Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8]CC)=[CH2:7])CCC.Br[C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH2:22][C:23]([CH3:41])([CH3:40])[N:24]=[C:25]2[C:30]1[CH:31]=[N:32][C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2.Cl.O.[NH4+]>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.C1(C)C=CC=CC=1>[C:6]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH2:22][C:23]([CH3:41])([CH3:40])[N:24]=[C:25]2[C:30]1[CH:31]=[N:32][C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:8])[CH3:7]
Reactant: CC1(C)Cc2c(Br)cccc2C(c2cnc3ccccc3c2)=N1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1cccc2c1CC(C)(C)N=C2c1cnc2ccccc2c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
Tributyl (1-ethoxyvinyl) tin (0.85 mL, 2.4 mmol) and dichlorobis(triphenylphosphine)palladium (15.8 mg, 0.022 mmol) were added to a toluene solution (0.9 mL) of 3-(5-bromo-3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)quinoline (806 mg, 2.2 mmol), and after stirring for 3 hours at 100° C., dilute hydrochloric acid was added to temporarily acidify followed by basifying with ammonium water, filtering, concentrating the filtrate and applying the resulting residue to chromatography to obtain 647 mg of the target compound (yield: 89%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:31])[NH:10][CH:11]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)[C:12](=[O:23])[NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][C:9]([NH:10][CH:11]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)[C:12]([NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2)=[O:23])=[O:31]
Reactant: CC(C)(C)OC(=O)NCC(=O)NC(C(=O)Nc1ccc2[nH]ncc2c1)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(=O)NC(C(=O)Nc1ccc2[nH]ncc2c1)c1cccc(Cl)c1
Reaction time: 1 h
Yield: 27.9 %

Procedure:
To a solution of ({[(3-chloro-phenyl)-(1H-indazol-5-ylcarbamoyl)-methyl]-carbamoyl}-methyl)-carbamic acid tert-butyl ester (0.09 mmol) in dichloromethane (2.5 mL) at 0° C. was added trifluoroacetic acid (2.5 mL) and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuo to afford compound the title compound (9 mg, 24%). 1H NMR (400 MHz, DMSO-d6) δ 3.8(2H, m), 5.8(1H, m), 7.4–7.7(5H, m), 7.9–8.2(4H, m), 9.3–9.4(1H, m), 10.6 (1H, s), 13.0(1H, br s); MS (ES+): m/e=358.3(40%), 134.3(100%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[N:5][O:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[OH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:35]=[C:34]3[C:29]([CH:30]=[CH:31][CH:32]=[C:33]3[C:36]([O:38][CH3:39])=[O:37])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:4]1[C:3]([CH2:2][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:35]=[C:34]4[C:29]([CH:30]=[CH:31][CH:32]=[C:33]4[C:36]([O:38][CH3:39])=[O:37])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)=[C:7]([CH:8]([CH3:10])[CH3:9])[O:6][N:5]=1
Reactant: COC(=O)c1cccc2ccc(-c3ccc(O)cc3)cc12
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc12
Yield: 75 %

Procedure:
A solution of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (0.11 g, 0.36 mmol), methyl 7-(4-hydroxyphenyl)-1-naphthalenecarboxylate (0.083 g, 0.30 mmol), and cesium carbonate (137 mg, 0.42 mmol) in dimethylformamide (0.73 mL) was heated to 65° C. for 3 hours. The solution was partitioned between ethyl acetate and water. The organic layer was dried with magnesium sulfate, filtered, and concentrated. The filtrate was purified by chromatography (silica gel, hexane to 1:4 ethyl acetate:hexanes) to provide the title compound (0.123 g, 75%). 1H NMR (DMSO-d6): 8.93 (s, 1H), 8.19-8.14 (m, 2H), 8.07 (d, J=9 Hz, 1H), 7.84 (dd, J=2, 9 Hz; 1H), 7.63 (d, J=8 Hz, 4H), 7.59-7.52 (m, 2H), 6.93 (d, J=9 Hz, 2H), 4.87 (s, 2H), 3.93 (s, 3H), 3.46 (septet, J=7 Hz, 1H), 1.33 (d, J=7 Hz, 6H). ESI LCMS m/z 546 (M+H)+.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH:5]1([Mg]Br)[CH2:7][CH2:6]1.C1COCC1.[CH:15]([C@H:18]1[C:22](=[O:23])[CH2:21][CH2:20][N:19]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])([CH3:17])[CH3:16]>>[CH:5]1([C@:22]2([OH:23])[CH2:21][CH2:20][N:19]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[C@H:18]2[CH:15]([CH3:16])[CH3:17])[CH2:7][CH2:6]1
Reactant: Br[Mg]C1CC1
Reactant: CC(C)[C@H]1C(=O)CCN1C(=O)OCc1ccccc1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)[C@@H]1N(C(=O)OCc2ccccc2)CC[C@@]1(O)C1CC1

Procedure:
By an operation in the same manner as in Reference Example 3 and using cerium chloride (7.40 g), 0.5 mol/L cyclopropylmagnesium bromide—THF solution (52.8 mL) and benzyl (2S)-2-isopropyl-3-oxopyrrolidine-1-carboxylate (3.14 g), the title compound was obtained as colorless oil (yield: 2.31 g, yield: 63%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:35][C:34]([CH3:37])([CH3:36])[C:33]2[C:28](=[CH:29][C:30]([NH2:38])=[CH:31][CH:32]=2)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:19]([O:23][C:24]([N:26]1[CH2:35][C:34]([CH3:37])([CH3:36])[C:33]2[C:28](=[CH:29][C:30]([NH:38][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:18][CH:17]=3)=[CH:31][CH:32]=2)[CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C(O)c1ccccc1NCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C(C)(C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3NCc3ccc(F)cc3)ccc2C(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The mixture of 2-(4-fluorobenzylamino)benzoic acid (Step A, 0.7 g, 1.20 mmol), 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.71 g, 2.57 mmol), TBTU (0.917 g, 2.86 mmol), and DIEA (0.5 mL) in 30 mL of CH2Cl2 was stirred at RT for 2 h, then diluted with more CH2Cl2. The organic layer was washed with water, and brine, dried with MgSO4, filtered, and condensed. The residue was purified by flash column chromatography (0 to 30% of EtOAc in CH2Cl2), and the titled compound was obtained as oil. MS (ES+): 504 (M+H)+. Calc'd for C30H34FN3O3-503.26.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].S(Cl)(Cl)=O.[NH2:19][C@H:20]1[CH2:25][C:24]2[C:26]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)=[CH:27][CH:28]=[CH:29][C:23]=2[O:22][CH2:21]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:36][N:33]1[CH2:34][CH2:35][N:30]([C:26]2[C:24]3[CH2:25][C@H:20]([NH:19][C:9](=[O:11])[C:8]4[CH:7]=[CH:6][C:5]([C:3]([N:2]([CH3:1])[CH3:14])=[O:4])=[CH:13][CH:12]=4)[CH2:21][O:22][C:23]=3[CH:29]=[CH:28][CH:27]=2)[CH2:31][CH2:32]1
Reactant: CN(C)C(=O)c1ccc(C(=O)O)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C(=O)N(C)C)cc2)CO3)CC1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 54 %

Procedure:
To 4-(N,N-dimethylaminocarbonyl)benzoic acid (110 mg, 0.56 mmol; described in: U.S. Pat. No. 3,607,918, 1971) was dropwise added thionyl chloride (500 μL, 6.9 mmol). The reaction mixture was stirred at ambient temperature for 1 min and then concentrated in vacuo. The excess of thionyl chloride was co-evaporated with toluene in vacuo. The crude acid chloride was dissolved in methylene chloride (8 mL) and dropwise added to a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4 dihydro-2H-1-benzopyran (130 mg, 0.53 mmol) and triethylamine (110 μL, 0.80 mmol) in methylene chloride (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for an additional 30 min. The solvent was evaporated in vacuo giving 300 mg of a crude product. Purification by preparative TLC on silica using chloroform/ethanol (saturated with ammonia) 10:1 as the eluent afforded 120 mg (54% yield) of the title compound as a white solid: mp 219° C. (dec); EIMS (70 eV) m/z (relative intensity) 422 (47, M+); [α]22D −12° (c 0.42, chloroform).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:23])[C:4]=1[CH2:24][CH2:25][C:26]([OH:28])=O)[CH3:2].C[CH2:30][N:31](C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN>CN(C=O)C.C1COCC1>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:23])[C:4]=1[CH2:24][CH2:25][C:26]([NH:31][CH3:30])=[O:28])[CH3:2]
Reactant: CCc1cc(-c2nc(-c3cc(C)c(CCC(=O)O)c(CC)c3)no2)cc(C)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCc1cc(-c2nc(-c3cc(C)c(CCC(=O)NC)c(CC)c3)no2)cc(C)n1
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of 3-{2-ethyl-4-[5-(2-ethyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionic acid (26 mg, 69 μmol) and DIPEA (27 mg, 207 μmol) in DMF (3 mL) is added PyBOP (40 mg, 76 μmol) at 0° C. The mixture is stirred for 15 min at 0° C. before methylamine (2.4 mg, 76 μmol, 38 μL of a 2 M solution in THF) is added. Stirring is continued for 1 h at 0° C. The reaction is quenched with water (2 mL), and the mixture is diluted with sat. aq. NaHCO3 solution. The mixture is extracted twice with ether. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with heptane:EA 1:4 to give 3-{2-ethyl-4-[5-(2-ethyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-N-methyl-propionamide (21 mg) as a white solid; LC-MS: tR=0.90 min; [M+1]+=393.45; 1H NMR δ 1.32 (t, J=7.5 Hz, 3 H), 1.40 (t, J=7.8 Hz, 3 H), 2.34-2.41 (m, 2 H), 2.45 (s, 3 H), 2.69 (s, 3 H), 2.77 (q, J=7.5 Hz, 2 H), 2.85 (d, J=4.8 Hz, 3 H), 2.95 (q, J=7.8 Hz, 2 H), 3.07-3.13 (m, 2H), 5.41 (s br, 1 H), 7.76 (s, 2 H), 7.84 (s, 1 H), 7.86 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[CH:5]=[CH:6][CH:7]=O.[CH3:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:15]>Cl.C(O)C>[CH3:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:15]=[CH:7][CH:6]=[CH:5][C:4]1[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: CN(N)c1ccccc1
Reactant: COc1ccccc1C=CC=O
Agent: Cl
Solvent: CCO
Product: COc1ccccc1C=CC=NN(C)c1ccccc1

Procedure:
3.2 g of 2-methoxycinnamaldehyde and 2.4 g of 1-methyl-1-phenylhydrazine were added to 50 ml of ethanol. To the mixture, two or three drops of 1 N hydrochloric acid were added. The mixture was heated and refluxed for about one hour. The reaction mixture was cooled and the crystals then separated, which were then collected on a suctional funnel. The thus obtained crude 2-methoxycinnamaldehyde 1-methyl-1-phenylhydrazone was recrystallized from ethanol. The yield was 2.6 g (49.1%) of light yellow scalelike crystals which melt at 100.5°-101.5° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][OH:19])=[CH:15][CH:16]=2)[N:11]([CH2:20][CH:21]2[CH2:23][CH2:22]2)[CH:10]=1)=[O:8].N[C:25]1SC=C(C)N=1>>[CH3:25][C:4]1[N:3]=[C:2]([NH:6][C:7]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][OH:19])=[CH:15][CH:16]=3)[N:11]([CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH:10]=2)=[O:8])[S:1][CH:5]=1
Reactant: O=C(Nc1nccs1)c1cn(CC2CC2)c2cc(CO)ccc12
Reactant: Cc1csc(N)n1
Product: Cc1csc(NC(=O)c2cn(CC3CC3)c3cc(CO)ccc23)n1

Procedure:
The compound was prepared according to the procedure given for 1-Cyclopropylmethyl-6-hydroxymethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide using 2-amino-4-methyl-thiazole.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][C:3]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][C:26]1=[O:31]>>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[N:28]2[CH2:29][CH2:30][N:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[Cl:18])[C:26](=[O:31])[CH2:27]2)=[CH:11][CH:12]=1
Reactant: COc1ccc(Cc2c[n+]([O-])ccc2Cl)cc1
Reactant: O=C1CNCCN1c1ccccc1Cl
Product: COc1ccc(Cc2cnccc2N2CCN(c3ccccc3Cl)C(=O)C2)cc1

Procedure:
The product of step B is heated with 1-(2-chlorophenyl)-piperazin-2-one (1 molar equivalent). The crude N-oxide of 4-[3-(4-methoxybenzyl)pyrid -4-yl]-I-(2-chlorophenyl)-piperazin-2-one is deoxygenated by treatment with triphenylphosphine (2 molar equivalents) to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH2:10]([OH:12])[CH3:11]>>[CH2:10]([O:12][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1)[CH3:11]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CCO
Product: CCOc1ccc(N)cc1

Procedure:
The method of claim 1 wherein nitrobenzene is reacted with ethanol to form p-ethoxyaniline.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19](=[O:21])[CH3:20].[I-].[Na+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][C:19](=[O:21])[CH3:20])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: CC(=O)CCl
Reactant: CCc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCc1cc(Br)ccc1OCC(C)=O
Reaction time: 0.08 h
Yield: 102.1 %

Procedure:
4-bromo-2-ethylphenol (72.79 g, 362 mmoles) was dissolved in acetone (1.3 liter) and potassium carbonate (100 g, 724 mmoles) was added. The reaction was stirred for five minutes. Chloroacetone (43.2 ml, 543 mmoles) and sodium iodide (13.6, 90 mmoles) was added and the reaction turned orange upon stirring. The reaction was stirred overnight at room temperature and the solvent removed in vacuo. Ethyl acetate (2.5 l) and water (800 ml) were added. The organic layer was separated, washed with aqueous Na2S2O3, dried over sodium sulfate and filtered. The solvent was removed in vacuo and the crude product run through a plug of silica gel (ca. 500 g) and eluted with 20% ethyl acetate in hexane. The solvent was removed to obtain 95 g of 1-(4-bromo-2-ethylphenoxy)propan-2-one 30.
Reaction SMILES: FC1C=C2C(C(C3C=NNC=3)=CN2S(C2C=CC=CC=2)(=O)=O)=CC=1.[C:25]1([S:31]([N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:46])([F:45])[F:44])[CH:41]=3)[C:36]([C:47]3[CH:48]=[N:49][N:50](C(OC(C)(C)C)=O)[CH:51]=3)=[CH:35]2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([S:31]([N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:45])([F:46])[F:44])[CH:41]=3)[C:36]([C:47]3[CH:48]=[N:49][NH:50][CH:51]=3)=[CH:35]2)(=[O:33])=[O:32])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(C(F)(F)F)ccc23)cn1
Agent: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Product: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(C(F)(F)F)cc21
Yield: 94.6 %

Procedure:
Following the general method as outlined in Intermediate 5, starting from tert-butyl 4-(1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indol-3-yl)-1H-pyrazole-1-carboxylate (Intermediate 41; 400 mg; 0.81 mmol), 300 mg (95%) of the title compound was obtained as a yellow oil, which was used directly without further purification.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[F:7][C:8]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:23][C:22]([C:28]4[CH:33]=[C:32]([Cl:34])[C:31]([Cl:35])=[C:30]([Cl:36])[CH:29]=4)([C:24]([F:27])([F:26])[F:25])[O:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:11][CH:10]([NH2:12])[CH2:9]1.CCN(C(C)C)C(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:7][C:8]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH2:23][C:22]([C:28]4[CH:33]=[C:32]([Cl:34])[C:31]([Cl:35])=[C:30]([Cl:36])[CH:29]=4)([C:24]([F:25])([F:26])[F:27])[O:21][N:20]=3)=[CH:17][CH:18]=2)[CH2:11][CH:10]([NH:12][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[CH2:9]1
Reactant: O=C(Cl)C1CC1
Reactant: NC1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1)C1CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
Cyclopropylcarbonylchloride (14.1 μL, 0.10 mmol) is added to 3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)cyclobutanamine (Preparation 16, 50.0 mg, 0.10 mmol) in DMF (1.5 mL) along with DIPEA (5.4 μL, 0.31 mmol) and DMAP (1.2 mg, 0.01 mmol). The reaction mixture is stirred for three days at room temperature. The mixture is partitioned between brine (5 mL) and EtOAc (5 mL). The organics are separated, dried over MgSO4, filtered and evaporated to give a residue, which is purified on regular silica eluting from neat DCM to 15% MeOH/DCM to give the title compound (22 mg): 1H NMR (DMSO-d6) δ: 8.83 (1H, d), 7.88 (2H, s), 7.79 (2H, d), 7.58 (2H, d), 4.61-4.53 (1H, m), 4.42-4.30 (2H, m), 2.89-2.78 (2H, m), 2.65-2.55 (2H, m), 1.50-1.44 (1H, m), 0.71-0.61 (4H, m); m/z (Cl) 548.
Reaction SMILES: [O:1]=[C:2]([NH:23][C:24]1[CH:25]=[C:26]2[C:39](=[CH:40][CH:41]=1)[CH2:38][C@:28]1([C:36]3[C:31](=[N:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]1=[O:37])[CH2:27]2)[CH2:3][NH:4][C@H:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:6][CH2:7][NH:8][C:9]1([C:14]([O-])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[K+].CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl>[O:15]=[C:14]1[C:9]2([CH2:10][CH2:11][CH2:12][CH2:13]2)[NH:8][CH2:7][CH2:6][C@@H:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]1[CH2:3][C:2]([NH:23][C:24]1[CH:25]=[C:26]2[C:39](=[CH:40][CH:41]=1)[CH2:38][C@:28]1([C:36]3[C:31](=[N:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]1=[O:37])[CH2:27]2)=[O:1]
Reactant: O=C(CN[C@@H](CCNC1(C(=O)[O-])CCCC1)c1ccccc1)Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(CN1C(=O)C2(CCCC2)NCC[C@H]1c1ccccc1)Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a stirred solution of potassium 1-({(3S)-3-[(2-oxo-2-{[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]amino}ethyl)amino]-3-phenylpropyl}amino)cyclopentanecarboxylate from Step B (0.147 g, 0.249 mmol) in DMF (8.3 mL) was added EDCI (0.0720 g, 0.374 mmol) and HOAt (0.0340 g, 0.249 mmol). The reaction mixture was then heated to 40° C. After 1 h, additional EDCI (0.0350 mg) was added and the reaction temperature was increased to 50° C., for 15 h. The reaction was allowed to cool to ambient temperature before being diluted with 5% aqueous sodium bicarbonate (100 mL) and chloroform (100 mL). The organics were washed successively with water (100 mL) and saturated brine (100 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—99:1 to 91:9, to give the title compound. MS: m/z=536 (M+1). HRMS: m/z=536.2694; calculated m/z=536.2656 for C32H34N5O3.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.Cl.[C:12](=N)(OCC)[CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:13]([C:12]1[NH:10][C:4]2[CH:3]=[C:2]([CH3:1])[C:7]([CH3:8])=[CH:6][C:5]=2[N:9]=1)[CH2:14][CH2:15][CH3:16]
Reactant: Cc1cc(N)c(N)cc1C
Reactant: CCCCC(=N)OCC
Agent: Cl
Product: CCCCc1nc2cc(C)c(C)cc2[nH]1
Yield: 74.9 %

Procedure:
Using the procedure of Step A of Example 1, 2.04 g of 4,5-dimethyl-1,2-phenylene diamine and 3.73 g of ethyl pentanimidoate hydrochloride [J.A.C.S-, Vol. 64, p. 1827 (1942)] were reacted to obtain 3.48 g of crude product which was chromatographed on silica (eluant: methylene chloride - methanol (9-1)) to obtain 2.27 g of the expected compound melting at 110° C. An analytical sample was prepared by crystallization of 120 mg of the product from isopropyl ether to obtain 88 mg of product melting at 110° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([O:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]=1[C:34](O)=[O:35])[CH3:22]>>[CH2:21]([O:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]=1[C:34]([N:17]1[CH2:16][CH:15]2[CH:19]([CH2:20][N:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][N:10]=3)[CH2:14]2)[CH2:18]1)=[O:35])[CH3:22]
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Reactant: CCOc1ccc2ccccc2c1C(=O)O
Product: CCOc1ccc2ccccc2c1C(=O)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 2-ethoxy-naphthalene-1-carboxylic acid. MS (ESI): mass calculated for C29H28N4O2, 464.57; m/z found 465.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.42-8.33 (m, 1H), 8.14-7.98 (m, 2H), 7.89-7.61 (m, 3H), 7.53-7.43 (m, 3H), 7.41-7.18 (m, 3H), 7.01-6.95 (m, 1H), 4.31-2.91 (m, 12H), 1.49-1.23 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:10]2[CH2:15][O:14][CH2:13][C@@H:12]3[CH:16]=[CH:17][CH2:18][C:19](=[O:20])[N:11]23)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[H][H]>CO.[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]([C@@H:10]2[CH2:15][O:14][CH2:13][C@@H:12]3[CH2:16][CH2:17][CH2:18][C:19](=[O:20])[N:11]23)[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: [H][H]
Reactant: O=C1CC=C[C@H]2COC[C@@H](c3cc(F)c(F)c(F)c3)N12
Agent: O=[Pt]
Solvent: CO
Product: O=C1CCC[C@H]2COC[C@@H](c3cc(F)c(F)c(F)c3)N12
Yield: 100.1 %

Procedure:
Platinum oxide (20.1 mg) was added to a solution of (4R,9aS)-4-(3,4,5-trifluorophenyl)-3,4,7,9a-tetrahydro-1H-pyrido[2,1-c][1,4]oxazin-6-one (250 mg) in methanol (6 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for two hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 252 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:10](O)=[O:11]>O1CCOCC1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:10]([Cl:3])=[O:11]
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride 3.7 mL, (50 mmol) was added drop wise, at room temperature, to a stirred solution of 3-methoxy4-nitro-benzoic acid ( 1.0 g, 5.07 mmol) in 15 mL of dioxane under a nitrogen atmosphere. After the addition was complete, the reaction was allowed to stir at room temperature for 1 hr. The reaction flask was then fitted with a distillation head, and excess thionyl chloride and about ½ of the solvent was removed by distillation in a 120° C. oil bath. The remaining solvent was removed by rotary evaporation, and the residue was taken up in 20 mL toluene and again about ½ of the solvent was removed by distillation. The remaining solution was then cooled to 0° C., and the white solid which precipitated, was collected by suction filtration, and rinsed with 1-1 Et2O-hexane. 1H-NMR (400 MHz, CDCl3) δ 7.87 (d, J=7.83 Hz, 1H), 7.82 (d, J=7.83 Hz, 1H), 7.77 (s, 1H), 4.04 (s, 3H).