Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1.CCN(C(C)C)C(C)C.[NH:34]1[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:34]4[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1
Reactant: OCC1CCNC1
Reactant: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CCC(CO)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-cyclohexylmethyl)-amide, DIPEA and pyrrolidin-3-ylmethanol. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.72 (1H), 7.75 (m, 1H), 7.55 (2H), 7.05 (1H), 4.73 (1H), 3.65 (m, 2H), 3.50 (m, 3H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 438 [M+H]
Reaction SMILES: [CH3:1][C:2]([CH3:13])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl[CH2:15][CH2:16][NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]([CH3:13])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:15][CH2:16][NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])=[CH:10][CH:11]=1
Reactant: CC(C)=CCOc1ccc(O)cc1
Reactant: CCOC(=O)NCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)NCCOc1ccc(OCC=C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(3-methyl-2-butenoxy)phenol (1.64 g, 9.2 mmol), ethyl 2-chloroethylcarbamate (1.81 g, 11.9 mmol), and potassium carbonate (2.54 g, 18.4 mmol) in 20 ml of dimethylformamide (DMF) is heated at 85° for 18 hours. The reaction mixture is cooled to room temperature (RT), poured into water and extracted with ether. The combined ether extracts are washed with water until neutral followed with brine and dried over calcium sulfate. The solvent was removed in vacuo and the residue was placed under high vacuum at 80° for ca. 2 hours to remove the excess ethyl 2-chloroethylcarbamate. Purification by preparative thin layer chromotography (prep. TLC) gave ethyl N-{2-[4-(3-methyl-2-butenoxy)phenoxy]ethyl }-carbamate (compound 1, Table A).
Reaction SMILES: [CH2:1]([CH:3]1[NH:7][C:6](=[O:8])[NH:5][CH:4]1[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13](F)=[CH:12][CH:11]=1)[CH3:2].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH2:1]([CH:3]1[CH:4]([C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:12][CH:11]=2)[NH:5][C:6](=[O:8])[NH:7]1)[CH3:2]
Reactant: C1CCNCC1
Reactant: CCC1NC(=O)NC1C(=O)c1ccc(F)cc1
Product: CCC1NC(=O)NC1C(=O)c1ccc(N2CCCCC2)cc1

Procedure:
A suspension of 10 g of 5-ethyl-4-(4-fluorobenzoyl)-2-imidazolidinone in 30 ml piperidine is stirred at reflux for 24 hours. Excess piperidine is evaporated under reduced pressure and the residue is purified by crystallization from alcohol.
Reaction SMILES: [CH3:1][C:2]1([NH:18]C(=O)OC(C)(C)C)[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:4][CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C>>[NH2:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:5]1[CH2:6][CH2:7][CH2:8][C:2]([NH2:18])([CH3:1])[CH2:3][CH2:4]1)=[O:48]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCCC(C)(NC(=O)OC(C)(C)C)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCCC(C)(N)CC1
Yield: 55 %

Procedure:
Following the procedure for Example 101 starting from tert-butyl 4-methyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid gave 411 as a pale brown solid (68 mg, 55% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 7.91 (s, 1H), 7.38-7.25 (m, 1H), 7.02 (t, J=8.7 Hz, 2H), 6.20 (s, 2H), 3.73 (s, 3H), 3.34-3.26 (m, 1H), 3.33-3.08 (m, 2H), 3.17-3.09 (m, 1H), 1.95-1.78 (m, 2H), 1.77-1.66 (m, 4H), 1.19 (s, 3H). Exchangeable NH2 not observed. LCMS (ES+) m/z 462 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2([C:24]([F:27])([F:26])[F:25])[C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:23])[O:11]2)=[O:7])=[CH:4][CH:3]=1.C1N=C[N:32](C(N2C=NC=C2)=O)[CH:31]=1.CN>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][C:10]2([C:24]([F:26])([F:25])[F:27])[C:15]3[CH:16]=[C:17]([C:20]([NH:32][CH3:31])=[O:22])[CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:23])[O:11]2)=[O:7])=[CH:28][CH:29]=1
Reactant: O=C1Nc2ccc(C(=O)O)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2c(c1)C(CNC(=O)c1ccc(F)cc1)(C(F)(F)F)OC(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-{[(4-Fluorobenzoyl)amino]methyl}-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine-6-carboxylic acid (30 mg, 0.073 mmol) and CDI (23.6 mg, 0.15 mmol) were dissolved in THF (230 μL) and DMF (90 μL), and the solution was stirred at room temperature for 30 minutes and thereafter, methylamine (182 μL, 0.36 mmol) was added thereto. The reaction solution was stirred at room temperature for 30 minutes and then diluted with ethyl acetate, which was washed sequentially with water and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography, whereby the objective compound (10.2 mg, 33%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16](C)[C:17](C(C)(C)C)=O)[N:9]=[CH:8][N:7]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[C:6]2=[O:32].C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH3:17])[N:9]=[CH:8][N:7]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:30])[CH3:29])[C:6]2=[O:32]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCN(C)C(=O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CNCCOc1cc2ncn(COC(=O)C(C)(C)C)c(=O)c2cc1OC
Yield: 73.4 %

Procedure:
A solution of 6-methoxy-7-(2-(N-methyl-N-(t-butylcarbonyl)amino)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.39 g, 3 mmol) in methylene chloride (4 ml) and TFA (4 ml) was stirred at ambient temperature for 1 hour. Toluene was added, and the volatiles were removed by evaporation. The residue was triturated with ether and the resulting solid was collected by filtration. The solid was dissolved in water, sodium hydrogen carbonate was added and the aqueous mixture was extracted with methylene chloride. The organic extract was dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether and the solid was collected by filtration to give 6-methoxy-7-(2-(methylamino)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (800 mg, 73%). 1H NMR Spectrum: (DMSOd6; CF3COOD) 1.13(s, 9H); 2.72(s, 3H); 3.45(br s, 2H); 3.95(br s, 3H); 4.5(t, 2H); 5.94(s, 2H); 7.31(s, 1H); 7.6(s, 1H); 8.47(s, 1H) MS-ESI: 364 [MH]+
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[CH:4]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:6]1[C:7]([OH:9])=[N:8][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:4][C:5]=1[OH:10])([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(O)nc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(O)cc(C(F)(F)F)nc1O
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
6-Trifluoromethyl-pyridine-2,4-diol (56 gm, 310 mmol) was added in 3-5 gm portions to conc. sulphuric acid (140 mL) with stirring to give a pale brown solution. The temperature increased to ˜50° C. during the addition. Nitric acid (21.1 mL 328 mmol, 70% HNO3 d=1.4 gm/ml) was added drop wise at such a rate as to maintain a reaction temperature of between 45° and 50° C. which took approximately 90 minutes. Once all the nitric acid had been added the reaction was allowed to cool to ambient temperature over 3 hours. The reaction mixture was then poured into ice/water (˜1.3 kg) with stirring, and after a few minutes a pale yellow precipitate formed which was filtered off, dissolved in ethyl acetate and dried over sodium sulphate, filtered and evaporated. A second crop of material was obtained by extraction of the aqueous filtrate with ethyl acetate. Combined batches and purified by crystallization from ethyl acetate/ n-heptane gave the title compound as a white ‘fluffy’ solid (49.5 gm 71% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9](C)[CH2:10][CH:11]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)[NH:12][C:13]1[C:22]([CH3:23])=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.Cl.[CH2:35]([O:37][C:38](=[O:42])[CH2:39][CH2:40][NH2:41])[CH3:36].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:23][C:22]1[C:13]([NH:12][CH:11]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH:41][CH2:40][CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:42])=[O:29])=[CH:31][CH:32]=2)[CH2:10][CH2:9][CH3:8])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: Cc1cc2ccccc2nc1NC(CC(C)C)c1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCCC(Nc1nc2ccccc2cc1C)c1ccc(C(=O)NCCC(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 66 h

Procedure:
(+/−)-4-(3-methyl-1-((3-methylquinolin-2-yl)amino)butyl)benzoic acid trifluoroacetic acid salt (461 mg, 1.00 mmol), β-alanine ethyl ester hydrochloride (645 mg, 3.99 mmol), and 1-hydroxybenzotriazole hydrate (80%, 20 wt % water, 674 mg, 3.99 mmol) were suspended in dichloromethane (10.0 mL). Triethylamine (1.40 mL, 9.97 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (776 mg, 3.99 mmol) were added, and the solution was stirred at room temperature for 66 hours. The reaction mixture was diluted with dichloromethane (40 mL), washed with water (3×30 mL) and sat. aq NaCl (20 mL), dried over Na2SO4, and filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel flash chromatography (ethyl acetate/heptane) followed by chiral SFC (Chiralpak AD-H column, 10 mm×250 cm, 25% methanol/carbon dioxide eluent, 0.2% isopropylamine modifier) gave ethyl 3-(4-(1-((3-methylquinolin-2-yl)amino)butyl)benzamido)propanoate, isomer 1 (analytical chiral SFC 6.1 min retention) and 3-(4-(1-((3-methylquinolin-2-yl)amino)butyl)benzamido) propanoate as a mixture of methyl and ethyl esters, isomer 2 (analytical chiral SFC 6.7 min retention). Ethyl ester: 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=8.2 Hz, 2 H), 7.66-7.57 (m, 2 H), 7.56-7.48 (m, 3 H), 7.44 (t, J=7.4 Hz, 1 H), 7.16 (t, J=7.4 Hz, 1 H), 6.81-6.73 (m, 1 H), 5.60-5.52 (m, 1 H), 4.73 (d, J=6.8 Hz, 1 H), 4.16 (q, J=7.0 Hz, 2 H), 3.71 (q, J=6.0 Hz, 2 H), 2.62 (t, J=5.9 Hz, 2 H), 2.28 (s, 3 H), 1.93-1.82 (m, 1 H), 1.81-1.70 (m, 1 H), 1.69-1.60 (m, 1 H), 1.26 (t, J=7.1 Hz, 3 H), 1.04 (d, J=6.4 Hz, 3 H), 0.97 (d, J=6.2 Hz, 3 H). Methyl ester: 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=8.2 Hz, 2 H), 7.66-7.57 (m, 2 H), 7.56-7.48 (m, 3 H), 7.44 (t, J=7.4 Hz, 1 H), 7.16 (t, J=7.3 Hz, 1 H), 6.81-6.71 (m, 1 H), 5.60-5.52 (m, 1 H), 4.77-4.69 (m, 1 H), 3.76-3.66 (m, 5 H), 2.66-2.59 (m, 2 H), 2.28 (s, 3 H), 1.93-1.82 (m, 1 H), 1.81-1.70 (m, 1 H), 1.69-1.60 (m, 1 H), 1.04 (d, J=6.4 Hz, 3 H), 0.97 (d, J=6.4 Hz, 3 H).
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]=1[F:18])(=O)C>O1CCOCC1.O>[C:14]([C:10]1[C:9]([F:18])=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][OH:6])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(=O)OCc1cccc(C(C)(C)C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1cccc(CO)c1F
Temperature: 50 °C
Reaction time: 7 h
Yield: 97.3 %

Procedure:
67 g of 8% strength aqueous sodium hydroxide solution are added to a solution of 25 g (0.11 mole) of 3-tert-butyl-2-fluorobenzyl acetate in 100 ml of dioxane and the mixture is stirred for 7 hours at 50° C., diluted with 100 ml of water and extracted three times with dichloromethane. Drying and evaporation give 19.5 g (97%) of 3-tert-butyl-2-fluorobenzyl alcohol.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[H-].[Na+].[CH3:15][CH:16]([OH:18])[CH3:17].O>O1CCCC1>[CH:16]([O:18][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10])([CH3:17])[CH3:15]
Reactant: FC(F)(F)c1cnccc1Cl
Reactant: CC(C)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccncc1C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To a solution of 4-chloro-3-trifluoromethylpyridine hydrochloride salt (2.0 g) in tetrahydrofuran (5 mL) were added sodium hydride (60%, 2.8 g) and propan-2-ol (2.8 g), and the mixture was stirred at 50° C. for 2 hours. After cooling to room temperature, to the reaction mixture was added water, and the resulting mixture was extracted with diethyl ether. The organic layer was dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give 4-isopropoxy-3-trifluoromethylpyridine (1.5 g). To a solution of the obtained compound (1.5 g) in ethyl acetate (20 mL) was added 4-bromomethylbenzoic acid methyl ester (2.0 g) at room temperature, and the mixture was heated under reflux overnight. After cooling to room temperature, the solvent was removed to give 4-isopropoxy-1-(4-methoxycarbonylbenzyl)-3-trifluoromethyl-pyridinium bromide (2.1 g). To a solution of the obtained compound (2.1 g) in dimethoxyethane (10 mL) were added acrylonitrile (1.3 g), manganese dioxide (2.1 g) and triethylamine (1.5 g), and the mixture was stirred at 80° C. for 6 hours. The reaction mixture was filtered through a Celite pad, and filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.04 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.COCCOC(N=NC(OCCOC)=O)=O>C1COCC1.O>[CH2:8]([N:33]1[C:29](=[O:39])[C:30]2[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:32]1=[O:34])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)c2ccccc21
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: OCCc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCc1ccccc1
Reaction time: 2.5 h

Procedure:
After 2-phenylethyl alcohol (300 mg, 2.46 mmol), triphenylphosphine (775 mg, 2.95 mmol), phthalimide (434 mg, 2.95 mmol), and THF (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (697 mg, 2.95 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 2.5 hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using ethyl acetate (10 ml, ×2). Then, the organic layer was washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 30% ethyl acetate-hexane solution) to give 2-phenethyl isoindole-1,3-dione as a white solid substance (579 mg, yield: 94%/2-phenylethyl alcohol).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=C)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:17].[Na+].C(Cl)Cl>O1CCOCC1.O.O=[Os](=O)(=O)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[O:17])=[CH:4][CH:3]=1
Reactant: C=CCn1c(=O)ccc2ccc(F)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: O=CCn1c(=O)ccc2ccc(F)cc21
Temperature: 25 °C
Yield: 54.4 %

Procedure:
A solution of 7-fluoro-1-(2-propen-1-yl)-2(1H)-quinolinone (0.909 g, 4.48 mmol) in 1,4-dioxane (50 ml) and water (30 ml) at 0° C. was treated with sodium periodate (2.20 g, 10.30 mmol) and OsO4 (4% in water, 5 ml). The reaction was warmed to rt and stirred at rt for 1 h before an extra 30 ml of water was added, after another 1 h more sodium periodate (2.20 g, 10.30 mmol) was added and after a further 2 h more sodium periodate (4.20 g, 19.70 mmol) was added. The reaction was then stirred at rt for 0.5 h before evaporation, treatment with water and extraction with DCM (×3). The combined organics were dried and evaporated to give the desired product (0.50 g, 88%). This material contained approximately 10% of the isomeric (5-fluoro-2-oxo-1(2H)-quinolinyl)acetaldehyde.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([NH:14][C:15](=[O:38])[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]([C:28](=[O:36])[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:18]=2[CH3:37])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:11]1([NH:14][C:15](=[O:38])[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]([C:28](=[O:36])[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:18]=2[CH3:37])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccc2c(c1)c(CC(=O)NN1CCN(C(=O)OC(C)(C)C)CC1)c(C)n2C(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)c(CC(=O)NN1CCNCC1)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
To a solution of 0.300 g (0.57 mmol) of N-(4-t-butoxycarbonylpiperazin-1-yl)-1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetamide in 8 mL of anhydrous dichloromethane was added 1.7 mL of trifluoroacetic acid (TFA). The reaction was stirred at room temperature for 1.75 hr then evaporated to dryness, diluted with more dichloromethane (20 mL) and re-evaporated. Residual TFA was removed with a sodium carbonate wash to give the title compound. 1H NMR (CDCl3) δ 7.58 (2H, d), 7.41 (2H, d), 6.93 (1H, d), 6.73 (1H, d), 6.60 (1H, dd), 3.75 (3H, s), 3.64 (2H, s), 3.57 (2H, m), 3.42 (2H, m), 2.75 (2H, m), 2.67 (2H, m), 2.32 (3H, s). Mass Spectrum m/e 426/428 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH3:20])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[C@@H:10]([CH2:22][CH2:23][CH3:24])[CH2:11][C:12](=[O:21])[CH2:13]4.[N:25]#CBr>>[C:20]([N:19]1[CH2:18][CH2:17][C@@:14]23[C:15]4[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[CH2:7][C@@H:8]1[C@@H:9]2[C@@H:10]([CH2:22][CH2:23][CH3:24])[CH2:11][C:12](=[O:21])[CH2:13]3)#[N:25]
Reactant: CCC[C@H]1CC(=O)C[C@]23CCN(C)[C@H](Cc4ccc(OC)cc42)[C@H]13
Reactant: N#CBr
Product: CCC[C@H]1CC(=O)C[C@]23CCN(C#N)[C@H](Cc4ccc(OC)cc42)[C@H]13
Yield: 97 %

Procedure:
To a rapidly stirred solution of 3-methoxy-17-methyl-8β-n-propylmorphinan-6-one (prepared in Part A) was added cyanogen bromide as in Example 1B. The product was obtained as a syrup, 97% yield, and was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH3:11].C1N2CN3CN(C2)CN1C3.[C:22]([O-])(O)=[O:23].[Na+]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([CH:22]=[O:23])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1ccc(OC)c(Cl)c1
Reactant: O=C([O-])O
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C=O)c(OC)cc1Cl
Temperature: 95 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
(Wright et al., J. Am. Chem. Soc. 2008, 130, 16786-16790; Bloomer et al., J. Org. Chem. 1993, 58, 7906-7912.) To a stirred solution of 2-chloro-1,4-dimethoxybenzene (25.0 g, 0.145 mol, 1 equiv) and hexamethylene tetramine (20.5 g, 0.145 mol, 1 equiv) at room temperature was carefully added TFA (250 mL). The resulting yellow suspension was heated to 95° C. and allowed to stir for 5 h. After 5 h, the hot brown solution was poured into a 2 L Erlenmeyer flask containing approximately 250 g of crushed ice. To the vigorously stirred mixture was added solid NaHCO3 (243 g, 2.90 mol, 20 equiv) cautiously in 5-10 g portions over two hours. The resulting yellow precipitate was filtered through Celite, washed with water, and dissolved in Et2O. The organic layer was washed with water, brine, dried (MgSO4), filtered, and concentrated under reduced pressure to yield 29.0 g (100% yield) of the desired product as an off-white solid: Mp 109-109° C.; Rf 0.70 (EtOAc/hexanes, 3:7); IR (neat) 2941, 2874, 1664, 1601, 1575, 1497, 1478, 1461, 1389, 1269, 1213, 1023, 977 cm−1; 1H NMR (400 MHz, CDCl3) δ 10.35 (s, 1 H), 7.33 (s, 1 H), 3.87 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 188.4, 156.1, 149.4, 130.4, 123.4, 114.5, 109.9, 56.5, 56.3; HRMS (EI+) m/z calcd for C9H9O3Cl 200.0240, found 200.02377. Characterization matches that reported by Bloomer et al. (J. Org. Chem. 1993, 58, 7906-7912.)
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)([O-:3])=[O:2].Cl.[NH2:15]O.C(O)C.[OH-].[Na+]>CO>[NH2:15][C:11]1[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[C:5]2[C:10]=1[CH:9]=[N:8][CH:7]=[CH:6]2
Reactant: NO
Reactant: O=[N+]([O-])c1cccc2cnccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: Nc1ccc([N+](=O)[O-])c2ccncc12
Temperature: 0 °C
Yield: 57.5 %

Procedure:
To 5-nitroisoquinoline (2.0 g) were added hydroxylamine hydrochloride (5.0 g) and ethanol (120 ml). A solution of sodium hydroxide (10 g) in methanol (65 ml) was slowly added at 50° C. over 90 min. The reaction mixture was poured into ice water (700 g) and the resulting precipitate was collected by filtration. The residue was washed with ethanol and dried under reduced pressure to give 8-amino-5-nitroisoquinoline (1.25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]3[CH:33]=[CH:32][C:31]([C:34]([OH:36])=O)=[CH:30][C:14]=3[C:15]=2[NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH2:21][CH2:20]2)=[O:18])=[O:10])=[N:6][CH:7]=1.Cl.[CH3:38][NH:39][CH3:40].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]3[CH:33]=[CH:32][C:31]([C:34]([N:39]([CH3:40])[CH3:38])=[O:36])=[CH:30][C:14]=3[C:15]=2[NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]([N:27]([CH3:28])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[O:18])=[O:10])=[N:6][CH:7]=1
Reactant: CN(C)C(=O)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(C(=O)O)cc23)CC1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](C(=O)N(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2-{[(5-Chloropyridin-2-yl)amino]carbonyl}-3-[({trans-4-[(dimethylamino)carbonyl]cyclohexyl}carbonyl)amino]-benzofuran-5-carboxylic acid (200 mg) obtained in Example 5 is suspended in chloroform-pyridine (1:3) (8 ml), and thereto are added successively dimethylamine hydrochloride (64 mg), 1-hydroxybenzotriazol (79 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (112 mg) under ice-cooling. The mixture is then stirred at room temperature for 17 hours. To the reaction solution is poured a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is washed with saturated brine and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the resulting residue is suspended in ethanol-diethyl ether. The precipitates are collected by filtration and dried to give the title compound (176 mg).