Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:17])[CH2:10][CH:11]2[CH2:16]COCC2)=[CH:5][C:4]=1[NH2:18].[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:30][C:31](C)=[O:32]>>[C:19]([NH:27][C:28]([NH:18][C:4]1[CH:5]=[C:6]([N:9]([CH3:17])[CH:10]2[CH2:11][CH2:16][O:32][CH2:31][CH2:30]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)=O
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1ccc(N(C)CC2CCOCC2)cc1N
Product: COc1ccc(N(C)C2CCOCC2)cc1NC(=S)NC(=O)c1ccccc1
Reaction time: 16 h
Yield: 56 %

Procedure:
To a stirred solution of 0.330 g (1.4 mmol) 4-methoxy-N1-methyl-N1-(tetrahydro-pyran-4-ylmethyl)-benzene-1,3-diamine in 5 ml acetone was added dropwise 0.2 ml (1.50 mmol) benzoyl isothiocyanate and stirring continued for 16 hrs at room temperature. The mixture was then concentrated in vacuo and the residue subjected to column chromatography (1/1 hexane/ethyl acetate) to afford 0.31 g (56%) 1-benzoyl-3-{2-methoxy-5-[methyl-(tetrahydro-pyra n-4-yl)-amino]-phenyl}-thiourea as a yellow solid. ES-MS m/e (%): 422 (M+Na+, 13), 400 (M+H+, 100).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])[CH2:18]/[C:19](=[N:27]\[OH:28])/[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=3)=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C.[Li+].[OH-].C(O)=O>O1CCOCC1.O>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([CH:17]([C:14]2[CH:13]=[CH:12][C:11]([C:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[S:7][CH:8]=3)=[CH:16][CH:15]=2)[CH2:18]/[C:19](=[N:27]\[OH:28])/[C:20]2[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=2)=[C:30]([F:36])[CH:31]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C(C/C(=N\O)c3ccnc(C)c3)c3ccc(Cl)cc3F)cc2)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=CO
Solvent: O
Product: Cc1cc(/C(CC(c2ccc(-c3csc(C(=O)O)c3)cc2)c2ccc(Cl)cc2F)=N/O)ccn1
Temperature: 100 °C
Yield: 98.6 %

Procedure:
To a solution of 4-{4-[1-(4-chloro-2-fluoro-phenyl)-3-[(E)-hydroxyimino]-3-(2-methyl-pyridin-4-yl)-propyl]-phenyl}-thiophene-2-carboxylic acid ethyl ester (15 mg) in dioxane/water (1.5 mL, 1:1) was added LiOH (7.2 mg) and the reaction mixture heated by microwave irradiation to 100° C. for 30 min. Formic acid was added to neutralize LiOH and the solvent mixture removed by evaporation under reduced pressure. Purification of the crude reaction product by silica column chromatography eluting with a mixture of dichloromethane/methanol (95:5, containing 4% formic acid) provided 14 mg (98%) of the title compound as an off-white powder, MS (ESI+): m/z=495.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:25])([F:24])[C:14](=O)[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH2:16]([C:15]1[C:14]([C:13]([F:12])([F:25])[F:24])=[N:1][C:2]2[C:3]([C:4]=1[OH:6])=[CH:7][C:8]([Br:11])=[CH:9][CH:10]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: O=C(CCc1ccccc1)C(F)(F)F
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: Oc1c(Cc2ccccc2)c(C(F)(F)F)nc2ccc(Br)cc12
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-amino-5-bromobenzoic acid (2.53 g, 11.7 mmol), 1,1,1-trifluoro-4-phenylbutan-2-one (2.83 g, 14.0 mmol, see reference Yang, D; Wong, M; Yan, Z. J. Org. Chem. 2000, 65, 4179-4184), and Eaton's reagent (8.8 mL) in a sealed pressure tube was heated at 100° C. for 4 hours. The mixture was then cooled down to room temperature, ice-water was added slowly, and the mixture was stirred vigorously for about 15 minutes. The precipitated solid was filtered, washed with water, and air dried over night to afford the title compound as a light brown solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13]([NH2:16])[CH:14]=[CH2:15].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(OCC)C.C(O)C>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([CH3:12])=[N:11][C:2]=1[NH:16][CH2:13][CH:14]=[CH2:15]
Reactant: COC(=O)c1ccc(C)nc1Cl
Reactant: C=CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: C=CCNc1nc(C)ccc1C(=O)OC

Procedure:
A stirred mixture of 9.25 g. (0.05 mole) of methyl 2-chloro-6-methylnicotinate, 2,85 g. (0.05 mole) of allylamine and 5.3 g. (0.05 mole) of sodium carbonate in 50 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was diluted with 50 ml. of water and was extracted with 50 ml. of diethyl ether. The ether layer was dried over magnesium sulfate, filtered and was evaporated. The residue was passed through a neutral aluminum oxide column using ethyl acetate as the eluent. Evaporation of the ethyl acetate gave 3.1 g. of product. A small amount of this oil was dissolved in diethyl ether containing a few drops of ethanol and this solution was acidified with an ethereal hydrochloric acid solution. The precipitate which formed was collected and was recrystallized from ethyl acetate to give 2-allylamino-6-methylnicotinic acid methyl ester, m.p. 140°-2° C.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]([C:18]([F:21])(F)F)[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([O-:3])=[O:2].Br[CH:23]([CH3:33])[C:24]([O:31][CH3:32])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:17]=[C:16]([CH2:18][F:21])[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH:23]([CH3:33])[C:24]([O:31][CH3:32])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1ccc(O)cc1
Reactant: CCOC(=O)C=C(OC)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C=C(OC)C(C)Oc1ccc(Oc2ccc(CF)cc2[N+](=O)[O-])cc1

Procedure:
A mixture of 4-(2-nitro-4-trifluoromethylphenoxy)phenol (9.36 mm), ethyl 4-bromo-3-methoxy-2-pentenoate (12 mm.) and K2CO3 (14 mm.) in acetone (20 ml.) is refluxed for 24 hours. After filtration, the filtrate is concentrated and the oily residue chromatographed on silica gel to yield ethyl 4-[4-(2-nitro-4-fluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoate.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.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.O>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:18]=2)=[N:7][CH:6]=1
Reactant: Brc1cnc(Br)nc1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cnc(-c2cccc(OCc3ccccc3)c2)nc1
Yield: 70.3 %

Procedure:
15.00 g (63.10 mmol) of 2,5-dibromopyrimidine (for preparation see: D. W. Arantz and D. J. Brown in Journal of the Chemical Society C, 1971, p. 1889), 14.40 g (63.10 mmol) of 3-benzyloxybenzeneboronic acid, 13.40 g (126.2 mmol) of sodium carbonate and 0.73 g (0.63 mmol) of tetrakis(triphenylphosphine)palladium(0) are heated at 80° C. for 4 hours in 150 ml of toluene, 75 ml of ethanol and 50 ml of water. The reaction mixture is subsequently partitioned between ether and water, the organic phase is washed twice with sodium chloride solution, dried over sodium sulfate and evaporated, and the residue is purified by chromatography (silica gel/dichloromethane), giving 15.14 g of 5-bromo-2-(3-benzyloxyphenyl)pyrimidine. ##STR14##
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14]Br)[CH2:2][CH2:3][CH3:4].[CH:16]([NH:19][CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17].C1(C)C=CC=CC=1>O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][N:19]([CH:20]([CH3:22])[CH3:21])[CH:16]([CH3:18])[CH3:17])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)NC(C)C
Reactant: CCCCOc1ccccc1OCCBr
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOc1ccccc1OCCN(C(C)C)C(C)C
Yield: 53.5 %

Procedure:
The thus obtained 1-n-butoxy-2-(2'-bromoethoxy)-benzene (2.73 g, 10 mmole) was heated under reflux for 160 hours with diisopropylamine (4.0 g; 40 mmole) and toluene (25 ml). The reaction mixture was shaken with water until the precipitated salt had dissolved. The toluene phase was then extracted with an excess of dilute hydrochloric acid. The extracts were washed twice with ether and then made alkaline with sodium hydroxide solution. The precipitated base was taken up in ether and the aqueous phase extracted once more with ether. The ether extracts were washed once with water and then dried over potassium carbonate. The solvent was evaporated and the residue distilled to yield 1.57 g (53.5%) of product with b p 104°-105° C at 0.02 mm Hg; nD25 = 1.4936.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[C:14]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[CH:33]=[C:32]([F:34])[C:31]([Cl:35])=[CH:30][C:29]=2[C:36]([NH:38][NH2:39])=[O:37])(=[O:26])=[O:25])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[CH:33]=[C:32]([F:34])[C:31]([Cl:35])=[CH:30][C:29]=2[C:36]([NH:38][NH:39][C:5](=[O:7])[CH2:4][CH2:3][S:2][CH3:1])=[O:37])(=[O:25])=[O:26])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CSCCC(=O)O
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(F)c(Cl)cc2C(=O)NN)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSCCC(=O)NNC(=O)c1cc(Cl)c(F)cc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
To a stirred solution of 3-methylsulfanyl-propionic acid (120 mg, 1.0 mmol) under an inert atmosphere in 6 mL of anhydrous DCM and DMF (200 μL) was added oxalyl chloride (89 μL, 1.0 mmol). The resultant solution was stirred at room temperature overnight and then added to a solution of 4-tert-butyl-N-(4-chloro-5-fluoro-2-hydrazinocarbonyl-phenyl)-benzenesulfonamide (400 mg, 1.0 mmol) and Et3N (0.35 mL, 2.5 mmol) at 0° C. The resultant solution was stirred at room temperature for 4 hours and the solvent was removed in vacuo. The residue was purified via automated silica gel chromatography to afford 4-tert-butyl-N-{4-chloro-5-fluoro-2-[N′-(3-methylsulfanyl-propionyl)-hydrazinocarbonyl]-phenyl}-benzenesulfonamide as an oil: MS (ES) M+H expected 502.1, found 502.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:31][CH3:32])=[CH:5][C:6]2[CH:12]([CH2:13][O:14][CH2:15][CH2:16]OS(C3C=CC([N+]([O-])=O)=CC=3)(=O)=O)[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:30]=1.CO[CH:35]1[CH2:40][NH:39][CH2:38][CH2:37][N:36]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C.[O:54]1CCC[CH2:55]1>>[CH3:1][O:2][C:3]1[C:4]([O:31][CH3:32])=[CH:5][C:6]2[CH:12]([CH2:13][O:14][CH2:15][CH2:16][N:39]3[CH2:40][CH2:35][N:36]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:46]=4[O:54][CH3:55])[CH2:37][CH2:38]3)[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:30]=1
Reactant: COC1CNCCN1c1ccccc1
Reactant: COc1cc2c(cc1OC)C(COCCOS(=O)(=O)c1ccc([N+](=O)[O-])cc1)OCCC2
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C(COCCN1CCN(c3ccccc3OC)CC1)OCCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
A mixture of 0.50 g (1.07 mmoles) of [2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl]-4-nitrobenzenesulfonate, 0.22 g (1.07 mmoles) of o-methoxyphenylpiperazine, 0.15 ml (1.07 mmoles) of triethylamine, and 20 ml of tetrahydrofuran is stirred at room temperature for 24 hours. After removing the tetrahydrofuran in vacuo, the reaction mixture is extracted with methylene chloride and aqueous sodium bicarbonate. The organic layer is filtered through sodium sulfate, taken to dryness, and chromatographed on silica gel using 3% methanol methylene chloride eluent to give 0.40 g (82%) of 1-[2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl]-4-(2-methoxyphenyl)piperazine. The dihydrochloride salt was prepared with hydrochloric acid in ethyl ether, m.p. 172°-175°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:39]([NH:41][NH2:42])=O.P(Cl)(Cl)(Cl)=O>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:16]2[C:17](=[O:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]2=[O:25])[CH2:12][C:13]2[O:15][CH:39]=[N:41][N:42]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC
Reactant: NNC=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C(Cc2nnco2)N2C(=O)c3ccccc3C2=O)cc1OC

Procedure:
2-[1-(3,4-Dimethoxyphenyl)-2-(1,3,4-oxadiazol-2-yl)ethyl]isoindoline-1,3-dione was prepared by the procedure of Example 8 from 3-(3,4-dimethoxyphenyl)-3-(1,3-dioxoisoindolin-2-yl)propanoic acid (2.0 g, 3.6 mmol), carbonyidiimidazole (1.0 g, 6.2 mmol), formic hydrazide (0.41 g, 6.8 mmol), and phosphorus oxychloride (1.3 mL, 14 mmol) in acetonitrile (20 mL). The product was obtained as a white solid (730 mg, 34% yield): mp, 83.0-85.0° C.; 1H NMR (CDCl3) δ 3.82 (dd, J=6.0, 16.0 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 3.90 (s, 3H, CH3), 4.39 (dd, J=10.3, 15.7 Hz, 1H, CHH), 5.84 (dd, J=6.0, 10.3 Hz, 1H, NCH), 6.81-6.85 (m, 1H, Ar), 7.16-7.19 (m, 2H, Ar), 7.68-7.73 (m, 2H, Ar), 7.77-7.83 (m, 2H, Ar), 8.30 (s, 1H, CH); 13C NMR (CDCl3) δ 27.66, 51.76, 55.79, 55.89, 111.00, 111.07, 120.29, 123.3,8, 130.16, 131.55, 134.07, 149.03, 149.11, 152.96, 163.90, 167.86; Anal Calcd for C20H17N3O6+0.3 Et2O: C, 63.22; H, 5.20; N, 10.32. Found: C, 63.40; H, 5.02; N, 10.46. (1H NMR showed that the sample contained 30% of ether).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[CH:5]=[CH:4][C:3]1=2.O[C:22]1[CH:36]=[CH:35][C:25]([C:26]([O:28][CH2:29][CH2:30][Si](C)(C)C)=[O:27])=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC.CCOCC>CN(C=O)C>[CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([O:19][C:22]3[CH:36]=[CH:35][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=3)=[O:18])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CC=C(c2cccs2)c2cc(C(=O)O)ccc21
Reactant: C[Si](C)(C)CCOC(=O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(c2cccs2)=CCC3(C)C)cc1

Procedure:
A solution of 5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalene-2-carboxylic acid (Compound E6, 79.0 mg, 0.280 mmol), 2-trimethylsilylethyl 4-hydroxybenzoate (73.3 mg, 0.308 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (70.0 mg, 0.364 mmol), and 4-N,N-dimethylaminopyridine (44.5 mg, 0.364 mmol) in 2.0 mL DMF was stirred overnight at room temperature. Et2O (100 mL) was added and the solution washed with H2O, 5% HCl, saturated aqueous NaCO3, and saturated aqueous NaCl before being dried over MgSO4. Removal of the sovents under reduced pressure and column chromatography (10% EtOAc-hexanes) of the residual off afforded the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:28](=[O:29])/[CH:27]=[CH:26]/[C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)/C=C/c3ccc(Cl)cc3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-(4-chloro-phenyl)-acrylic acid.
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:41]([CH:45]6[CH2:47][CH2:46]6)[CH:42]=[N:43][CH:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])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:41]([CH:45]6[CH2:46][CH2:47]6)[CH:42]=[N:43][CH:44]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=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(SCc4cncn4C4CC4)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)Cc4cncn4C4CC4)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-cyclopropylimidazol-4-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.3 g) was dissolved in dichloromethane (10 ml), and the mixture was cooled to −78° C. 3-chloroperbenzoic acid (0.17 g) in dichloromethane solution (5 ml) was added dropwise to the solution. The mixture was stirred for 1 hour at −78° C., and then, sodium thiosulfate solution was added to the mixture. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-cyclopropylimidazol-4-yl)methylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 74) (0.22 g) as yellow amorphous.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH2:19][C:20]2[C:28]3[C:23](=[N:24][N:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][OH:30])[N:21]=2)=[CH:4][CH:3]=1.C(Cl)Cl.[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:19][C:20]2[C:28]3[C:23](=[N:24][N:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][O:30][C:34](=[O:36])[CH3:35])[N:21]=2)=[C:6]([F:18])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]([C:12]#[N:13])[CH:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(Cc3nn(CO)c4nnccc34)c2F)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCn1nc(Cc2ccc(Br)c(Oc3cc(Cl)cc(C#N)c3)c2F)c2ccnnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 12 (0.1 g, 0.2 mmol) and DCM (3 mL) was added pyridine (0.08 mL, 1.0 mmol) and acetic anhydride (612 mg, 6 mmol). The resulting solution was stirred overnight at RT under an inert atmosphere. Starting material was still evident and additional aliquots of pyridine (0.08 mL) and Ac2O (0.612 g) were added and the resulting mixture stirred at 55° C. for ca. 5 h. The volatile contents were evaporated and the residue purified in two batches on a preparative SiO2 TLC plate developed with 60% EtOAc/hexane containing 1% TEA. The product was eluted from the plate and crystallized from DCM/hexane to afford 0.076 g of I-8: Anal. Calcd. for C22H14BrClFN5O3: C, 49.79; H, 2.66; N, 13.20. Found: C, 49.87; H, 2.63; N, 12.92.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[CH3:15][OH:16].CCN(CC)CC>C1COCC1>[CH3:15][O:16][C:8](=[O:9])[C:7]([O:6][C:5]1[CH:13]=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:12])[CH3:11]
Reactant: CC(C)(Oc1ccc(Br)cc1)C(=O)Cl
Reactant: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
2-(4-Bromophenoxy)-2-methylpropanoyl chloride (2.34 g, 8.4 mmol) in THF (10 mL) was added dropwise whilst stirring to anhydrous MeOH (1.34 g, 42 mmol), Et3N (1.7 g, 16.8 mmol) and THF at 0° C. The mixture was stirred at room temperature for 3 h, concentrated and distilled to afford the sub-title compound (1.74 g, 97%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2]C.I[CH2:26]CC>>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)([CH3:26])[CH3:2]
Reactant: CCCI
Reactant: CCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Product: CC(C)Oc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3

Procedure:
Following the procedure for the preparation of 10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole and substituting 2-iodopropane for 1-iodopropane while making non-critical variations the title compound was obtained as 236 mg (56%) of a brown oil: 1H NMR (400 MHz, CDCl3) δ 7.88 (br s, 1H), 7.36-7.26 (m, 3H), 7.16-7.12 (m, 1H), 7.05-7.00 (m, 2H), 6.95 (d, J=7.2 Hz, 1H), 4.33-4.27 (m, 1H), 3.11-3.03 (m, 2H), 2.96-2.94 (m, 2H), 2.87-2.81 (m, 2H), 2.48-2.35 (m, 2H), 1.15-1.08 (m, 6H); HRMS (FAB) calcd for C21H24N2O+H1: 321.1967 found 321.1949.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]2[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]2)[CH2:10][C@H:9]1[C:23]([O:25]C)=[O:24])=[O:7])([CH3:4])[CH3:3].[OH-].[Li+]>O1CCCC1.O>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]2[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:20])=[O:21])[CH2:15][CH2:14]2)[CH2:10][C@H:9]1[C:23]([OH:25])=[O:24])=[O:7])([CH3:1])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@H](C2CCN(S(C)(=O)=O)CC2)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](C2CCN(S(C)(=O)=O)CC2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of the compound prepared in Example 62 (2.87 g, 7.36 mmol) in tetrahydrofuran (20 mL) and water (20 mL) at 0° C. was added lithium hydroxide (0.35 g, 14.7 mmol). The reaction was warmed to room temperature and stirred overnight whereupon it was partitioned between methyl tert-butyl ether and water. The aqueous layer was separated and carefully acidified to pH 1 with 6 N hydrochloric acid. The aqueous solution was extracted with ethyl acetate (2×300 mL) and the combined organic extracts concentrated to give the title compound (2.35 g, 85%) as a white solid.