Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:23](=[O:27])[C:24]([NH2:26])=[O:25])=[C:9]([CH3:22])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].CCOC(C)=O>CO>[NH2:26][C:24](=[O:25])[C:23]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:28])=[O:2])[N:10]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:9]=1[CH3:22])=[O:27]
Reactant: COC(=O)COc1cccc2c1c(C(=O)C(N)=O)c(C)n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
A mixture of 660 mg (1.7 mmol) of [[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester and 10 mL of 1N NaOH in 30 mL of methanol was heated to maintain reflux for 1 hour, cooled to room temperature and stirred for 0.5 hour. The mixture was concentrated at reduced pressure and the residue taken up in EtOAc/water. The aqueous layer was separated, made acidic to pH 2-3 with 1N HCl and extracted with EtOAc. On concentrating the EtOAc solution, 431 mg (69% yield) of [[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid crystallized, melting at 218-220° C.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH3:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12](C)[C:13](O)=O)(=[O:4])=[O:3].C1C=CC(OP(OC2C=CC=CC=2)([N:27]=[N+]=[N-])=O)=CC=1.C(N(CC)CC)C.Cl.C(O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:27][CH:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]([CH3:17])[S:2]([CH3:1])(=[O:4])=[O:3])[CH3:13]
Reactant: CC(C(=O)O)c1ccccc1N(C)S(C)(=O)=O
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CC(N)c1ccccc1N(C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
197 f) To a solution of 2-[2-(methanesulfonyl-methyl-amino)-phenyl]-propionic acid (0.755 g, 2.93 mmol) and diphenylphosphonic azide (0.95 mL, 4.4 mmol) in dichloromethane (25 mL) was added triethylamine (0.65 mL, 4.7 mmol). The mixture was stirred at room temperature for 24 hours then cooled to 5° C. and 2N Hydrochloric acid (30 mL) was added and the mixture stirred for 10 minutes. The layers were separated and the aqueous was washed with dichloromethane (2×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue dissolved in tert-butyl alcohol (10 mL, 100 mmol) and heated at 80° C. for 18 hours. The volatiles were evaporated and the residue was dissolved in ethyl acetate (50 mL). The organic layer was washed with saturated aqueous sodium carbonate (30 mL), dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2 mL, 20 mmol) was added. The mixture was stirred at room temperature overnight. The volatiles were evaporated. The residue was dissolved in ethyl acetate (50 mL) and was extracted with 2N Hydrochloric acid (3×20 mL). The combined acidic aqueous layers were basified with 2M sodium hydroxide to pH 10. The basic aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. N-[2-(1-Amino-ethyl)-phenyl]-N-methyl-methanesulfonamide was isolated as a crude tan viscous oil (0.380 g, 56%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH2:16])[C:5]2[N:6]([N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:7]=1.[CH2:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:18][CH2:19][C:20]#[CH:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCOC(C)=O.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.[Cu]I>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[N:10]=[C:5]2[C:4]([NH2:16])=[N:3][C:2]([C:21]#[C:20][CH2:19][CH2:18][CH2:17][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:7][N:6]2[N:8]=1
Reactant: Nc1nc(Br)cn2nc(-c3ccco3)nc12
Reactant: C#CCCCc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1nc(C#CCCCc2ccccc2)cn2nc(-c3ccco3)nc12
Yield: 40.8 %

Procedure:
A solution of 6-bromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine (56 mg, 0.2 mmol; see Examples 1 and 2 above), pent-4-ynyl-benzene (44 mg, 0.3 mmol), Pd(PPh3)4 (26 mg, 0.03 mmol), CuI (4 mg, 0.03 mmol), PPh3 (8 mg, 0.03 mmol), and TEA (11 μL, 2.5 mmol) in DMF (5 mL) was heated (at around 105° C.) under N2 for 2 hours. The reaction was diluted with EtOAc (15 mL) and washed with brine (3×10 mL) and dried with MgSO4. The solvent was removed and the reaction purified by HPLC (C18, H2O:MeCN gradient) to afford the product as a brown solid (28 mg,). 1H NMR (400 MHz, DMSO-d6) δ 1.85 (quin, J=7.5 Hz, 2H) 2.44 (t, J 7.1 Hz, 2H), 2.74 (t, J=7.8 Hz, 2H), 6.72 (dd, J=3.4, 1.8 Hz, 1H), 7.14 (dd, J=3.5, 0.8 Hz, 1H), 7.2-7.30 (br m, 5H), 7.92 (dd, J=1.7, 0.8 Hz, 1H), 8.35 (s, 1H). MS: m/z 344 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14](=[O:29])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][Mg]Cl>C1COCC1>[F:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C@:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)([OH:29])[CH2:35][CH2:34][CH2:33][CH2:32][O:31][CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2Oc2cccc(F)c2)C1
Reactant: COCCCC[Mg]Cl
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1ccccc1Oc1cccc(F)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 43 %

Procedure:
To a solution of (3R)-1-(tert-butoxycarbonyl)-3-((3-fluorophenoxy)benzoyl)piperidine (0.95 g, 2.37 mmol) in THF (3 mL) at −20° C. was added 1.45 M 4-methoxybutyl magnesium chloride in THF (3.3 mL, 4.76 mmol) dropwise. The resulting solution was warmed to rt slowly, and the completion of reaction was confirmed by LC-MS (˜20 min). The reaction was quenched with sat'd aq NH4Cl (4 mL) and extracted with Et2O (4×5 mL). The combined organic layers were washed with water and brine, and the solvent was removed in vacuo to give a crude product which was purified by flash column chromatography to afford (R)-tert-butyl 3-((S)-1-(2-(3-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (0.50 g, 43%).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C:12]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][C:12]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CCOC(=O)C1(CCCOCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(CCCO)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 4 h
Yield: 109.3 %

Procedure:
To a solution of 2.0 g of 1-tert-butyl 4-ethyl 4-(3-(benzyloxy)propyl)piperidine-1,4-dicarboxylate in 20 mL of ethanol, a suspension of 0.30 g of 10% palladium carbon in 2 mL of ethanol was added, and the mixture was stirred for 4 hours under a hydrogen atmosphere. The insoluble substance was filtered off, and the solvent was distilled off under reduced pressure to obtain 1.7 g of 1-tert-butyl 4-ethyl 4-(3-hydroxypropyl)piperidine-1,4-dicarboxylate as a colorless oily substance.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[CH:34]=[C:35]([C:49]2([OH:53])[CH2:52][O:51][CH2:50]2)[CH:36]=[C:37]([F:48])[C:38]=1B1OC(C)(C)C(C)(C)O1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:38]3[C:33]([F:32])=[CH:34][C:35]([C:49]4([OH:53])[CH2:50][O:51][CH2:52]4)=[CH:36][C:37]=3[F:48])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: CC1(C)OB(c2c(F)cc(C3(O)COC3)cc2F)OC1(C)C
Product: Cn1ncc(NC(=O)c2csc(-c3c(F)cc(C4(O)COC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with 3-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol (see US2012/225062) gave 224. LCMS (ES+) m/z 524 (M+1).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH:52]1[CH2:56][CH2:55][CH2:54][CH:53]1[CH2:57][C:58]1[C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=2[O:60][C:59]=1[CH2:67][CH2:68][CH2:69][OH:70]>CN1C(=O)CCC1.O>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:18]([N:52]1[CH2:56][CH2:55][CH2:54][CH:53]1[CH2:57][C:58]1[C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=2[O:60][C:59]=1[CH2:67][CH2:68][CH2:69][OH:70])=[O:20])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: OCCCc1oc2ccccc2c1CC1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(O)cc1)C(=O)N1CCCC1Cc1c(CCCO)oc2ccccc12
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
A solution containing Boc-L-tyrosine (577 mg, 2.1 mmol) and HATU (716 mg, 1.8 mmol) in anhydrous NMP (6 mL) was treated with NMM (0.3 mL, 2.7 mmol) at ambient temperature. After 10 min, a solution containing 61 (429 mg, 1.7 mmol) in NMP (5 mL) was added. After 2 d, the reaction mixture was diluted with water and the product was extracted with diethyl ether. The combined ether extracts were washed with water and dilute aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash silica gel chromatography (10% MeOH/DCM) to afford 821 mg (92%) of 62 as a pale yellow foam. 1H NMR (CDCl3, 300 MHz) δ8.54 (br 2, 1H), 7.66-7.63 (m, 1H), 7.36-7.32 (m, 1H), 7.21-7.06 (m, 5H), 6.83 (d, J=8.4 Hz, 2H), 5.58 (d, J=9.0 Hz, 1H), 4.64-4.56 (m, 1H), 4.34-4.31 (m, 1H), 3.92-3.88 (m, 1H), 3.70 (app t, J=5.7 Hz, 2H), 3.51-3.26 (m, 1H), 3.18-2.79 (m, 4H), 2.01-1.97 (m, 2H), 1.69-1.47 (m, 1H), 1.42 (s, 9H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[OH:15][CH2:16][CH2:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([S:18]([CH2:17][CH2:16][OH:15])(=[O:20])=[O:19])=[CH:29][CH:28]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)CCO)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)CCO)cc1

Procedure:
Procedure T to give 4-(2-hydroxyethylthio)benzoic acid. 1.0 g of 4-(2-hydroxyethylthio)benzoic acid was reacted via Procedure R to give 4-(2-hydroxyethylsulfonyl)benzoic acid. 80 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-hydroxyethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxyethylsulfonyl)benzamide. MS (Q1) 417.0 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14].[OH-].[K+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1.O>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N:11]([CH2:25][C:24]1[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)[C:12](=[O:16])[CH:13]([CH3:14])[CH3:15]
Reactant: COc1cc(NC(=O)C(C)C)c(Br)cc1C
Reactant: COc1ccc(CCl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CN(C(=O)C(C)C)c2cc(OC)c(C)cc2Br)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.9 %

Procedure:
To a solution of N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (6.83 g) in DMSO (40 mL) was added powder KOH (2.68 g, 47.7 mmol) and 4-methoxybenzyl chloride (7.5 g, 47.7 mmol) under argon. The mixture was stirred at room temperature for 17 hours. Water (30 mL) was added and the mixture extracted with EtOAc, washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:EtOAc/10:1 t0 3:1) to give 8.72 g of N-(2-bromo-5-methoxy-4-methyl-phenyl)-N-(4-methoxy-benzyl)-isobutyramide (90%). 1H NMR (300 MHz, CDCl3, ppm): δ: 1.00 (d, J=7.03 Hz, 3 H), 1.13 (d, J=6.45 Hz, 3 H), 2.17 (s, 3 H), 2.28 (m, 1 H), 3.48 (s, 3 H), 3.78 (s, 3 H), 3.84 (d, J=14.07 Hz, 1 H), 5.62 (d, J=14.07 Hz, 1 H), 6.06 (s, 1 H), 6.78–6.81 (m, 2 H), 7.10–7.13 (m, 2 H), 7.38 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:21]([C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[N:1]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: COc1ccc(C=O)cc1
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1ccc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc1
Yield: 44 %

Procedure:
5,7-Dimethoxy-2-(4-methoxyphenyl)quinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-methoxy benzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 5,7-Dimethoxy-2-(4-methoxyphenyl)quinazolin-4(3H)-one (106 mg, 44%) was isolated as an off-white solid. Selected data: MS (m/z): 312.99; MP 276-277° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:18][CH2:17][CH2:16][O:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>[Ni]>[OH:1][CH:2]1[CH2:18][CH2:17][CH2:16][O:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1CCCCCCCCCCC(=O)OCCC1
Agent: [Ni]
Product: O=C1CCCCCCCCCCC(O)CCCO1

Procedure:
According to Russian Inventor's Certificate 1 133 274, 12-oxo-15-pentadecanolide is reduced in the presence of Raney nickel to give 12-hydroxy-15-pentadecanolide, which is then dehydrated, for example in the presence of phosphoric acid, to give the corresponding 15-pentadec-11- and -12-enolides, and these products are then hydrogenated in the presence of a nickel catalyst to give I.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[N:26]=1)[C:21](O)=[O:22]>>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:21](=[O:22])[C:20]1[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[N:26]=[C:18]([C:17]([F:32])([F:16])[F:31])[CH:19]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.). The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of CH2Cl2: EtOAc (100:0 to 70:30). Light yellow foam (61%). MS (ESI): m/z=440.118 [M+H]+.
Reaction SMILES: [C:1]1([S:7]/[CH:8]=[CH:9]/[C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2(C3C=CC=CC=3)OB(C)N3CCC[C@@H]23)C=CC=CC=1.CSC.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[C:1]1([S:7]/[CH:8]=[CH:9]/[C@H:10]([OH:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)/C=C/Sc1ccccc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CSC
Solvent: Cc1ccccc1
Product: C[C@@H](O)/C=C/Sc1ccccc1
Reaction time: 2 h

Procedure:
(E)-4-phenylthio-3-buten-2-one (178 mg, 1.0 mmol), (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c] [1,3,2] oxazaborol (28 mg, 0.1 mmol) and MS4A (Nacalai Tesque Inc., 500 mg) were dried by a vacuum pump, followed by substituting with an argon gas. Dry toluene (5 ml) and dimethylsulfide (3.0 mmol) were added thereto and, after ice cooling, a solution of borane dimethylsulfide complex in toluene (1.07M, 0.65 ml, 0.7 mmol) was dropwise added. After stirring for two hours, an aqueous saturated ammonium chloride solution was added, followed by filtering through a cotton plug. The filtrate was washed with ethyl acetate and, after separating an aqueous layer, the organic layer was washed with 2NHCl, water, an aqueous saturated sodium hydrogen carbonate solution, water and saturated brine. After drying with anhydrous magnesium sulfate, the extract containing the titled compound as a main component was obtained by concentrating under a reduced pressure. The NMR chemical shifts of the titled compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:18][C:17]3[CH:16]=[N:15][C:14]4[N:19](CC5C=CC(OC)=CC=5)[N:20]=[CH:21][C:13]=4[C:12]=3[C:11]3[CH:31]=[CH:32][CH:33]=[CH:34][C:10]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=C(C2C3C(=CC=CC=3)C(=O)/C(=C/N(C)C)/C2)C=CC=1Cl.Cl.COC1C=CC(CN2C(N)=CC=N2)=CC=1.CCN(C(C)C)C(C)C>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:18][C:17]3[CH:16]=[N:15][C:14]4[NH:19][N:20]=[CH:21][C:13]=4[C:12]=3[C:11]3[CH:31]=[CH:32][CH:33]=[CH:34][C:10]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CC(c2ccc(Cl)c(Cl)c2)c2ccccc2-4)cc1
Agent: CN(C)/C=C1\CC(c2ccc(Cl)c(Cl)c2)c2ccccc2C1=O
Agent: COc1ccc(Cn2nccc2N)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(C2Cc3cnc4[nH]ncc4c3-c3ccccc32)cc1Cl
Temperature: 110 °C
Yield: 53 %

Procedure:
Synthesis of 7-(3,4-dichlorophenyl)-3-(4-methoxybenzyl)-6,7-dihydro-3H-benzo[f]pyrazolo[3,4-c]isoquinoline. To the mixture of (E)-4-(3,4-dichlorophenyl)-2-((dimethylamino)methylene)-3,4-dihydronaphthalen-1(2H)-one (0.20 g, 0.58 mmol) and 1-(4-methoxybenzyl)-1H-pyrazol-5-amine hydrochloride (0.14 g, 0.58 mmol) was added glacial acetic acid (5 mL) and Hunig's Base (0.4 mL). The mixture was heated at 110° C. for 1 hour, then transferred to microwave vial and heated at 220° C. for 90 minutes. The reaction mixture was evaporated and dissolved in dichloromethane (100 mL), washed with water (30 mL), brine (30 mL), dried over sodium sulfate and concentrated to dryness. The crude was purified by flash column chromatography (SiO2, 10% EtOAc in hexane) to give the pure desired product as a brown solid (0.15 g, 53%). M.p.=76-78° C.; 1H NMR (CDCl3, 400 MHz) δ 9.53 (d, J=8 Hz, 1H), 8.32 (s, 1H), 8.02 (s, 1H), 7.54 (t, J=6.8 Hz, 1H), 7.45 (t, J=8 Hz, 1H), 7.35-7.26 (m, 4H), 7.06 (d, J=8 Hz, 1H), 6.96 (d, J=8 HZ, 1H), 6.843 (d, J=7.2 Hz, 2H), 4.28 (t, J=8 Hz, 1H), 4.17 (s, 2H), 3.77 (s, 3H), 3.29-3.26 (m, 2H); LCMS: 486 [M+1].
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C@H:12]3[NH:15][CH2:16][CH2:17][C@:6]4([C@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)[C:5]=2[CH:4]=[C:3]([C:18](=[O:20])[CH3:19])[CH:2]=1.C(=O)(O)[O-].[Na+].[CH:26]1([CH2:29]Cl)[CH2:28][CH2:27]1>CN(C)C=O>[CH:26]1([CH2:29][N:15]2[CH2:16][CH2:17][C@@:6]34[C:5]5[CH:4]=[C:3]([C:18](=[O:20])[CH3:19])[CH:2]=[CH:1][C:14]=5[CH2:13][C@@H:12]2[C@@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)[CH2:28][CH2:27]1
Reactant: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: ClCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(CC1CC1)CC3
Temperature: 25 °C
Yield: 83.3 %

Procedure:
To a mixture of 0.8 g of (-)-1-(morphinan-3-yl)-ethanone, 0.6 g of sodium bicarbonate and 10 ml dimethylformamide, was added 0.3 g of cyclopropylmethyl chloride. After the mixture had been heated at reflux for 18 hours, it was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in 60 ml ether. The ether solution was washed with water, dried over magnesium sulfate and removal of the solvent gave 0.8 g (83%) of crude (-)-1-[N-(cyclopropylmethyl)morphinan-3-yl]ethanone. For analysis, a sample of this compound was distilled, bp 185°-195° (0.1 mm), [α]25D-83.21° (c 1.02, MeOH).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:7]([C:8]2[CH:9]=[C:10]3[C:19](=[CH:20][C:21]=2B2OC(C)(C)C(C)(C)O2)[O:18][CH2:17][C:16]2[N:11]3[C@H:12]([CH3:32])[C:13](=[O:31])[NH:14][N:15]=2)[CH2:6][CH2:5][N:4]([C:33]([OH:35])=[O:34])[CH2:3]1.Br[C:37]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=1[F:44].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:2]([O:35][C:33]([N:4]1[CH2:5][CH2:6][C@@H:7]([C:8]2[CH:9]=[C:10]3[C:19](=[CH:20][C:21]=2[C:37]2[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=2[F:44])[O:18][CH2:17][C:16]2[N:11]3[C@H:12]([CH3:32])[C:13](=[O:31])[NH:14][N:15]=2)[C@@H:2]([CH3:1])[CH2:3]1)=[O:34])([CH3:7])([CH3:3])[CH3:1]
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(B4OC(C)(C)C(C)(C)O4)c([C@@H]4CCN(C(=O)O)C[C@@H]4C)cc3N21
Reactant: Fc1cccc(F)c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4c(F)cccc4F)c([C@@H]4CCN(C(=O)OC(C)(C)C)C[C@@H]4C)cc3N21
Temperature: 90 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a mixture of (3R,4R)-3-methyl-4-[(R)-4-methyl-3-oxo-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-piperidine-1-carboxylic acid (0.028 g, 0.052 mmol), 2-bromo-1,3-difluoro-benzene (0.015 g, 0.078 mmol) and sodium carbonate (0.018 g, 0.130 mmol) in 1,4-dioxane (3.0 mL) and water (0.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (0.008 g, 0.010 mmol) and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was partitioned between EtOAc (20 mL) and water (20 mL). The organic portion was separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Table 3, Method 36) to give (3R,4R)-4-[(R)-7-(2,6-difluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.005 g, 18%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.41-7.51 (m, 1H), 7.08 (m, 2H), 6.95 (s, 1H), 6.82 (s, 1H), 4.57-4.65 (m, 5H), 4.25 (m, 1H), 3.83 (m, 1H), 2.80 (m, 1H), 2.43-2.74 (m, 2H), 2.15-2.30 (m, 1H), 1.40-1.51 (m, 12H), 1.29 (s, 3H). LC/MS (Table 1, Method 25) Rt=0.930 min; MS (ESI): m/z 527 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:29](N2C=NC=C2)=[O:30])C=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:16]3=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=[C:21]3[NH:22][C:29]2=[O:30])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cnc(Nc2ccc(OCc3ccccc3)cc2)c(N)c1
Solvent: C1CCOC1
Product: Cc1cnc2c(c1)[nH]c(=O)n2-c1ccc(OCc2ccccc2)cc1
Yield: 93.6 %

Procedure:
A solution of N2-[4-(benzyloxy)phenyl]-5-methylpyridine-2,3-diamine (0.63 g) and CDI (0.67 g) in THF (20 mL) was refluxed overnight. The mixture was concentrated in vacuo. The residual solid was washed with AcOEt to give 3-[4-(benzyloxy)phenyl]-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.64 g) as an off-white solid.