Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:41])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([O:32][C:33]([CH3:38])([CH3:37])[C:34](O)=[O:35])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:40])[CH3:39])=[CH:4][CH:3]=1.Cl.C[N:44](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>CN(C)C=O.C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:41])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([O:32][C:33]([CH3:38])([CH3:37])[C:34]([NH2:44])=[O:35])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:39])[CH3:40])=[CH:4][CH:3]=1
Reactant: CC(C)(Oc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(Oc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2)C(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 30.5 %

Procedure:
To a solution of 2-(5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yloxy)-2-methyl-propionic acid (72 mg, 0.125 mmol) in dimethyl formamide (3 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (48 mg, 0.25 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and ammonium hydroxide (170 μL, 0.50 mmol) and triethylamine (100 μL). Stir at rt 48 h. The mixture was poured into chloroform and washed with water. The organic phase was washed with additional water and brine; dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (methylene chloride—90:10 methylene chloride/methanol gradient) to yield the titled compound (22 mg, 31%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([O:7][C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([C:15]3[N:16]=[C:17]([NH:20][C:21](=[O:31])[C:22]4[CH:27]=[CH:26][N:25]=[C:24]([N+:28]([O-])=O)[CH:23]=4)[S:18][CH:19]=3)=[C:10]([CH3:32])[CH:9]=2)=[CH:5][CH:4]=1>C(O)C.[Pd]>[NH2:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][N:25]=1)[C:21]([NH:20][C:17]1[S:18][CH:19]=[C:15]([C:11]2[C:10]([CH3:32])=[CH:9][C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:34][CH:33]=3)=[CH:13][C:12]=2[CH3:14])[N:16]=1)=[O:31]
Reactant: COc1ccc(Oc2cc(C)c(-c3csc(NC(=O)c4ccnc([N+](=O)[O-])c4)n3)c(C)c2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(Oc2cc(C)c(-c3csc(NC(=O)c4ccnc(N)c4)n3)c(C)c2)cc1
Reaction time: 8 h
Yield: 61.6 %

Procedure:
A mixture of N-(4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-yl)-2-nitroisonicotinamide (0.20 g, 0.40 mmol) and Pd/C (0.15 g, 10% w/w) in ethanol (10 mL) was stirred under H2 overnight. The reaction was filtered through diatomaceous earth and concentrated under reduced pressure to afford 2-amino-N-(4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (0.11 g) as yellow solids in 59% yield: 1H-NMR (500 MHz, DMSO-d6) δ 7.88-7.89 (m, 1 H), 7.10-7.11 (m, 2 H), 6.95-6.97 (m, 2 H), 6.62 (s, 1 H), 5.76 (s, 1 H), 3.29 (s, 3 H), 2.03 (s, 6 H); ESI-MS: m/z 446.6 [M+H]+.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([OH:16])=[C:7]([NH:9][C:10](=O)[C:11](F)(F)F)[CH:8]=1.BrCC=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[O:16][CH2:11][CH:10]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH:9][C:7]=2[CH:8]=1
Reactant: O=C(Nc1cc(Cl)ccc1O)C(F)(F)F
Reactant: CCOC(=O)C=CCBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC1COc2ccc(Cl)cc2N1
Temperature: 0 °C
Yield: 72.1 %

Procedure:
420 ml of ethanol are introduced into a 3 litre reactor, with magnetic stirring, cooled to 0° C., and 3.8 g (0.166 mol) of sodium are added slowly, in small portions, followed by successive and dropwise addition of 40 g (0.166 mol) of N-(5-chloro-2-hydroxyphenyl)trifluoroacetamide and 40 g (0.155 mol) of 75% pure ethyl 4-bromo-2-butenoate, and the mixture is heated at 85° C. for 2 hours. The solvent is evaporated off and the residue is taken up in 100 ml of water and 40 ml of 1N sodium hydroxide and extracted with diethyl ether. The organic phase is separated out, washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated. 28.58 g of product are obtained, which product is purified by chromatography on a column of silica gel, eluting with a cyclohexane/isopropyl ether (1/1 ratio) mixture.
Reaction SMILES: [NH2:1][CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH3:15][N:16]([CH3:30])[C:17]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:13]1[C:14]2[CH:2]([NH:1][CH:20]3[CH2:19][CH2:18][C:17]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)([N:16]([CH3:30])[CH3:15])[CH2:22][CH2:21]3)[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: NC1c2ccccc2-c2ccccc21
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(NC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.5 %

Procedure:
9-Aminofluorene (362 mg, 2 mmol) and 4-dimethylamino-4-phenylcyclohexanone (434 mg, 2 mmol) were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (2 mmol) and sodium triacetoxyborohydride (600 mg) were added to this mixture and the mixture was stirred for 24 hours at RT. For working up, the mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (5×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product was chromatographed over silica gel with ethyl acetate/ethanol (1:1). 440 mg N′-(9H-fluoren-9-yl)-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a white solid which, for preparation of the hydrochloride, was dissolved in 2-butanone (10 ml), and 1.85 M ethanolic HCl (1.55 ml) was added. The mixture of N′-(9H-fluoren-9-yl)-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride obtained was filtered off with suction and dried (460 mg, m.p. 202-205° C.).
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38].O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:38][CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([Cl:33])[CH:35]=2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reactant: NCc1cccc(Cl)c1
Solvent: O
Solvent: CCO
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NCc4cccc(Cl)c4)ncnc32)[C@]1(C)F
Yield: 61.4 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.4 g, 0.86 mmol) in ethanol (about 5 ml) was added 3-chlorobenzylamine (about 1.26 ml, 10.38 mmol) and refluxed for about 20 minutes. Completion of the reaction mixture monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compound (0.30 g) as a colorless gummy mass. Yield: 61.2%; 1H NMR (300 MHz, CDCl3): δ 8.42 (s, 1H), 8.06-8.01 (m, 4H), 7.58-7.24 (m, 6H), 6.56 (d, 1H, J=22.8 Hz), 6.45 (bs, 1H), 4.84-4.78 (m, 3H), 4.49-4.42 (m, 1H), 2.17 (s, 3H), 1.89 (d, 3H, J=2.4 Hz), 1.46 (d, 3H, J=23.1 Hz); Mass: [M+1]+ 568 (50%), [M+Na]+ 590 (70%); IR cm−: 3782, 3414, 2929, 2294, 2177, 1619, 1274, 1061, 712; HPLC: 96%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:16][NH:17][O:18][CH3:19].C(Cl)Cl>C1(C)C=CC=CC=1.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:16][N:17]([O:18][CH3:19])[C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[O:8]
Reactant: CNOC
Reactant: O=C(O)c1ccoc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccoc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a solution of furan-3-carboxylic acid (36 g, 0.32 mol) in 250 mL of toluene was added 49 mL (0.385 mol) of oxalyl chloride and 1 drop of pyridine and the mixture was heated at 80°-90° C. for 1.5 h. The mixture was cooled to room temperature, N,O-dimethylhydroxylamine hydrochloride (35 g, 0.36 mol), 4-dimethylaminopyridine (DMAP, 1.8 g, 0.0147 mol), and 600 mL of methylene chloride were added. The mixture was cooled to 0° C., 68.4 g of pyridine was added slowly, the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was filtered, and the filtrate was washed with water, 5% aqueous dimethylaminopropylamine, water, 6 N HCl solution, water, and brine. The organic layer was dried and concentrated in vacuo, and the residue was distilled (b.p. 85°-87° C./0.2 mm) to afford 44 g (88.7%) of 3-(N-methyl-N-methoxycarbamoyl)furan.
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[C:4]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([NH:28][CH3:29])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([N:28]([CH3:29])[C:2]2[C:14]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6]=3[N:5]=[C:4]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=2)=[CH:26][CH:25]=1
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)c2c(n1)[nH]c1ccccc12
Reactant: CNc1ccc(OC)cc1
Product: COc1ccc(N(C)c2nc(NC(=O)C(C)(C)C)nc3[nH]c4ccccc4c23)cc1
Reaction time: 120 h
Yield: 37 %

Procedure:
Using the general procedure described above, the reaction of 6 (180 mg, 0.59 mmol) and 4-methoxy-N-methylaniline (612 mg, 4.46 mmol) was run for 120 hours, to provide 88 mg of 11 as a brown solid in 37% yield. TLC Rf 0.57 (chloroform-methanol 15:1); mp 288.5-289.4° C.; 1H NMR (DMSO-d6) 81.26 (s, 9H, C(CH3)3,) 3.60 (s, 3H, OCH3), 3.69 (s, 3H, NCH3), 5.87-7.33 (m, 8H, Ar—H), 9.58 (s, 1H, 2-NH, exch), 11.88 (s, 1H, 9-NH, exch).
Reaction SMILES: [NH2:1][C:2]1[C:16]2[C:15](=[O:17])[C:14]([C:18]([O:20]CC)=[O:19])=[CH:13][N:7]3[C@@H:8]([CH2:11][F:12])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([F:23])[C:3]=1[F:24]>OS(O)(=O)=O.O.CC(O)=O>[NH2:1][C:2]1[C:16]2[C:15](=[O:17])[C:14]([C:18]([OH:20])=[O:19])=[CH:13][N:7]3[C@@H:8]([CH2:11][F:12])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([F:23])[C:3]=1[F:24]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c(N)c3c1=O)OC[C@@H]2CF
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3[C@@H](CF)CO2
Temperature: 0 °C
Yield: 95.6 %

Procedure:
A suspension of ethyl (3R)-8-amino-9,10-difluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate (270 mg, 0.789 mmol) in a mixture of H2SO4—H2O—AcOH (1:5:6, 3 mL) was heated under reflux for 1 h. The reaction mixture was poured into ice-water and the resulting precipitates were collected by filtration. The filtered precipitates were washed with water, and dried in vacuo to give (3R)-8-amino-9,10-difluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (237 mg, 96%) as a yellow powder.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[CH:17]=[C:16]([C:18]([OH:20])=O)[NH:15][N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:21][C:22]1[CH:34]=[C:33]([CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:32]=[CH:31][C:23]=1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[CH2:35]([C:33]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[C:22]([NH:21][C:18]([C:16]2[NH:15][N:14]=[C:13]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:17]=2)=[O:20])[CH:34]=1)[CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Reactant: O=C(O)c1cc(-c2ccccc2)n[nH]1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1NC(=O)c1cc(-c2ccccc2)n[nH]1
Reaction time: 1 h

Procedure:
2.0 mL of methylene chloride, 2.7 μL of N,N-dimethylformamide and 0.061 mL of oxalyl chloride were sequentially added to 0.13 g of 3-phenyl-1H-pyrazole-5-carboxylic acid at room temperature and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 3.0 mL of methylene chloride and 0.45 mL of triethylamine containing 60 mg of tert-butyl 2-amino-4-phenethylbenzoate at room temperature was stirred at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane; ethyl acetate=4.1] to obtain tert-butyl 4-phenethyl-2-(3-phenyl-1H-pyrazole-5-carboxamido)benzoate.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23](Cl)=[O:24])[CH:16]=[N:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:26][O:27][C:28]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][NH3+:45])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)=[O:29].[Cl-]>C(Cl)Cl>[CH3:26][O:27][C:28](=[O:29])[CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][NH:45][C:23]([C:17]3[CH:16]=[N:15][N:14]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:18]=3[C:19]([F:22])([F:21])[F:20])=[O:24])=[CH:40][CH:39]=2)=[CH:36][CH:37]=1
Reactant: O=C(Cl)c1cnn(-c2ccccc2)c1C(F)(F)F
Reactant: COC(=O)COc1ccc(-c2ccc(C[NH3+])cc2)cc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(-c2ccc(CNC(=O)c3cnn(-c4ccccc4)c3C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
Triethylamine (275 μL, 1.97 mmol) was added under nitrogen to a mixture of 1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (272 mg, 0.992 mmol) and 4′-methoxycarbonylmethoxy-biphenyl-4-ylmethyl-ammonium; chloride (304 mg, 0.986 mmol), prepared in the previous step, in 20 mL of methylene chloride at room temperature. The reaction was stirred at room temperature for 6 h. The reaction was extracted with water, 5% NaHCO3, dried (MgSO4) and the solvent removed under reduced pressure to give methyl({4′-[({[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}amino)methyl][1,1′-biphenyl]-4-yl}oxy)acetate (508 mg, 100%) as a white solid, mp 174-176° C. Elemental Analysis for C27H22F3N3O4+0.07 CH2Cl2. Calc'd C, 63.08; H, 4.33; N, 8.15. Found: C, 63.01; H, 4.17; N, 8.16.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][CH2:16][NH:17][C:18](=[O:21])[CH2:19][CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][CH2:16][NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: CCC(=O)NCCc1c[nH]c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc2[nH]cc(CCNC(=O)CC)c2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
Allyl bromide (11 g, 90.8 mmol.) was added, under argon atmosphere, to a mixture of N-[2-(5-hydroxyindol-3-yl)ethyl]propionamide (20.0 g, 92.5 mmol.), cesium carbonate (31.6 g, 97 mmol.) and N,N-dimethylformamide (150 mL) at 0° C. The reaction mixture was stirred for one hour at 50° C., to which was added water. The product was extracted with ethyl acetate. The extract solution was washed with water and dried. The solvent was then distilled off to leave the title compound (yield 20.0 g, 79.4%) as an oily product. This product was used, without further purification, for the subsequent reaction.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[CH2:10][CH2:9][NH:8][C:7](=[O:11])[CH2:6]1)[CH3:4].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br>C1COCC1.O.C(OCC)(=O)C>[CH2:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=2)[C:7](=[O:11])[CH2:6]1)[CH3:4]
Reactant: CCN1CCNC(=O)C1
Reactant: Fc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCN1CCN(Cc2cccc(F)c2)C(=O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
Sodium hydride (60% oil dispersion, 0.176 g) was added to a stirred solution of 4-ethyl-piperazin-2-one (Intermediate 176, 0.512 g) in anhydrous THF (10 mL) and the mixture was stirred at room temperature for 10 minutes. 3-Fluorobenzyl bromide (0.827 g) was added and stirring was continued for 2 hours. The solution was diluted with water and ethyl acetate and the organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-5% to give 4-ethyl-1-(3-fluorobenzyl)piperazin-2-one (0.595 g) as a colourless oil.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)[CH2:4][CH2:3]1>O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH:8]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH2:4][CH2:3]1
Reactant: C[C@H]1CC[C@H](C(=O)NCCc2ccccc2)CC1
Solvent: O
Product: C[C@H]1CC[C@H](C2NCCc3ccccc32)CC1
Temperature: 120 °C

Procedure:
Ethyl polyphosphoric acid (10 mL) was added to trans-4-methyl-N-(2-phenylethyl)cyclohexanecarboxamide (2 g), followed by stirring under heating at 120° C. for 2 hours. Water was added to the reaction liquid which was then extracted with EtOAc. The organic layer was washed with water and saturated brine, and then dried over magnesium sulfate. The solvent was evaporated. To the resulting residue were added EtOH (10 mL) and then sodium borohydride (0.31 g) under ice-cooling, directly followed by stirring for 2 hours. Water was added to the reaction liquid, followed by extraction with EtOAc. The organic layer was washed with water and saturated brine, and then dried over magnesium sulfate. The solvent was evaporated to obtain 1-(trans-4-methylcyclohexyl)-1,2,3,4-tetrahydroisoquinoline (2 g).
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]2[N:23]4[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]4=[N:21][N:20]=2)[CH:15]=[CH:14]3)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:28][C:25]1[CH:26]=[CH:27][C:22]2[N:23]([C:19]([C:16]3[CH:15]=[CH:14][C:13]4[C:18](=[C:9]([O:8][C@H:7]5[CH2:6][CH2:5][NH:4][CH2:3][C@H:2]5[F:1])[CH:10]=[CH:11][CH:12]=4)[N:17]=3)=[N:20][N:21]=2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc3ccc(-c4nnc5ccc(F)cn45)nc23)[C@H](F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2nnc(-c3ccc4cccc(O[C@H]5CCNC[C@H]5F)c4n3)n2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.1 %

Procedure:
(cis)-tert-butyl 3-fluoro-4-(2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)piperidine-1-carboxylate (33 mg, 0.069 mmol) was dissolved in 2 mL DCM at ambient temperature. TFA (2 mL) was added and the mixture stirred at ambient temperature 1 hour. The reaction was evaporated under reduced pressure, and purified by preparative TLC eluting with 1:10 mixture of (0.5% NH4OH in MeOH):DCM to give the product (4.5 mg, 17% yield). MS APCI (+) m/z 382.1 (M+1) detected.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C@:17]3([C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C@H:20]([C:30](O)=[O:31])[NH:19][C@H:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][CH:65]=1>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)#[N:69]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C#N)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 136 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.7 mmol), diphenylphosphinic chloride (0.35 g, 1.1 mmol), then reacted with 4-aminobenzonitrile (Aldrich) (0.13 g, 1.1 mmol) to give chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a off white foam (Yield 0.12 g, 41%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[CH:10]([CH3:20])[C:11]([O:18][CH3:19])=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>CC(C)=O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH:10]([CH3:20])[C:11]([O:18][CH3:19])=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=C(OC)C(C)Br
Reactant: Oc1ccc(O)cc1
Solvent: CC(C)=O
Product: CCOC(=O)C=C(OC)C(C)Oc1ccc(O)cc1

Procedure:
The above 3-oxo ester is reduced using NaBH4 in ethanol to yield ethyl 4-[4-(6,7-dichloro-2-quinoxalyloxy)phenoxy]-3-hydroxypentanoate. Ethyl 4-(4-hydroxyphenoxy)-3-methoxy-2-pentenoate is prepared by the reaction of hydroquinone and ethyl 4-bromo-3-methoxy-2-pentenoate in the presence of base in acetone or the like under reflux.