Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([Br:15])=[C:4]([Br:14])[C:5]([Br:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([Cl:29])=[C:21]([CH:28]=1)[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23]>C1(C)C=CC=CC=1>[Br:13][C:5]1[C:4]([Br:14])=[C:3]([Br:15])[C:2]([Br:1])=[C:7]([C:8]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:29])=[C:21]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH:28]=2)=[O:9])[C:6]=1[C:11]([OH:10])=[O:12]
Reactant: CC(C)OC(=O)c1cc(N)ccc1Cl
Reactant: O=C1OC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1cc(NC(=O)c2c(Br)c(Br)c(Br)c(Br)c2C(=O)O)ccc1Cl
Yield: 87 %

Procedure:
Tetrabromophthalic anhydride (7.03 g, 0.015 mole), 1-methylethyl 5-amino-2-chlorobenzoate (3.24 g, 0.015 mole) and toluene (about 150 ml) were heated almost to reflux over 30 minutes. The reaction mixture was cooled and filtered to give the title compound, m.p. 169°-171° C. (decomp.) (8.92 g, 87% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8](=[O:11])(=[O:10])[NH2:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)=[O:14].[CH3:22][O:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][O:29][CH3:30]>>[NH2:9][S:8]([C:6]1[CH:5]=[CH:4][C:3]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([N:26]([CH2:27][CH2:28][O:29][CH3:30])[CH2:25][CH2:24][O:23][CH3:22])[N:18]=[CH:17][N:16]=2)=[O:14])=[C:2]([CH3:1])[CH:7]=1)(=[O:11])=[O:10]
Reactant: COCCNCCOC
Reactant: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(Cl)ncn1
Product: COCCN(CCOC)c1cc(C(=O)Nc2ccc(S(N)(=O)=O)cc2C)ncn1
Yield: 84 %

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (2-methyl-4-sulfamoyl-phenyl)amide (Intermediate 17) and bis(2-methoxyethyl)amine (Aldrich), the title compound was obtained as a white solid in 84% yield.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=1)=[N:5]2.[H-].[Na+].[CH3:22]I.O>CN(C)C=O>[CH3:22][N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[CH:7]=[CH:8][C:9]3[N:4]([CH:3]=[N:2][N:1]=3)[N:5]=2)[CH:11]=1)[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)Nc1cccc(-c2ccc3nncn3n2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1cccc(-c2ccc3nncn3n2)c1
Reaction time: 1 h

Procedure:
To 2.53 g of N-[3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide in 100 ml of dry dimethylformamide was added 0.6 g of sodium hydride (50% in oil). This mixture was stirred under argon, for 1 hour, then 0.78 ml of methyl iodide was added. This mixture was stirred overnight, then poured into 300 ml of water and extracted with 50 ml portions of dichloromethane. The extracts were combined, dried and evaporated in vacuo. The residue was chromatographed on a silica gel column, eluting with dichloromethane:methanol (98:2). The active fractions were combined, evaporated and the solid recrystallized from dichloromethane-hexane, giving 1.39 g of the desired product as light orange crystals mp 166°-169° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[O:21][CH3:22])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH:23]O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N+:10]([O-:23])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[O:21][CH3:22])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OO
Reactant: CCOC(=O)N1CCc2nc3ccccc3c(OC)c2CC1
Product: CCOC(=O)N1CCc2c(OC)c3ccccc3[n+]([O-])c2CC1
Yield: 15 %

Procedure:
11-Methoxy-1,2,4,5-tetrahydro-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester-6-oxide was prepared from 11-methoxy -1,2,4,5-tetrahydro-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester and hydrogen peroxide analogous to Example 163. Yield: 15% of theory; m.p. 135° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=2)=[C:11]([CH3:24])[N:10]=[N:9]1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:25][CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:21])=[CH:17][N:16]=2)=[C:11]([CH3:24])[N:10]=[N:9]1
Reactant: NC1CCOCC1
Reactant: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Product: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 61 %

Procedure:
As described for example 67, 6-((1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinic acid (55 mg, 0.17 mmol), was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (42 mg, 61%) which was obtained as a white foam. MS: m/e=412.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1F>C1COCC1>[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1[O:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([CH3:9])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cc1ccc(O)c(C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2F)c(C)n1
Temperature: 25 °C

Procedure:
To a solution of 2,6-dimethyl-3-pyridinol (3 g, 24.35 mmol) in THF (30 ml) at r.t., were added Cs2CO3 (15.87 g, 48.71 mmol) and 3,4-difluoro-1-nitro-benzene (3.87 g, 24.35 mmol). The reaction mixture was heated at reflux for 2 h. After cooling to r.t. the solids were filtered off and the filtrate was evaporated to dryness. The crude product was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 2% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D21 (5.88 g, 92%).
Reaction SMILES: Br[CH2:2][CH2:3][CH3:4].[Br:5][C:6]1[CH:7]=[CH:8][C:9]([OH:26])=[C:10]([CH:25]=1)[CH2:11][N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:16]=1)[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:26][CH2:2][CH2:3][CH3:4])=[C:10]([CH:25]=1)[CH2:11][N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:16]=1)[CH2:13][CH3:14]
Reactant: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)OC)cn1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(Br)cc1CN(CC)c1ccc(C(=O)OC)cn1
Reaction time: 18 h
Yield: 54.5 %

Procedure:
1-Bromopropane (0.12 g, 0.69 mmol) was treated with a solution of methyl 2-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]-5-pyridylcarboxylate (0.2 g, 0.55 mmol) in DMF (4 ml). Potassium carbonate (230 mg, 1.7 mmol) was added to this solution and the reaction mixture was stirred for 18 hours. The solvent was evaporated and the residue taken up in water (4 ml) and extracted with ethyl acetate (3×3 ml). The combined extracts were evaporated and the residue subjected to chromatography (eluant: ethyl acetate/hexane) to give the title compound as a pale yellow oil (0.122 g, 54%) which was used in the subsequent step without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[C:9]([N:18]([CH3:20])[CH3:19])([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:10])=[CH:4][CH:3]=1.[NH2:22][CH2:23][CH2:24][CH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[OH:26][CH2:25][CH2:24][CH2:23][NH:22][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[C:9]([N:18]([CH3:20])[CH3:19])([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:10])=[CH:4][CH:3]=1
Reactant: NCCCO
Reactant: CN(C)C(C)(Cc1ccccc1)C(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)C(C)(Cc1ccccc1)C(=O)c1ccc(NCCCO)cc1
Reaction time: 12 h

Procedure:
10.0 g (0.035 mol) of 1-(4-fluorophenyl)-2-dimethylamino-2-benzyl-propan-1-one and 18.4 g (0.25 mol) of 3-amino-1-propanol are dissolved in 20 ml of dry dimethylacetamide, and the solution is heated up to 150° C. together with 9.7 g (0.07 mol) of potassium carbonate, and stirred overnight (about 12 hours). After the solution is cooled down, it is poured into 300 ml of water and extracted with toluene. The organic phase is washed with water and saturated sodium chloride solution, and dried over MgSO4. After distilling off the toluene, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:1) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm]:1.14 (s, 3H), 1.50 (br, 1H), 1.93 (m, 2H), 2.33 (s, 6H), 2.96 (d, 1H), 3.37 (m, 2H), 3.42 (d, 1H), 3.85 (m, 2H), 4.45 (br, 1H), 6.56 (d, 2H), 6.89-6.91 (m, 2H), 7.10-7.12 (m, 3H), 8.45 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6]O.P(Br)(Br)[Br:14]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][Br:14]
Reactant: BrP(Br)Br
Reactant: COc1cc(CO)cc(OC)c1
Solvent: ClCCl
Product: COc1cc(CBr)cc(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
(Snyder et al., Angewandte Chemie International Edition 2007, 46, 8186-8191.) To a stirred solution of 5 (17.5 g, 104 mmol, 1 equiv) in CH2Cl2 (500 mL) at 0° C. was added PBr3 (12.1 mL, 125 mmol, 1.2 equiv) dropwise. The reaction mixture was slowly allowed to warm to room temperature and stir for 3 h. The crude mixture was quenched with a saturated solution of aqueous. NaHCO3 and allowed to stir at room temperature for 1 h. The organic layer was separated and the aqueous layer was extracted with Et2O. The organic layers were combined, dried (MgSO4), filtered, and concentrated under reduced pressure to give 22.2 g (92% yield) of 6 as a white solid: Mp 70-72° C.; Rf 0.75 (EtOAc/hexanes, 1:2); IR (CDCl3) 2999, 2954, 1596, 1458, 1428, 1345, 1323, 1297, 1204, 1152, 1062, 930 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.54 (d, 2 H, J=2.0 Hz), 6.39 (d, 1H, J=2.4 Hz), 4.42 (s, 2 H), 3.79 (s, 6 H); 13C NMR (150 MHz, CDCl3) δ 160.9, 139.7, 106.9, 100.6, 55.4, 33.6. Characterization matches that reported by Snyder et al. (Angewandte Chemie International Edition 2007, 46, 8186-8191.)
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[CH:13]1([N:19]=[C:20]=S)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([NH:19][C:20]2[N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=3[N:12]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: S=C=NC1CCCCC1
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Product: Cn1c(NC2CCCCC2)nc2cc([N+](=O)[O-])ccc21
Yield: 73.2 %

Procedure:
N1-methyl-4-nitro-benzene-1,2-diamine (2.0 g, 12.0 mmol) and cylcohexyl isothiocyanate (1.80 ml, 13.2 mmol) were coupled using the procedure of intermediate example one part B to give the title compound as a yellow solid (2.41 g, 73%). 1H NMR (300 MHz, d6-DMSO) δ 7.98 (d, J=2.4 Hz, 1H), 7.88 (dd, J=8.7 and 2.4 Hz, 1H), 7.30 (d, J=8.7 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 3.74 (m, 1H), 3.56 (s, 3H), 2.00 (M, 2H), 1.75 (m, 2H), 1.63 (m, 1H), 1.25-1.36 (M, 4H), 1.17 (M, 1H) ppm.
Reaction SMILES: CON(C)[C:4](=[O:30])[CH:5]=[C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH2:16][CH2:15]2)[CH2:8][CH2:7]1.[CH3:32][Mg]Cl.O>O1CCCC1>[F:29][C:26]([F:28])([F:27])[C:22]1[CH:21]=[C:20]([N:17]2[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][CH:9]3[CH2:10][CH2:11][C:6](=[CH:5][C:4](=[O:30])[CH3:32])[CH2:7][CH2:8]3)[CH2:19][CH2:18]2)[CH:25]=[CH:24][CH:23]=1
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)C=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)C=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 44 %

Procedure:
To a solution of 114 mg (0.25 mmol) of N-methoxy-N-methyl-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}-cyclohexylidene)acetamide in 5 mL of dry tetrahydrofuran cooled to 0° C. is added 0.2 mL (0.50 mmol) of a 22% methylmagnesium chloride solution in tetrahydrofuran. The mixture is warmed up to 5° C. and stirred for 90 minutes. Hydrolysis is performed by slow addition of 3 mL of water. The product is extracted 3 times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue is purified over 5 g of silica gel (eluant dichloromethane/methanol 95/5) to give 43 mg (44%) of 1-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylidene)propan-2-one as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][CH3:19])=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.N[C:21]1N=C(C2C=C(Br)C=CC=2O)C=C(Cl)N=1>C(O)CCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][CH2:19][CH3:21])=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1
Reactant: Nc1nc(Cl)cc(-c2cc(Br)ccc2O)n1
Reactant: CCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Solvent: CCCCO
Product: CCCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Yield: 51 %

Procedure:
Following the method described in Example 135 for the synthesis of 4-(5-bromo-2-propoxy-phenyl)-6-chloro-pyrimidin-2-ylamine, 2-(2-amino-6-chloro-pyrimidin-4-yl)-4-bromo-phenol and butan-1-ol provided 4-(5-bromo-2-butoxy-phenyl)-6-chloro-pyrimidin-2-ylamine (51% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:18]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:3]=12.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][CH:40]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2nc(-c3ccc(N)cc3)c3c(N)ncnc32)C1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc1)nn2[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (R)-tert-butyl 3-(4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (0.055 g, 0.14 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this, 3-(trifluoromethyl)benzoyl chloride (0.021 mL, 0.14 mmol) diluted in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to warm to room temperature and left stirring for 4 hours, yielding the benzamide derivative. Boc-deprotection was completed through the addition of formic acid (5 mL) and concentrated HCl (0.5 mL) added dropwise directly to the reaction mixture. The reaction mixture was left stirring for 12 hours and then was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to afford AD72. ESI-MS m/z [M+H]+ found 468.5, calculated 468.2.
Reaction SMILES: [CH2:1]([CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:9]([NH2:11])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](N)[CH:19]=[CH2:20]>>[CH2:20]([NH:11][C:9](=[S:10])[CH:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH:19]=[CH2:18]
Reactant: C=CCN
Reactant: NC(=S)C(Cc1ccccc1)c1ccccn1
Product: C=CCNC(=S)C(Cc1ccccc1)c1ccccn1

Procedure:
By the procedure of Example 7, 2-benzyl-2-(2-pyridyl)thioacetamide is reacted with allylamine to give N-allyl-2-benzyl-2-(2-pyridyl)thioacetamide.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>C(N(CC)CC)C>[CH2:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][N:2]([NH:1][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=2)[CH2:7][CH2:6]1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NN1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCN(CC)CC
Product: O=C(NN1CCN(C(=O)OCc2ccccc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
Crude 1-amino-4-benzyloxycarbonylpiperazine (433 g) and triethylamine (254 ml) were dissolved in dry methylene chloride(1.81) and to this solution was added dropwise p-fluorobenzoyl chloride (225 g) under cooling in an ice-bath at 8~25° C. for a period of 20 minutes. The reaction mixture was stirred for 1 hour at ambient temperature and then the resultant crystal was collected by filtration and washed with methylene chloride (300 ml), diisopropyl ether (500 ml) and water (1.51) successively to give N-(4-benzyloxycarbonyl-1-piperazinyl)-4-fluorobenzamide (327 g) as a white powder.
Reaction SMILES: [CH:1]1([NH:8][C:9]([NH2:11])=[S:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:13]1([C:17](OCC)=[O:18])[CH2:16][CH2:15][CH2:14]1>C(N(CC)C(C)C)(C)C.C(O)C>[CH:1]1([NH:8][C:9]2[S:10][C:13]3([C:17](=[O:18])[N:11]=2)[CH2:16][CH2:15][CH2:14]3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=S)NC1CCCCCC1
Reactant: CCOC(=O)C1(Br)CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C1N=C(NC2CCCCCC2)SC12CCC2
Temperature: 155 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1-cycloheptylthiourea (0.255 g, 1.48 mmol) and ethyl 1-bromocyclobutanecarboxylate (0.25 mL, 1.48 mmol, Aldrich) in N,N-diisopropylethylamine (0.5 mL) and ethanol (1.0 mL) was heated in a sealed tube in a microwave oven (Emrys Optimizer from Personal Chemistry) at 155° C. for 2 h, then at 170° C. for 1.5 h. After removing the low-boiling solvents in vacuo, the residue was partitioned between EtOAc and water. The organic portion was separated, washed with brine, and conc. in vacuo. The residue was purified by flash column chromatography (0 to 35% of EtOAc in hexanes) to give the title compound as a tan solid. MS m/z: 253.2 (M+H)+
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]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][N:42]=5)=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])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]([C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][N+:42]=5[O-:58])=[CH:38][CH:39]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccc(Cl)cn4)cc2)CCN3C(=O)C(F)(F)F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccc(Cl)c[n+]4[O-])cc2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-chloropyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (682 mg) in dichloromethane (15 ml) was added 3-chloroperbenzoic acid (70%, 0.29 g) at 0° C. and the mixture was stirred for 24 hours at room temperature. 3-chloroperbenzoic acid (70%, 0.29 g) was further added to the mixture at room temperature and the mixture was stirred for 18 hours. To the reaction solution was added sodium thiosulfate solution 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 (ethyl acetate) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-chloro-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 108) (233.8 mg) as colorless crystals.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[C:33]([NH:34]N)[C:28]=2[O:27][CH2:26]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[C:33]([N:34]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)[C:28]=2[O:27][CH2:26]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: NNc1cccc2c1OCO2
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc4c3OCO4)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and benzo[1,3]dioxol-4-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91. MS: M=437.3 (M+H)+
Reaction SMILES: [N:1]([C@@H:4]([C@@H:40]([C:49]1[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=1)[C:41]1[CH:46]=[C:45]([F:47])[CH:44]=[C:43]([F:48])[CH:42]=1)[C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([F:39])[C:13]=1[CH2:14][CH2:15][C@H:16]1[O:21][CH2:20][C@H:19]([CH2:22][O:23][C:24]([NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[O:25])[N:18]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:17]1)=[O:6])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][C@@H:4]([C@@H:40]([C:49]1[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=1)[C:41]1[CH:42]=[C:43]([F:48])[CH:44]=[C:45]([F:47])[CH:46]=1)[C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([F:39])[C:13]=1[CH2:14][CH2:15][C@H:16]1[O:21][CH2:20][C@H:19]([CH2:22][O:23][C:24]([NH:26][CH2:27][C:28]([F:31])([F:29])[F:30])=[O:25])[N:18]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:17]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N=[N+]=[N-])[C@@H](c2ccc(F)cc2)c2cc(F)cc(F)c2)OC[C@@H]1COC(=O)NCC(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N)[C@@H](c2ccc(F)cc2)c2cc(F)cc(F)c2)OC[C@@H]1COC(=O)NCC(F)(F)F

Procedure:
A solution of (2S,3S)-2-azido-3-(4-fluorophenyl)-3-(3,5-difluorophenyl)-N-(5-fluoro-4-(2-((2R,5R)-4-(tert-butyloxycarbonyl)-5-(2,2,2-trifluoroethylaminocarbonyloxymethyl)morpholine-2-yl)ethyl)pyridin-3-yl)propanamide (36 mg, 0.046 mmol) in 1 mL of MeOH was purged with nitrogen gas for 1 min. To the solution was added 10% palladium on carbon (18 mg) and the mixture was stirred under 1 atmosphere of hydrogen gas for 4 h. The catalyst was removed by filtration and the filtrate solvents were removed in vacuo to give a gum. LC MS: RT=1.20 min, M+H=758 (2 min gradient)
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.[OH-].[Na+].[Cl:12][CH2:13][C:14](Cl)=[O:15]>O>[Cl:12][CH2:13][C:14]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1)=[O:15]
Reactant: O=C(Cl)CCl
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CCl)N[C@H]1CC[C@H](O)CC1

Procedure:
15.1 g. (0.1 mole) trans-4-aminocyclohexanol hydrochloride are suspended in 100 ml. water and adjusted to a pH of 12.5 by the addition of 50 ml. 2N aqueous sodium hydroxide solution. 9.5 ml. (0.12 mole) chloroacetyl chloride are then added dropwise thereto and the pH maintained at 12 to 12.5 by the simultaneous dropwise addition of 2N aqueous sodium hydroxide solution. After the end of the reaction, the reaction mixture is extracted with n-butanol and the organic phase is distilled off in a vacuum. The residue is again dissolved in ethanol, filtered, evaporated and triturated with diethyl ether. After filtering off with suction, there are obtained 12.9 g. of the title compound, i.e. 67% of theory; m.p. 149°-151° C.