Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[CH:15][CH2:16][C:17]#[N:18].[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([Cl:30])[C:21]=1[NH:31][NH:32][CH2:33][CH2:34][C:35]#[N:36]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[CH:15][CH2:16][C:17]#[N:18].[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:23]=[C:22]([Cl:30])[C:21]=1[N:31]=[N:32][CH2:33][CH2:34][C:35]#[N:36]
Reactant: N#CCCNNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: N#CCC=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: Clc1ccccc1
Product: N#CCCN=Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 65 °C

Procedure:
Preparation of 3-(2,6-dichloro-4-trifluoromethylphenylhydrazono)propionitrile from 3-(2,6-dichloro-4-trifluoromethylphenylhydrazino)propionitrile Cupric chloride (0.673 g, 2.5 equivalents) was added in one portion to a solution of 3-(2,6-dichloro-4-trifluoromethylphenylhydrazino)propionitrile (0.591 g, 2 mmol) in chlorobenzene, and the mixture heated at 65° C. for 50 minutes. The reaction was judged to be complete and was cooled, washed (water), dried (magnesium sulfate), evaporated and separated by chromatography on silica gel to give 3-(2,6-dichloro-4-trifluoromethylphenylhydrazono)propionitrile, NMR 3.37 (d, 2H), 7.03 (t, 1H), 7.5 (s, 2H), 7.75 (s, 1H) (35% yield), and 3-(2,6-dichloro-4-trifluoromethylphenylazo)propionitrile, NMR 3.0 (t, 2H), 4.6 (t, 2H), 7.6 (s, 2H) (60% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:12]=[C:13]([NH:17]C(=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=1)=[O:8])([O-:3])=[O:2].[ClH:28]>O1CCOCC1>[ClH:28].[NH2:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:25]=[CH:26][CH:27]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CNC(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cccc(CNC(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-butyl (3-{[(3-nitrobenzoyl)amino]methyl}phenyl)carbamate (1.00 g, 2.69 mmol) was mixed with 4 M of hydrogen chloride in 1,4-dioxane (10 mL) and stirred at rt for 2 h. After concentration, the desired product was isolated as a white powder (0.82 grams, 99% yield) and used in the next step without further purification. MF=C14H13N3O3; LCMS calculated for C14H13N3O3 (M+H)+: m/z=272.0. 1H NMR (400 MHz, CD3OD): δ 8.73 (t, J=2.0 Hz, 1H), 8.42 (ddd, J=8.4, 2.4, 1.2 Hz, 1H), 8.28 (ddd, J=8.0, 2.4, 1.2 Hz, 1H), 7.76 (t, J=8.4 Hz, 1H), 7.52 (m, 2H), 7.45 (s, 1H), 7.31 (ddd, J=8.4, 2.0, 1.2, 1H), 4.66 (s, 2H).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][N:20]1C(=O)C2=CC=CC=C2C1=O.O.NN.Cl>C(#N)C.C(O)C>[CH:1]1([CH2:6][CH2:7][N:8]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:17][CH2:18][CH2:19][NH2:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc(CNCCC2CCCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: Cl
Agent: NN
Solvent: CC#N
Solvent: CCO
Solvent: O
Product: NCCCN(CCC1CCCC1)Cc1ccccc1
Temperature: 25 °C

Procedure:
Combine 20.3 g (0.1 mol) N-[2-(cyclopentyl)ethyl] benzenemethanamine and 26.8 g (0.1 mol) of N-(3-bromopropyl)phthalimide in 100 mL of acetonitrile. Heat the reaction mixture at reflux and monitor the progress of the reaction by thin-layer chromatography on silica gel. At the completion of the reaction remove the solvent in vacuo. To the residue add 100 mL of ethanol and 15 g (0.3 mol) of hydrazine hydrate. Reflux the reaction mixture and follow the progress of the reaction by thin-layer chromatography on silica gel. At the completion of the reaction, cool the mixture and add 50 mL of 4N hydrochloric acid. Reflux the mixture for ca. 15 min. then cool to room temperature. Filter the resulting solid. Evaporate the filtrate in vacuo, then add 100 mL of 4N sodium hydroxide solution (pH 11). Extract the aqueous mixture with four 100 mL portions of methylene chloride. Combine the organic extracts and dry over anhydrous sodium sulfate. Remove the drying agent by filtration and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13](Cl)(=[O:20])[CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:13](=[O:20])[CH2:14][CH2:15][CH2:16][C:17]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[O:18])=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: O=C(Cl)CCCC(=O)Cl
Reactant: CCOC(=O)c1ccc(O)cc1
Product: CCOC(=O)c1ccc(OC(=O)CCCC(=O)Oc2ccc(C(=O)OCC)cc2)cc1

Procedure:
A similar procedure to Example 1 is carried out by using 16.6 g of ethyl p-hydroxybenzoate and 8.5 g of glutaric acid dichloride to yield di(p-ethyloxycarbonylphenyl)glutarate, m.p. 81°-82° C., as white crystals.
Reaction SMILES: [CH2:1]1[S:5][CH2:4][NH:3][CH:2]1[C:6]([OH:8])=[O:7].C1(NC2CCCCC2)CCCCC1.O1CCOCC1.[C:28]([CH2:36][CH:37]([CH3:41])[C:38](O)=[O:39])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(#N)C>[C:28]([CH2:36][CH:37]([CH3:41])[C:38]([N:3]1[CH:2]([C:6]([OH:8])=[O:7])[CH2:1][S:5][CH2:4]1)=[O:39])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)C1CSCN1
Reactant: CC(CC(=O)c1ccccc1)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC#N
Solvent: C1COCCO1
Product: CC(CC(=O)c1ccccc1)C(=O)N1CSCC1C(=O)O

Procedure:
A mixture of 2.0 g. (0.015 mole) of L-thiazolidine-4-carboxylic acid and 2.72 g. (0.015 mole) of dicyclohexylamine is heated on a steam bath then 50 ml. of dry dioxane and 50 ml. of acetonitrile are added. To this mixture is added 4.2 g. (0.015 mole) of 3-benzoyl-2-methylpropionic acid, N-hydroxysuccinnimide ester, then the mixture is refluxed for 48 hours. The mixture is evaporated in vacuo. The residue is stirred with ethyl acetate and filtered. The filtrate is concentrated in vacuo and the residue is dissolved in dichloromethane. The dichloromethane is washed with sodium bisulfate and then extracted with saturated sodium bicarbonate solution. The sodium bicarbonate wash is added to dilute aqueous hydrochloric acid and the mixture is extracted with dichloromethane. The organic layer is dried over sodium sulfate and concentrated to an oil. The oil is crystallized from acetone-hexane to give [4R-(4R*,2'R*)]-3-(3-benzoyl-2-methylpropionyl)-4-thiazolidinecarboxylic acid as white crystals, m.p. 182°-183° C.; [α]D 23 -63°±4 (C, 0.24, CH3OH).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:5]1=[O:22])(=O)C.[CH3:23][N:24]([CH2:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH3:25].[OH-].[Na+]>CN(C=O)C.CO>[CH3:25][N:24]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([NH:31]/[C:13](=[C:6]2\[C:5](=[O:22])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[CH:32][CH:33]=1)[CH3:23]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2cccc(Cl)c2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2cccc(Cl)c2)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(3-chlorophenyl)-methylidene)-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[OH:28][C:29]1([CH2:33][C:34](OCC)=[O:35])[CH2:32][CH2:31][CH2:30]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34](=[O:35])[CH2:33][C:29]5([OH:28])[CH2:32][CH2:31][CH2:30]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CCOC(=O)CC1(O)CCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1(O)CCC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (58 mg, 52%), MS (ISP) m/z=443.5 [(M+H)+], mp 155° C., was prepared in accordance with the general method of example 2 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and ethyl 2-(1-hydroxy-cyclobutyl)-acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]([CH3:20])[CH3:19])[N:13]=1)(=[O:10])=[O:9].Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[CH3:19][N:18]([CH3:20])[C:14]1[N:13]=[C:12]([N:11]2[C:22](=[O:24])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2(=[O:9])=[O:10])[CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)c1cccc(NS(=O)(=O)c2ccccc2N)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CN(C)c1cccc(N2C(=O)Nc3ccccc3S2(=O)=O)n1
Yield: 26.4 %

Procedure:
The title compound (0.20 g, 0.63 mmol) was prepared from 2-amino-N-[6-(dimethylamino)pyridin-2-yl]benzenesulfonamide (0.7 g, 2.39 mmol) and triphosgene (2.5 g, 8.3 mmol) in 1,4-dioxane (25 mL) using the methods of (IntA1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[Cl:19][CH2:20][C:21](Cl)=[O:22]>CC(C)=O.O>[CH3:1][N:2]([C:21](=[O:22])[CH2:20][Cl:19])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CNc1ccccc1C(=O)OC
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1N(C)C(=O)CCl
Reaction time: 1 h

Procedure:
25 Grams of methyl o-methylaminobenzoate was dissolved in 125 ml of acetone, to this solution was added a solution prepared by dissolving 20.92 g of potassium carbonate in 60 ml of water. Under an ice-cooled condition, 17.95 g of chloroacetyl chloride was added dropwise thereto, then the reaction mixture was stired at a room temperature for 1 hour. Acetone was removed by distillation, the residue obtained was extracted with chloroform, then the chloroform layer was washed with water, dried and the solvent was removed by distillation. The residue thus obtained was purified by a silica gel column chromatography to obtain 16.80 g of N-methyl-o-methoxycarbonyl-α-chloroacetanilide in the form of colorless oily substance.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[CH3:31][NH:32][CH3:33]>CN(C=O)C>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:32]([CH3:33])[CH3:31])[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: CNC
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccnc(N(C)C)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
2-Chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide and dimethylamine (40% in water) in DMF (1 ml) were heated at 85° C. for 96 h in a sealed tube. The reaction mixture was concentrated under vacuum, purified by preparative HPLC and the product fractions reduced to dryness under vacuum to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(dimethylamino)isonicotinamide. NMR; δH [2H6]—DMSO 10.29,(1H, s), 8.62,(1H, t), 8.22,(1H, d), 7.93,(2H, d), 7.70,(1H, dd), 7.65,(1H, d), 7.44,(2H, d), 7.30,(1H, d), 7.03,(1H, s), 6.99,(1H, d), 3.16,(2H, t), 3.07,(6H, s), 2.20,(3H, s), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 2.88 min, MH+429.
Reaction SMILES: [ClH:1].[CH:2]([N:5]([CH:18]([CH3:20])[CH3:19])[CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)([CH3:4])[CH3:3].[CH3:21][S:22]([O:25][C:26]1[CH:27]=[CH:28][C:29]2[CH:33]=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][S:41]([CH3:44])(=[O:43])=[O:42])=[CH:36][CH:35]=3)[S:31][C:30]=2[CH:45]=1)(=[O:24])=[O:23].[Cl-].[Al+3].[Cl-].[Cl-]>C(O)C>[ClH:1].[CH:18]([N:5]([CH:2]([CH3:3])[CH3:4])[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([C:33]2[C:29]3[CH:28]=[CH:27][C:26]([O:25][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:45][C:30]=3[S:31][C:32]=2[C:34]2[CH:35]=[CH:36][C:37]([O:40][S:41]([CH3:44])(=[O:42])=[O:43])=[CH:38][CH:39]=2)=[O:15])=[CH:16][CH:17]=1)([CH3:20])[CH3:19]
Reactant: CC(C)N(CCOc1ccc(C(=O)O)cc1)C(C)C
Reactant: CS(=O)(=O)Oc1ccc(-c2cc3ccc(OS(C)(=O)=O)cc3s2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Product: CC(C)N(CCOc1ccc(C(=O)c2c(-c3ccc(OS(C)(=O)=O)cc3)sc3cc(OS(C)(=O)=O)ccc23)cc1)C(C)C

Procedure:
A 7.6 g. portion of 4-(2-diisopropylaminoethoxy)benzoic acid, hydrochloride, was converted to the acid chloride as described in Example 1 above, and was used to acylate 5 g. of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)benzo[b]thiophene in the presence of 20 g. of aluminum chloride. Work up according to Example 4 gave 7.4 g. of crystalline product after trituration of the isolated oil with denatured ethanol. The product was recrystallized from denatured ethanol to obtain 6.5 g. of purified product, and a 1.5 g. portion was further purified by chromatography over silica gel, eluting with 1:3 methanol:chloroform to obtain 1.15 g. of analytical sample, m.p. 198°-201°.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH2:11][C:12]1[C:16]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=2[O:14][CH:13]=1)C>C1COCC1>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]2[O:14][CH:13]=[C:12]([CH2:11][CH2:10][OH:9])[C:16]=2[CH:17]=1
Reactant: CCOC(=O)Cc1coc2ccc(OC)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2occ(CCO)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of LiAlH4 (200 mg, excess) in THF at 0° C., ethyl(5-methoxy-1-benzofuran-3-yl)acetate (1.17 g, 5 mmol) in THF (20 ml) was added slowly. After the addition, reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH4Cl solution. The product was extracted with chloroform and washed well with water. It was dried over anhydrous MgSO4, filtered and concentrated. The product, 2-(5-methoxy-1-benzofuran-3-yl)ethanol, was obtained as a white oil and was pure enough to be taken to the next step without purification, yielding a yellow oil. Yield: 900 mg (93%); (M+H): 193.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][OH:29])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:30](Cl)([CH3:33])(=[O:32])=[O:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=2)=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCc1ccc(NC(=O)C(CO)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Product: COC(=O)CCc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-3-hydroxypropanamide (882 mg) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(4-(2-methoxycarbonylethyl)phenyl)propanamide (246 mg).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH:7]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>O1CCCC1>[CH:7]1([NH:14][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C=C1CC(=O)O1
Reactant: NC1CCCCCC1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NC1CCCCCC1
Temperature: 6 °C
Reaction time: 4 h
Yield: 68.9 %

Procedure:
37.1 g of diketene were added with stirring over 15 minutes to a mixture of 50 g of cycloheptylamine and 600 ml of tetrahydrofuran cooled to 6° C. and the mixture was stirred for 4 hours at room temperature. The mixture was distilled to dryness under reduced pressure and the residue was chromatographed over silica gel with elution with an 8-2 methylene chloride-acetone mixture to obtain 60 g of N-cycloheptyl-acetylacetamide melting at 52° C. 40 g of the said product and 1 g of p-toluene sulfonic acid were added to a mixture of 32 g of methyl orthoformate and 100 ml of methanol and after stirring the mixture for 8 hours at room temperature, 2 ml of quinoline were added thereto. The mixture was distilled to dryness under reduced pressure and the residue was added to toluene. The mixture was heated at 145° C. for 4 hours while distilling a toluene-methanol azeotrope. The toluene was evaporated by distillation under reduced pressure and the residue was chromatographed over silica gel. An 8-2 methylene chloride-methanol mixture was the eluant and the product was empasted with isopropyl ether to obtain 22 g of N-cycloheptyl-3-methoxy-crotonamide melting at 120° C. The RMN spectra showed the product to be the E isomer.
Reaction SMILES: [CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[CH:12]=[C:11]([CH3:13])[N:10]([C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[C:21]([N:23]2[C@H:32]([CH2:33][OH:34])[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[O:22])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].I[CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:50]([O:49][C:47](=[O:48])[CH2:46][O:20][C:18]1[CH:17]=[CH:16][C:15]([C:21]([N:23]2[C@H:32]([CH2:33][OH:34])[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[O:22])=[C:14]([N:10]2[C:11]([CH3:13])=[CH:12][C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:9]2)[CH:19]=1)[CH3:51]
Reactant: CCCCN(CCCC)C(=O)c1cc(C)n(-c2cc(O)ccc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Reactant: CCOC(=O)CI
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)c1cc(C)n(-c2cc(OCC(=O)OCC)ccc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of 1-[5-hydroxy-2-((S)-3-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-phenyl]-5-methyl-1H-pyrazole-3-carboxylic acid dibutylamide (100 mg, 0.19 mmol) and potassium tert-butoxide (0.21 mL, 1 M, 0.21 mmol) in tetrahydrofuran (2 mL) was stirred at ambient temperature for 10 minutes. Ethyl 2-iodoacetate (0.027 mL, 0.23 mmol) was added and the mixture was stirred at ambient temperature for 1 hour. Ethyl acetate and aqueous HCl solution was added until the pH was about 7. The organic layer was dried over sodium sulfate and removed in vacuo. The crude material was purified by eluting through a short pad of silica gel column to afford the title compound (100 mg, 86% yield). MS (ESI) [m/e, (M+H)+]=605.3. 1H NMR (400 MHz, chloroform-d) δ ppm 6.30-7.41 (m, 8H), 2.68-5.46 (m, 18H), 2.20-2.61 (m, 3H), 0.70-1.74 (m, 15H).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].CC1(C)[C:13]2([CH2:17]S(O)(=O)=O)[C:14]([CH2:16][CH:10]1[CH2:11][CH2:12]2)=[O:15].N1C=CC=CC=1.C[C@@H]1CCCC[C@H]1O>C1COCC1.CCCCCCC.C(OCC)(=O)C>[CH3:17][C@@H:13]1[CH2:12][CH2:11][CH2:10][CH2:16][C@H:14]1[O:15][C:2](=[O:3])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: C[C@@H]1CCCC[C@H]1O
Solvent: CCCCCCC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(Cl)OC(=O)O[C@@H]1CCCC[C@H]1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-chloroethyl chloroformate [CSA No. 50893-53-3] (0.416 mL), pyridine (0.624 mL), and THF (25 mL), (1R,2R)-2-methylcyclohexanol [CSA No. 19043-03-9] (441 mg) dissolved in THF (5 mL) was added at −78° C. After stirring the mixture overnight at room temperature, ethyl acetate (100 mL) and heptane (100 mL) were added to the mixture. The resulting mixture was sequentially washed with 0.5 N hydrochloric acid (50 mL), saturated aqueous sodium hydrogen carbonate solution (50 mL), water (50 mL), and saturated aqueous sodium chloride solution (50 mL), and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure to obtain the captioned compound (482 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH2:9])=O.[BH4-].[Na+].II>C1COCC1>[NH2:9][CH2:7][C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[OH:11]
Reactant: NC(=O)c1cc(Br)ccc1O
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NCc1cc(Br)ccc1O
Temperature: 0 °C

Procedure:
5-bromo-2-hydroxybenzamide (2.16 g, 10 mol) and NaBH4 (1.52 g, 40 mol) are dissolved in dry THF (150 ml) in a two-neck septum capped round-bottom flask. Iodine (5.06 g, 20 mol)) in dry THF is added under nitrogen atmosphere at 0° C. over 2.5 hours. The reaction mixture is refluxed for 3 hours and then cooled to 0° C. The excess hydride is destroyed by careful addition of 1N HCl. After removing most organic solvent by vacuum, the acidic aqueous solution is diluted in 1N HCl (150 ml) and washed three times with ether (30 ml each time). The pH of the aqueous solution is adjusted to pH=6-7 by careful addition of sodium bicarbonate solid. The product is collected by filtration and then washed with water. The product is further dried in vacuum oven overnight giving 2-(aminomethyl)-4-bromophenol which is used directly in the next step without further purification.
Reaction SMILES: BrC([C:4]1[C:9]2=[N:10][O:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1)Br.C[CH2:14][OH:15]>O.[N+]([O-])([O-])=O.[Ag+]>[CH:14]([C:6]1[CH:5]=[CH:4][C:9]2[C:8]([CH:7]=1)=[N:12][O:11][N:10]=2)=[O:15]
Reactant: BrC(Br)c1cccc2nonc12
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: O=Cc1ccc2nonc2c1
Reaction time: 2 h
Yield: 78 %

Procedure:
AgNO3 (163 g) in 2 L of water was added to a refluxing mixture of dibromomethylbenzofurazan (122 g, 418 mmol) in EtOH (1 L). Heating at reflux temperature was continued for 2 h. The mixture was cooled, the precipitated AgBr was removed by filtration through Celite, and the solvent was concentrated. The resulting solution was extracted with toluene (10×100 mL), dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was chromatograghed (EtOAc/hexane, 1/125), giving the title aldehyde (48.2 g, 78%) as a white solid: 1H NMR δ 7.92 (m, 2H), 8.39 (s, 1 H), 10.10 (s, 1 H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])=[C:11]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[CH:10]=2)[CH2:4][CH2:3]1.[C:41](OC(=O)C)(=[O:43])[CH3:42].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:41]([N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])=[C:11]([O:35][CH2:36][C:37]([F:40])([F:38])[F:39])[CH:10]=2)[CH2:6][CH2:7]1)(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cc1ccc(OC2CCNCC2)cc1OCC(F)(F)F)N1CCC(N2C(=O)OCc3ccccc32)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)OCc5ccccc54)CC3)c(OCC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(1-(4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one hydrochloride (0.90 g, 1.5 mmol) from Example 2 in CH2Cl2 (50 mL) was added acetic anhydride (0.31 mL, 3.0 mmol) and DIEA (0.52 mL, 3.0 mmol). The solution was stirred at ambient temperature for 1 h and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with 0.25 M aqueous citric acid (50 mL), H2O (25 mL), and saturated aqueous NaHCO3 (75 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give the title compound as an amorphous solid.