Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11][CH2:12][C:13]2[N:14](CC)[N:15]=[CH:16][N:17]=2)=[N:9][N:8]2[C:20]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=3[F:31])=[N:21][N:22]=[C:7]2[CH:6]=1)([CH3:4])[CH3:3].[CH3:32]N1C=NC(CO)=N1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:3][C:2]([C:5]1[C:10]([O:11][CH2:12][C:13]2[N:17]=[CH:16][N:15]([CH3:32])[N:14]=2)=[N:9][N:8]2[C:20]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=3[F:31])=[N:21][N:22]=[C:7]2[CH:6]=1)([CH3:1])[CH3:4]
Reactant: Cn1cnc(CO)n1
Reactant: CCn1ncnc1COc1nn2c(-c3c(F)ccc(F)c3F)nnc2cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cn1cnc(COc2nn3c(-c4c(F)ccc(F)c4F)nnc3cc2C(C)(C)C)n1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To the product of Example 4 Step a) (0.559 g) and (1-methyl-1H-1,2,4-triazol-3-yl)methanol (prepared as described in EP-A-421210) (0.20 g) in dry dimethylsulfoxide (2 ml) was added caesium carbonate (0.67 g), and the mixture stirred at 60° C. under an atmosphere of dry nitrogen for 48 hours. On cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic phase was separated, washed with water, evaporated at reduced pressure, and the residue chromatographed on silica gel (eluent 2% methanol-dichloromethane). The product was crystallised from ethyl acetate/diethyl ether, to afford the title compound as a colourless solid. 1H NMR (400 MHz, DMSO-d6) δ1.39 (9H, s), 3.85 (3H, s), 5.30 (2H, s), 7.46 (1H, m), 7.86 (1H, m), 8.14 (1H, s) 8.46 (1H, s); MS (ES+) m/z 418 [MH]+.
Reaction SMILES: [Mg].II.Br[CH:5]([CH2:7][CH2:8][CH3:9])[CH3:6].[CH2:10]([N:17]1[CH2:21][CH:20]([CH2:22]I)[CH2:19][C:18]1=[O:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([N:17]1[CH2:21][CH:20]([CH2:22][CH:5]([CH3:6])[CH2:7][CH2:8][CH3:9])[CH2:19][C:18]1=[O:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CC(CI)CN1Cc1ccccc1
Reactant: CCCC(C)Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC(C)CC1CC(=O)N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To a suspension of magnesium turnings (0.50 g, 0.021 mol) in 15 mL of dry THF under nitrogen, was added an iodine crystal and 2-bromopentane (2.88 g, 0.019 mol). After an exothermic reaction which was periodically cooled in an ice bath, the reaction was stirred at room temperature for 2 hours. Eight milliliters of Li2CuCl4 (made from 84 mg LiCl and 134 mg CuCl2 in 10 mL of dry THF) was added at 0° C. followed by dropwise addition of 1-Benzyl-4-iodomethyl-pyrolidine-2-one 75 in 15 mL dry THF, and the resulting suspension was let stir at 0° C. for 3 hours. Stirring was continued at room temperature for 1 hour before quenching with a saturated solution of ammonium chloride. Water was added to dissolve the precipitate formed, and the solution was then extracted with ether and dried over magnesium sulfate. The solvent was evaporated under vacuum and the residue chromatographed on silica eluting with 1:1 acetone/hexane to give 1.13 g, 69% of the 1-benzyl-4-(2-methyl-pentyl)-pyrrolidin-2-one 76. 1H NMR (CDCl3) δ 7.30 (m, 5H), 4.44 (m, 2H), 3.32 (m, 1H), 2.86 (m, 1H), 2.56 (m, 1H), 2.40 (m, 1H), 2.10 (m, 1H), 1.30 (m, 6H), 1.10 (m, 1H), 0.90 (m, 6H). MS, m/z (relative intensity): 261 [M+2H, 100%], 301 [M−H+CH3CN, 82%], 260 [M+H, 72%].
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:9][OH:10])(C)(C)C.[CH:19]1([CH2:25]O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:15]([O:14][C:12](=[O:13])[NH:11][CH:8]1[CH2:7][C:6](=[O:5])[O:18][CH:9]1[O:10][CH2:25][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH:16]=[CH2:17]
Reactant: OCC1CCCCC1
Reactant: C=CCOC(=O)NC(CO)CC(=O)OC(C)(C)C
Product: C=CCOC(=O)NC1CC(=O)OC1OCC1CCCCC1
Yield: 35 %

Procedure:
Prepared from 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester as described for 40 using cyclohexylmethanol to afford 1.04 g (higher RF) (35% yield) of anti diastereomer of the title compound and 1.295 g (lower Rf) (44% yield) of syn diastereomer. 1H-NMR (500 MHz, CDCl3) for anti diastereomer: δ 0.90-0.96 (m, 2H), 1.10-1.30 (m, 3H), 1.55-1.85 (m, 6H), 2.37-2.41 (d, H), 2.97-3.03 (m, H), 3.34-3.38 (m, H), 3.58-3.62 (m, H), 4.55-4.70 (m, 2H), 4.70-4.73 (m, H), 5.03 (bs, H), 5.22-5.37 (m, 3H), 5.87-5.93 (m, H); for syn diastereomer 0.91-0.97 (m, 2H), 1.10-1.31 (m, 3H), 1.56-1.90 (m, 7H), 2.44-2.48 (m, H), 2.81-2.87 (m, H), 3.35-3.39 (m, H), 3.63-3.67 (m, H), 4.53-4.70 (m, 3H), 5.20-5.50 (m, 3H), 5.89-5.95 (m, H); LC-MS: m/z=298 (M+H+) for both of diastereomers.
Reaction SMILES: Cl.[C:2]([C:4]1[C:5]([CH2:30][CH3:31])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH:28]=[O:29])=[C:20]([CH:23](OC)[O:24]C)[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3].C([O-])(O)=O.[Na+]>C1COCC1.O>[C:2]([C:4]1[C:5]([CH2:30][CH3:31])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH:28]=[O:29])=[C:20]([CH:23]=[O:24])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3]
Reactant: CCc1cc(NC(=O)N2CCCc3cc(C=O)c(C(OC)OC)nc32)ncc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(NC(=O)N2CCCc3cc(C=O)c(C=O)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Concentrated hydrochloric acid (0.10 ml) was added to a solution of N-(5-cyano-4-ethylpyridin-2-yl)-7-(dimethoxymethyl)-6-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 110, 50 mg, 0.122 mmol) in THF (4 ml) and water (0.5 ml) at room temperature. After stirring for 3 h additional concentrated hydrochloric acid (0.10 ml) was added and the reaction mixture stirred for a further 48 h at room temperature. Saturated aqueous NaHCO3 was added, the mixture extracted with DCM (2×), the organic layers dried over Na2SO4 and evaporated to give the title compound as a beige solid. (UPLC-MS 6) tR 1.13 min, ESI-MS 364.2, [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:42])[N:10]2[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([N:23](C(OC(C)(C)C)=O)[CH2:24][C:25]2[CH:34]=[CH:33][C:28]3[O:29][CH2:30][CH2:31][O:32][C:27]=3[CH:26]=2)[CH2:19][CH2:18]1.[ClH:44].O1CCOCC1>O1CCOCC1>[ClH:44].[CH3:1][O:2][C:3](=[O:43])[NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:42])[N:10]2[CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][CH:20]([NH:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]3[O:29][CH2:30][CH2:31][O:32][C:27]=3[CH:26]=2)[CH2:21][CH2:22]1
Reactant: COC(=O)Nc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Nc1cccc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 35 mg of N-(1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yl)carbamic acid methyl ester, 2 mL of 1,4-dioxane and 0.8 mL of 4 mol/L hydrogen chloride/1,4-dioxane were added, and stirred at room temperature for 3 hours. The resulting solid was filtered to give 23 mg of N-(1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yl)carbamic acid methyl ester hydrochloride as a yellow solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].CC1(C)C(C)(C)OB([C:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14]
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(O)c1oc(=O)c2ccccc2c1C1=CCN(C(=O)OC(C)(C)C)CC1
Yield: 17.8 %

Procedure:
The title compound was made in a similar way as that of the intermediate B1 using 4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (intermediate A2, 0.55 g, 2.04 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.79 g, 2.55 mmol), Pd(PPh3)4 (118 mg, 0.102 mmol) and Cs2CO3 (1.0 g, 3.27 mmol) to afford the title compound (0.135 g, 18%) as a yellowish oil.
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][C:17]([O:19]C)=O)=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[NH2:21]/[C:22](/[C:29]([F:32])([F:31])[F:30])=[CH:23]\[C:24]([O:26]CC)=O.[H-].[Na+].[N+:35](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O.O>[NH2:35][N:21]1[C:22]([C:29]([F:30])([F:31])[F:32])=[CH:23][C:24](=[O:26])[N:16]([C:15]2[C:2]([F:1])=[CH:3][C:4]3[O:9][CH2:8][C:7](=[O:10])[N:6]([CH2:11][C:12]#[CH:13])[C:5]=3[CH:14]=2)[C:17]1=[O:19]
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C#CCN1C(=O)COc2cc(F)c(NC(=O)OC)cc21
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN1C(=O)COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(N)c3=O)cc21

Procedure:
A mixture of 7-fluoro-6-methoxycarbonylamino-4-propargyl-2H-1,4-benzoxazin-3(4H)-one (1.4 g) and ethyl 3-amino-4,4,4-trifluorocrotonate was dissolved in dimethylformamide (5 g), and sodium hydride (0.2 g) was added thereto. The resultant mixture was stirred for 30 minutes while cooling with ice and heated under reflux for 3 hours. After cooling, 2,4-dinitrophenoxyamine (1.2 g) was added thereto, and the resultant mixture was stirred at 40° C. for 3 hours. After completion of the reaction, the reaction mixture was combined with water, extracted with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-amino-1-[7-fluoro-4-propargyl-2H-1,4-benzoxazin-3(4H)-on-6yl]-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione (0.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>C(O)C>[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:10][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH3:9])=[CH:14][CH:13]=1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: O=Cc1ccc(O)cc1
Solvent: CCO
Product: CC(N=Cc1ccc(O)cc1)c1ccc(Br)cc1
Yield: 100 %

Procedure:
4.44 g (0.0222 mole) of (R)-(+)-1-(p-bromophenyl)ethylamine and 2.85 g (0.0233 mole) of p-hydroxybenzaldehyde were dissolved in 30 ml of ethyl alcohol, and the solution thus formed was stirred under reflux for 3 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and refined by a column chromatography using 30 g of silica gel to give 6.75 g of (-)-N-(p-hydroxybenzylidene)-1-(p-bromophenyl)ethylamine. Yield: 97.9%. m.p. 156°-161° C.; α!D25 -87.6° (C 0.7, CHCl3) NMR-spectral data (δ ppm, DMSO-d6) 1.48 (d) 3H; 4.34 (q) 1H; 6.75-7.9 (m) 9H;
Reaction SMILES: Cl.[CH2:2]([NH2:6])[CH2:3][CH:4]=[CH2:5].C([O-])(=O)C.[Na+].Br[C:13]1[C:14]([NH:16][C:17](=[O:19])[CH:18]=1)=[O:15]>CO>[CH2:2]([NH:6][C:13]1[C:14]([NH:16][C:17](=[O:19])[CH:18]=1)=[O:15])[CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCN
Reactant: O=C1C=C(Br)C(=O)N1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCCNC1=CC(=O)NC1=O
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To 3-butenylamine hydrochloride (200 mg, 1.12 mmol) and sodium acetate (184 mg, 2.24 mmol) in methanol (15 mL) was added bromomaleimide (200 mg, 1.12 mmol) dropwise in methanol (15 mL). After 10 minutes, solvent was removed in vacuo and purification by flash chromatography (10% ethyl acetate in petroleum ether) afforded the desired compound as a bright yellow waxy solid (142 mg, 0.85 mmol) in 76% yield. δH (500 MHz, CDCl3) 7.10 (s, 1H, NH), 5.77 (tdd, 1H, J=6.9, 10.7 and 17.4, H-2), 5.38 (s, 1H, NH), 5.18-5.15 (m, 2H, H2-1), 4.83 (d, 1H, J=1.3, H-6), 3.24 (t, 2H, J=6.7, H2-4), 2.40 (dtd, 2H, J=1.2, 6.8 and 6.9, H2-3); δC (125 MHz, CDCl3) 171.94 (C═O), 167.45 (C═O), 149.53 (C5), 133.89 (C2), 118.51 (C1), 85.80 (C6), 43.30 (C4), 32.68 (C3); IR (solid, cm−1) 3290 (m), 1703 (m), 1629 (s); MS (ES−) m/z (relative intensity): 165 ([M−H], 100); Exact Mass Calcd for [C8H10N2O2]−H requires m/z 165.0659 Found 165.0664 (ES−); m.p. 68-76° C.; UV (Acetonitrile) ε241=8300 and ε348=6100 cm−1M−1 d3.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[NH2:24][CH:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26]1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:24][CH:25]3[CH2:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26]3)=[O:18])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: NC1Cc2ccccc2C1
Product: O=C(NC1Cc2ccccc2C1)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid was coupled with 2-aminoindane as in EXAMPLE 1, Part C. HPLC: RT=10.24 min. MS (ESI−): mass calcd. for C22H17ClN4O3S2, 484.04; m/z found, 483 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.64 (s, 1H), 8.37 (dd, J=7.0, 1.0, 1H), 8.23 (dd, J=8.8, 1.0, 1H), 7.72 (dd, J=8.8, 7.0, 1H), 7.72 (d, J=2.0, 1H), 7.28-7.19 (m, 4H), 7.14 (d, J=8.4, 1H), 6.89 (dd, J=8.4, 2.0, 1H), 6.12 (br d, J=7.5, 1H), 4.87-4.80 (m, 1H), 3.41 (dd, J=16.3, 7.0, 2H), 2.83 (dd, J=16.3, 3.9, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12]C(=O)OC(C)(C)C)[CH2:8]2)=[CH:4][CH:3]=1.Cl>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([NH2:12])[CH2:8]2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(CN2CC[C@@H](NC(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(CN2CC[C@@H](N)C2)cc1
Reaction time: 3 h
Yield: 69.7 %

Procedure:
To a stirred solution of tert-butyl [(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]carbamate (4.6 g) in ethyl acetate (10 mL) was added 4N hydrogen chloride in ethyl acetate (60 mL) at ambient temperature and the resulting mixture was stirred at the same temperature for three hours. The mixture was concentrated in vacuo and the residual syrup was dissolved in chloroform (100 mL). To this solution was added saturated sodium bicarbonate (50 mL) and the resulting biphasic mixture was vigorously stirred at ambient temperature for half an hour. The organic layer was separated and the aqueous layer was reextracted with chloroform (50 mL) two times. The combined organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to afford (3R)-1-(4-methylbenzyl)-3-pyrrolidinamine (2.1 g) as a pale brown viscous oil, which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[NH:12][CH:11]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:10]3[CH2:22][CH2:23][CH2:24][O:25][CH:9]3[C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>>[CH:16]1([CH:11]2[CH:10]3[CH2:22][CH2:23][CH2:24][O:25][CH:9]3[C:8]3[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:15]=[CH:14][C:13]=3[NH:12]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1ccc2c(c1)C1OCCCC1C(C1CCCCC1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc2c(c1)C1OCCCC1C(C1CCCCC1)N2
Temperature: 65 °C
Yield: 69.1 %

Procedure:
To (4aSR*,5SR*,10bSR*)-ethyl-5-cyclohexyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline-9-carboxylate (Base of example 10, obtained according to example 1 procedure) (145 mg, 0.422 mmol) was added a 0.5 NaOH solution (6 mL, in MeOH/H2O 1:1) and the reaction mixture heated at 65° C. for 24 h. After cooling back to r.t., the reaction mixture was neutralized with 10% HCl solution. The product was extracted with AcOEt twice. The combined organic fractions were dried over Na2SO4 and the solvent removed under reduced pressure after filtration to afford (4aSR*,5SR*,10bSR*)-5-cyclohexyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline-9-carboxylic acid (92 mg, 69%).
Reaction SMILES: C([O:3][C:4](=[O:31])[C@H:5]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[NH:6][C:7](=[O:22])[C:8]([NH:11][C:12](=[O:21])[C@@H:13]([S:17]C(=O)C)[CH:14]([CH3:16])[CH3:15])([CH3:10])[CH3:9])C.[OH-].[Na+]>CO>[SH:17][C@@H:13]([CH:14]([CH3:16])[CH3:15])[C:12]([NH:11][C:8]([CH3:9])([CH3:10])[C:7]([NH:6][C@H:5]([C:4]([OH:31])=[O:3])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1)=[O:22])=[O:21]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C(C)(C)NC(=O)[C@@H](SC(C)=O)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H](S)C(=O)NC(C)(C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reaction time: 5 h

Procedure:
To a solution of N-[2-(2(S)-acetylthio-3-methyl-1-oxobutylamino)-2-methyl-1-oxopropyl]-L-tyrosine ethyl ester (0.18 g, 0.39 mmol) in methanol (10 mL) is added 1N sodium hydroxide (1.55 mL, 1.55 mmol). The mixture is stirred for 5 hours and then the solvent is removed in vacuo. The residue is dissolved in water (50 mL) and washed with ethyl acetate (10 mL). The aqueous phase is acidified to pH 1 with 1N hydrochloric acid and extracted with ethyl acetate (3×50 mL). The organic phase is washed with brine, dried over magnesium sulfate and the solvent is concentrated to yield a clear oil which is crystallized from ethyl ether to give N-[2-(2(S)-mercapto-3-methyl-1-oxobutylamino)-2-methyl-1-oxopropyl]-L-tyrosine, m.p. 180°-181° C., the compound of formula II wherein R1 is 4-hydroxyphenyl, R2 and R3 are hydrogen, R4 is isopropyl, and R6 and R7 are methyl.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25].C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: O=C(O)c1ccccn1
Reactant: Nc1ccccc1F
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1F)c1ccccn1
Yield: 67.4 %

Procedure:
Picolinic acid (10.0 g, 81 mmol) was added to a solution of 1,1'-carbonyldiimidazole (13.18 g, 81 mmol) in anhydrous dimethylformamide (80 mL), followed by the addition of 2-fluoroaniline (8.6 mL, 89 mmol) 1 hour later. The reaction mixture was poured into saturated sodium bicarbonate solution (900 mL) after 26 hours, and extracted with ether (3×400 mL). The dried organic material was concentrated in vacuo and recrystallized from a mixture of ether and petroleum ether to yield N-(2-fluorophenyl)-2-pyridinecarboxamide as a white solid (11.81 g) m.p. 112°-115° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[F:22])[C:16](Cl)=[O:17]>>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[F:22])[C:16]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)=[O:17]
Reactant: O=C(Cl)c1ccc(F)c(Br)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(F)c(Br)c1

Procedure:
3-Bromo-4-fluoro-N-(3-(trifluoromethyl)phenyl)benzamide was synthesized from 3-trifluoromethylaniline and 3-bromo-4-fluorobenzoyl chloride according to the procedure described in Example 183, affording the title compound as a white solid. MS (M−H+) 360.0; Calculated for C14H8BrF4NO: 361.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][OH:17])=[O:10])[CH2:5][CH2:4]1.O[C:21]1[C:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:23][CH:24]=[CH:25][CH:26]=1.ClC1C=C(O)C=NC=1>>[F:19][C:2]([F:1])([F:18])[C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][O:17][C:21]2[C:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:10])[CH2:7][CH2:8]1
Reactant: O=C([C@H]1CC[C@H](C(F)(F)F)CC1)N1CCC[C@H]1CO
Reactant: CCOC(=O)c1ncccc1O
Agent: Oc1cncc(Cl)c1
Product: CCOC(=O)c1ncccc1OC[C@@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 29 using [(2S)-1-{[trans-4-(trifluoromethyl)cyclohexyl]carbonyl}pyrrolidin-2-yl]methanol (EXAMPLE 60 Step 1) and ethyl 3-hydroxypicolinate instead of (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate and 5-chloropyridin-3-ol.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[NH:24]1[CH2:25][CH2:26][CH2:27][C@H:23]1[CH2:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N(C[C@@H]2CCCN2)c2ccccc2C12COc1cc3c(cc12)CCO3
Yield: 88 %

Procedure:
A solution of tert-butyl (2S)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]pyrrolidine-1-carboxylate (0.74 g, 1.60 mmol) and trifluoroacetic acid (1.6 mL) in dichloromethane (8 mL) was stirred at ambient temperature for 80 h. The reaction was made basic with 1 M sodium hydroxide (30 mL) and was extracted with dichloromethane (3×25 mL). The combined organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 1′-[(2S)-pyrrolidin-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.51 g, 89%) as a pale yellow solid: mp 83-86° C. (hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ 7.29 (dd, J=7.8, 7.5 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.07-6.99 (m, 2H), 6.52, 6.46 (s, 1H), 6.40 (s, 1H), 4.95, 4.91 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.53 (t, J=8.7 Hz, 2H), 3.91-3.71 (m, 2H), 3.69-3.60 (m, 1H), 3.14-2.90 (m, 5H), 1.98-1.70 (m, 3H), 1.66-1.51 (m, 1H); MS (ES+) m/z 363.1 (M+1).
Reaction SMILES: COC1C=CC(C2N(C)C3C(C=2)=CC=C(OC)C=3)=C(N)C=1.BrC1C=CC(OCCN2CCCCC2)=C(F)C=1.[F:39][C:40]1[CH:41]=[C:42]([NH:55][C:56]2[CH:61]=[C:60]([O:62]C)[CH:59]=[CH:58][C:57]=2[C:64]2[N:65]([CH3:75])[C:66]3[C:71]([CH:72]=2)=[CH:70][CH:69]=[C:68]([O:73]C)[CH:67]=3)[CH:43]=[CH:44][C:45]=1[O:46][CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1>>[F:39][C:40]1[CH:41]=[C:42]([NH:55][C:56]2[CH:61]=[C:60]([OH:62])[CH:59]=[CH:58][C:57]=2[C:64]2[N:65]([CH3:75])[C:66]3[C:71]([CH:72]=2)=[CH:70][CH:69]=[C:68]([OH:73])[CH:67]=3)[CH:43]=[CH:44][C:45]=1[O:46][CH2:47][CH2:48][N:49]1[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3n2C)c(Nc2ccc(OCCN3CCCCC3)c(F)c2)c1
Agent: COc1ccc(-c2cc3ccc(OC)cc3n2C)c(N)c1
Agent: Fc1cc(Br)ccc1OCCN1CCCCC1
Product: Cn1c(-c2ccc(O)cc2Nc2ccc(OCCN3CCCCC3)c(F)c2)cc2ccc(O)cc21
Yield: 44.1 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1-methyl-1H-indol-2-yl)phenylamine and 1-[2-(4-bromo-2-fluorophenoxy)ethyl]piperidine according to an analogous synthetic method to Example 116, [3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl][5-methoxy-2-(6-methoxy-1-methyl-1H-indol-2-yl)phenyl]amine (60 mg) was used according to an analogous synthetic method to Example 364 described below to provide the title compound (25 mg).