cc1Cl
Reactant: NOCc1cccc(OC2CCCCO2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2cccc(O)c2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
To 400 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid were added 8 ml of DMF, 243 mg of O-[3-(tetrahydro-2H-pyran-2-yl oxy)benzyl]hydroxylamine, 159 mg of HOBt, and 243 mg of WSC, followed by stirring at room temperature for 3 hours. The reaction solution was added with ethyl acetate and water to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. To the residue was added methanol, and concentrated hydrochloric acid was added dropwise thereto under ice-cooling, followed by stirring under ice-cooling for 1 hour. The precipitated crystal was collected by filtration to obtain 275 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-[(3-hydroxybenzyl)oxy]-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([CH3:20])=[CH:18][C:17]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])=[N:16]1.ClC1C=CC=C(C(OO)=[O:38])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:10][C:11]([F:12])([F:13])[F:14])=[O:38])=[CH:4][C:3]=1[N:15]1[C:19]([CH3:20])=[CH:18][C:17]([O:21][CH2:22][C:23]([F:28])([F:29])[C:24]([F:25])([F:26])[F:27])=[N:16]1
Reactant: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2C)cc1SCC(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2C)cc1S(=O)CC(F)(F)F
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
0.3 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-methyl-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole was dissolved in 10 mL of chloroform, and 0.16g of m-chloroperbenzoic acid (purity: 75%) was slowly added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:hexane=1:2) to obtain 0.30 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-5-methyl-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]#[N:11])=[CH:3][CH:2]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Co]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: N#CCCCc1ccncc1
Agent: [Co]
Solvent: CCN(CC)CC
Solvent: CCO
Product: NCCCCc1ccncc1
Yield: 31.5 %

Procedure:
A solution of 30.0 g of 4-pyridinebutanenitrile in 200 ml of ethanol containing 7.5 ml of triethylamine was hydrogenated over 7.5 g of Raney cobalt at 100° C. and 1200 lbs. hydrogen pressure. The crude product obtained after filtration and concentration, was distilled to give 9.7 g (31%) of 4-pyridinebutanamine, bp 105°-112° C./0.8 mm. A second fraction (15.3 g, bp 112°-122° C.) consisted of a mixture by thin layer chromatography and was redistilled to give 4.74 g (15%) of 4-pyridinebutanamine, bp 95°-98° C./0.15 mm. The product was further characterized as the hydrochloride salt, mp 124°-125° C. (ethanolether).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.O>C1C=CC=CC=1>[CH2:11]1[O:12][CH:6]([C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)[O:7][CH2:10]1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OCCO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Solvent: c1ccccc1
Product: Brc1ccc(C2OCCO2)cc1
Yield: 100 %

Procedure:
To a solution of 4-bromobenzaldehyde (102 g, 0.55 mol) and ethylene glycol (100 g, 1.65 mol) in benzene (1 l) were added a small amount of 10-camphorsulfonic acid, and the mixture was refluxed for 3 hours, while water was removed with Dean-Stark. After allowing to cool, saturated sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled to give the title compound (126 g, 0.55 mol, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13](=O)[CH3:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:16]([NH:19][C:20]([NH2:22])=[S:21])(=[O:18])[CH3:17]>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:21][C:20]([NH:19][C:16](=[O:18])[CH3:17])=[N:22][C:13]=2[CH3:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CC(=O)NC(N)=S
Reactant: CC(=O)Cc1ccc(S(C)(=O)=O)c(F)c1
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1

Procedure:
This material is prepared from 1-(3-fluoro-4-methanesulfonyl-phenyl)-propan-2-one (AA3) following the procedure outlined in step (AA4), replacing thiourea with N-acetylthiourea. The titled compound crystallises from the reaction mixture.