Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47]O.N1C=CC=CC=1.P(Br)(Br)[Br:56]>CCOCC.C(OCC)(=O)C>[CH2:31]([O:30][C@H:11]1[C@H:12]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:47][Br:56])[CH:4]=2)[O:9][C@H:10]1[CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Clc1ccc(C2O[C@@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1CBr
Temperature: 25 °C

Procedure:
To a solution of (2-chloro-5-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxy-methyl) tetrahydro-2H-pyran-2-yl)phenyl)methanol (compound 5, 130 g, 195 mmol) from Step 6 in ether (600 mL) at 0° C. was added pyridine (0.79 mL, 9.8 mmol) and phosphorus tribromide (6.4 mL, 68 mmol). The reaction was allowed to slowly warm to room temperature over 15 h and refluxed 1 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water then brine. The organic extract was dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the title compound as a yellow oil, which was used without further purification.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.[N:15]1([CH2:21][CH2:22][O:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([NH2:34])=[CH:26][CH:25]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([CH2:21][CH2:22][O:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([NH:34][C:9](=[O:11])[C:8]3[CH:12]=[CH:13][CH:14]=[C:6]([N:1]4[CH:2]=[CH:3][CH:4]=[CH:5]4)[CH:7]=3)=[CH:26][CH:25]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: O=C(O)c1cccc(-n2cccc2)c1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(-n2cccc2)c1

Procedure:
Compound is prepared from 3-pyrrol-1-yl-benzoic acid and 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-ylamine according to conditions described in general procedure G. (96 mg) (40%). Mp: 142-143° C. 1H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.25 (m, 2H), 7.90 (m, 2H), 7.83 (d, J=8.1, 1H), 7.66-7.47 (m, 6H), 7.06 (d, J=8.4 Hz, 1H), 6.32 (brs, 2H), 4.33 (t, J=5.4, 2H), 3.62 (brt, 4H), 2.93 (brs, 2H), 2.62 (brs, 4H). MS: 442 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:54])([O:4][C:5]([N:7](CC1C=CC(OC)=CC=1)[C@@H:8]1[C@@H:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:11]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:10]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:9]1[CH:37]([OH:44])[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:6])[CH3:3].C(#N)C.O.[Cl-].[Na+]>O.C(OCC)(=O)C>[CH3:54][C:2]([CH3:3])([O:4][C:5]([NH:7][C@@H:8]1[C@@H:12]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:11]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@H:10]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@H:9]1[CH:37]([OH:44])[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:6])[CH3:1]
Reactant: CCOC(=O)CC(O)[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1N(Cc1ccc(OC)cc1)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CC(O)[C@H]1[C@H](NC(=O)OC(C)(C)C)[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
Dissolve [1R,2S,3R,4S,5R]-2-[[(1,1-dimethylethoxy)carbonyl][(4-methoxyphenyl)methyl]amino]-β-hydroxy-3,4,5-tris(phenylmethoxy)-cyclopentanepropanoic acid, ethyl ester (2.018 g, 2.73 mmol) in a 4:1 mixture of acetonitrile/water (75 mL) and cool to 0° C. with an ice bath. Add ceric ammonium nitrate (4.23 g, 7.72 mmol) and stir for 1 hour. Pour into a mixture of water/ethyl acetate containing sodium chloride, separate the organic phase, wash with dilute sodium hydrogen carbonate and aqueous sodium chloride. Dry (MgSO4), evaporate the solvent in vacuo and subject to Kugelrohr distillation to remove p-methoxybenzaldehyde (94° C. @ high vacuum) to give the title compound remaining as a white solid which is recrystallized from cyclohexane.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17](=[O:30])[NH:18][C:19]2[CH:24]=[C:23]([Cl:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=2[O:28][CH3:29])[C:6]1=[O:31].[OH-].[K+]>CO.O>[Cl:25][C:23]1[C:22]([O:26][CH3:27])=[CH:21][C:20]([O:28][CH3:29])=[C:19]([NH:18][C:17]([CH2:16][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:15])[N:5]([CH2:4][C:3]([OH:32])=[O:2])[C:6]2=[O:31])=[O:30])[CH:24]=1
Reactant: COC(=O)Cn1c(=O)c2ccccc2n(CC(=O)Nc2cc(Cl)c(OC)cc2OC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)O)c(=O)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A white suspension of {1-[(5-chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-acetic acid methyl ester (Intermediate B) (10 mg) in MeOH (300 μL) is treated with 5 M KOH (200 μL). The white suspension is left to stir at RT overnight. The reaction mixture is diluted with water to give a thick white precipitate which is filtered-off, washed with water and vacuum dried. The aqueous phase is acidified to pH 4 with dilute HCl followed by extraction with EtOAc (3×). The organic phase is dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as off-white solid. This is taken up in a minimal amount of DMF and purified further by reverse phase column chromatography (Isolute™ C18: 0-100% MeCN in water—0.1% TFA) to afford the title compound, [M+H]+ 448.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](Cl)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:5]1)(=O)C.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[NH:24][NH2:25]>>[C:28]([O:27][C:23]([NH:24][NH:25][C:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][N:5]=[C:6]2[C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)=[O:14])=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1

Procedure:
The product was synthesized as described in Example 109 A using 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (500 mg, 1.58 mmol) and tert-butyl carbazate (230 mg, 1.74 mmol). 1H NMR (DMSO-d6) δ 10.35 (s, 1H), 8.95 (s, 1H), 8.4 (s, 1H), 8.1 (m, 2H), 7.9 (d, 1H), 7.65 (d, 1H), 7.4 (t, 2H), 1.3–1.5 (m, 9H), ES-MS m/z 371 [M+1]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:11](OC)(=[O:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14].N1CCCCC1>CO>[CH3:1][N:2]1[C:3]2[C:4](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[C:11]1=[O:17]
Reactant: COC(=O)CC(=O)OC
Reactant: CNc1ncccc1C=O
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)c1cc2cccnc2n(C)c1=O
Temperature: 80 °C
Reaction time: 7 h
Yield: 83.2 %

Procedure:
8.66 g (64.5 mmol) of 2-(methylamino)nicotinaldehyde was dissolved in methanol (100 mL), and 12.68 g (96.0 mmol) of dimethyl malonate and 2.18 g (25.6 mmol) of piperidine were added to the solution. The resulting mixture was stirred for 7 hours at 80° C. The mixture was cooled, and a solid precipitated therefrom was separated by filtration. The solid was washed with diisopropyl ether, and thus 11.71 g (yield: 84%) of the title compound was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:13][CH3:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[N:11][OH:12].[Cl:15]Cl>C(Cl)Cl>[Cl:15][CH:10]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4](=[N:11][OH:12])[C:3]1([O:2][CH3:1])[O:13][CH3:14]
Reactant: COC1(OC)CCCCCCC1=NO
Reactant: ClCl
Solvent: ClCCl
Product: COC1(OC)C(=NO)CCCCCC1Cl
Reaction time: 2 h

Procedure:
Following the general procedure of Example 1, to a solution of 5.025 parts of 2,2-dimethoxycyclooctanone oxime in 40 parts dry methylene chloride at about 35° C., was added 1.78 parts elemental chlorine over about 3/4 of an hour. The contents were stirred at 25° to 30° C. for about 21/2 hours after the addition. The contents were then treated according to the procedure of Example 1 to yield 5.3 parts of product 3-chloro-2,2-dimethoxycyclooctanone oxime as determined by elemental analysis and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2CCN(C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.[N:31]1([C:36](=[NH:38])[NH2:37])[CH:35]=[CH:34]C=N1>Cl.O1CCOCC1>[F:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:34][CH2:35][N:31]([C:36](=[NH:38])[NH2:37])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: N=C(N)n1cccn1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(CF)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)N1CCN(c2cccc(CF)c2)CC1
Temperature: 25 °C

Procedure:
Tert-butyl 4-(3-(fluoromethyl)phenyl)piperazine-1-carboxylate (201.3 mg, mmol) was dissolved in a 4.0 M solution of HCl and dioxane (2 mL) and stirred at room temperature. After 45 min. the reaction mixture was concentrated and re-dissolved in ACN (2 mL). Diisopropylethylamine (22 μL, 1.51 mmol) and 1H-pyrazole-1-carboximidamide (110 mg, 0.75 mmol) were added to the stirring reaction mixture. The next day, the reaction mixture was concentrated to yield a crude oil, which was purified by HPLC using a Phenomenex Luna C-18 (2) column (10 250×21.2 mm, gradient method 0-100% B over 14 min., where B=90% ACN in water using 0.1% TFA as a modifier and A=water using 0.1% TFA as a modifier) with a flow rate of 20 ml/min to isolate 4-(3-(fluoromethyl)phenyl)piperazine-1-carboximidamide as a white solid (42.7 mg, 23% isolated yield over 4 steps). 1H NMR (300 MHz, DMSO-d6): δ 7.58 (br s, 3H), 7.28 (t, 1H, J=7.8 Hz), 7.01 (br s, 1H), 6.98 (br s, 1H), 6.87 (d, 1H, J=7.3 Hz), 5.35 (d, 2H, J=47.9 Hz), 3.58 (dd, 4H, J=5.4, 4.9 Hz), 3.26 (dd, 4H, J=5.4, 4.8 Hz); 13C NMR (75.5 MHz, DMSO-d6): δ 156.1, 150.3, 137.1 (136.8), 129.2, 118.8 (118.7), 115.9, 114.9 (114.8), 84.6 (83.4), 47.2, 44.7; HRMS calcd for C12H17FN4: 237.15100 found 237.1514.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH2:11][CH3:12])=[CH:4][N:3]=1.[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[CH2:11]([O:10][CH2:9][O:8][C:5]1[CH:4]=[N:3][C:2]([C:19]2[CH:18]=[CH:17][C:16]([O:15][C:14]([F:13])([F:25])[F:26])=[CH:21][CH:20]=2)=[N:7][CH:6]=1)[CH3:12]
Reactant: CCOCOc1cnc(Cl)nc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: CCOCOc1cnc(-c2ccc(OC(F)(F)F)cc2)nc1
Yield: 91 %

Procedure:
Suzuki coupling of chloropyrimidine 108 (see Example 2S) and 4-(trifluoromethoxy)phenylboronic acid as in Example 2S above for 2 h, followed by chromatography of the product on silica gel, eluting with 0-2% Et2O/petroleum ether (foreruns) and then with 2% Et2O/petroleum ether, gave 5-(ethoxymethoxy)-2-[4-(trifluoromethoxy)phenyl]pyrimidine (110) (91%) as a white solid: mp (petroleum ether) 41-43° C.; 1H NMR (CDCl3) δ 8.60 (s, 2H), 8.41 (dt, J=9.0, 2.4 Hz, 2H), 7.30 (br dd, J=9.0, 0.9 Hz, 2H), 5.31 (s, 2H), 3.77 (q, J=7.1 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H); HRESIMS calcd for C14H14F3N2O3 m/z [M+H]+ 315.0951. found 315.0944.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:7])([CH3:6])[CH2:4][NH2:5].[CH2:8]([O:10]C=O)C>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:8]([NH:5][CH2:4][C:3]([O:2][CH3:1])([CH3:7])[CH3:6])=[O:10]
Reactant: CCOC=O
Reactant: COC(C)(C)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(C)(C)CNC=O
Yield: 92.2 %

Procedure:
To a stirred solution of 2-methoxyisobutylamine (16.4 g, 0.16 mol) and a catalytic amount of p-toluenesulphonic acid (75 mg) at 0° C. was added slowly ethylformate (11.79 g, 12.92 ml, 0.16 mol). After the slightly exothermic reaction ceased, the solution was refluxed for 16 hours, and distilled through a Vigreux column to give 19.36 g (93%) of N-formyl-2-methoxyisobutylamine, bp 74° C./15 mm.
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][C:8]3([NH2:11])[CH2:10][CH:4]([CH2:5]2)[CH2:3][CH:2]1[CH2:9]3.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].CN(P(N(C)C)(N(C)C)=O)C>O>[C:8]12([NH:11][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)[CH2:10][CH:4]3[CH2:5][CH:6]([CH2:1][CH:2]([CH2:3]3)[CH2:9]1)[CH2:7]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=[N+]([O-])c1ccc(NC23CC4CC(CC(C4)C2)C3)cc1

Procedure:
A mixture of 1.51 g. (0.01 mole) of 1-adamantamine, 1.41 g. p-fluoronitrobenzene and 1.38 g. K2CO3 in 10 ml. HMPA was stirred overnight in an oil bath at 135°. The mixture was allowed to cool, diluted with H2O and extracted thoroughly with C6H6. The organic layer was washed in turn with H2O and brine and taken to dryness. The waxy residue was recrystallized twice from Me2CO:cyclohexane to give 1.82 g. (67%) of N,1-adamantyl-p-nitroaniline, m.p. 188°-189°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[C:16]3[CH:23]4[CH2:24][CH:19]5[CH2:20][CH:21]([CH2:25][CH:17]3[CH2:18]5)[CH2:22]4)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[C:16]3[CH:23]4[CH2:24][CH:19]5[CH2:20][CH:21]([CH2:25][CH:17]3[CH2:18]5)[CH2:22]4)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: Oc1ccc2c(c1)Oc1ccccc1C2=C1C2CC3CC(C2)CC1C3
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)Oc1ccccc1C2=C1C2CC3CC(C2)CC1C3
Reaction time: 2 h
Yield: 89.9 %

Procedure:
Hydroxy alkene 5a (0.577 g, 1.5 mmol) was dissolved in 20 mL of CH2Cl2 with 1.25 mL (1.22 g, 15.5 mmol) of pyridine. Acetyl chloride (0.6 mL, 0.662 g, 8.4 mmol) was dissolved in 5 mL of CH2Cl2 and added dropwise to the solution with 5a. A precipitate formed immediately. After stirring for 2 hours, the solvent was removed to give a yellow-orange solid. This material was treated with 50 mL of CH2Cl2 to leave a white solid which was separated by filtration. The CH2Cl2 solution was then concentrated and chromatographed over silica with 5% ethyl acetate/hexane to give 0.502 g (77.2%) of 5c as a white solid: mp 162°-163° C.; 1H NMR (CDCl3 delta 1.80-2.05 (m, 12H), 2.265 (s, 3H), 3.45-3.55 (m, 2H), 6.833 (dd, 1H, J=8.38, 2.32 Hz), 6.961 (d, 1H, J=2.33 Hz), 7.072 (ddd, 1H, J=8.11, 5.45, 2.08 Hz), 7.12-7.28 (m, 4H); 13C NMR (CDCl3) delta 20.96, 27.78, 32.50, 36.88, 39.36, 110.08, 115.72, 116.41, 122.75, 124.38, 126.44, 126.90, 127.42, 127.68, 146.81, 149.24, 154.86, 155.48, 169.18. ##STR37##
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:37][OH:38])[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[C:27]([NH:29][C@@H:30]([CH2:35][OH:36])[C:31]([O:33]C)=O)=[O:28])=[O:21])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[NH3:41]>CO>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@@H:12]([CH2:37][OH:38])[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[C:27](=[O:28])[NH:29][C@@H:30]([CH2:35][OH:36])[C:31]([NH2:41])=[O:33])=[O:21])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](CO)NC(=O)OCc1ccccc1
Solvent: CO
Product: NC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
To a solution of (S)-methyl-2-((S)-1-((S)-1-((S)-2-(benzyloxycarbonylamino)-3-hydroxypropanoyl)-pyrrolidine-2-carbonyl)-pyrrolidine-2-carboxamido)-3-hydroxypropanoate (6) (60 mg, 1.04 mmol) in MeOH was added MeOH—NH3 (3 mL) was stirred at RT for 16 h. The volatiles were evaporated under reduced pressure to afford compound 7 (30 mg, 55%).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][C:6]=2[CH:5]=[C:4]([Cl:21])[CH:3]=1.[F-].[NH4+].[CH2:24](OCC)[CH3:25]>C1(C)C=CC=CC=1>[CH:19]([O:18][C:16]([C:8]1[CH:9]([C:12]([F:15])([F:14])[F:13])[O:10][C:11]2[C:2]([CH:24]=[CH2:25])=[CH:3][C:4]([Cl:21])=[CH:5][C:6]=2[CH:7]=1)=[O:17])=[CH2:20]
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(Br)c2OC1C(F)(F)F
Reactant: CCOCC
Agent: [F-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: C=COC(=O)C1=Cc2cc(Cl)cc(C=C)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
In a 100 mL round bottomed flask under N2, ethyl 8-bromo-6-chloro-2-trifluoromethyl-2H-benzopyran-3-carboxylate (Example 74, Step 1)(2.21 g, 5.73 mmol) was dissolved in toluene (30 mL of anhydrous reagent). Tetrakis (triphenylphosphine)palladium(0) (0.132 g, 0.115 mmol) was added, followed by tributylethyenylstannane (2.0 g, 6.31 mmol). The resulting solution was heated to reflux for 5 hours. The reaction mixture was allowed to cool to room temperature, was poured into 50 mL of 20% ammonium fluoride solution and stirred for one hour. Diethyl ether (100 mL) was added and the mixture was washed with water (2×50 mL). The organic phase was dried over MgSO4, filtered, and evaporated to yield a yellow oil. The crude material was purified by flash chromatography (0.5% ethyl acetate in hexanes) to afford the ester as a yellow solid (0.86 g, 45%): mp 75.9–77.2° C. 1H NMR (CDCl3/300 MHz) 7.64 (s, 1H), 7.45 (d, 1H, J=2.5 Hz), 7.12 (d, 1H, J=2.6 Hz), 6.92 (dd, 1H, J=17.7 Hz, 11.3 Hz), 5.81 (d, 1H, J=17.7 Hz), 5.76 (q, 1H, J=6.8 Hz), 5.41 (d, 2H, J=11.1 Hz), 4.36–4.29 (m, 2H), 1.36 (t, 3H, J=7.3 Hz). FABLRMS m/z 350.1 (M+NH4+). ESHRMS m/z 350.0796 (M+NH4+, Calc'd. 350.0771). Anal. Calc'd. for C15H12ClF3O3+4.07% H2O: C, 51.95; H, 3.94. Found: C, 51.67; H, 3.69.
Reaction SMILES: O[CH:2]([C:6]1[C:7]([CH3:19])=[C:8]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]([C:16](=[O:18])[CH3:17])[CH2:10][CH2:9]2)[C:3]([OH:5])=[O:4].Cl.[CH:21](N(C(C)C)CC)(C)[CH3:22].C(Cl)(=O)C>[Pd].C(O)C.C(OCC)(=O)C.O.CC(C)=O>[C:16]([N:11]1[C:12]2[C:8](=[C:7]([CH3:19])[C:6]([CH2:2][C:3]([O:5][CH2:21][CH3:22])=[O:4])=[C:14]([CH3:15])[CH:13]=2)[CH2:9][CH2:10]1)(=[O:18])[CH3:17]
Reactant: CC(=O)N1CCc2c1cc(C)c(C(O)C(=O)O)c2C
Reactant: CCN(C(C)C)C(C)C
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC(=O)Cl
Solvent: CC(C)=O
Product: CCOC(=O)Cc1c(C)cc2c(c1C)CCN2C(C)=O
Temperature: 70 °C
Reaction time: 5 h
Yield: 91.2 %

Procedure:
To hydroxy(1-acetyl-4,6-dimethylindolin-5-yl)acetic acid (3.0 g) obtained in Example 1 and 7.5% palladium on charcoal (1.3 g, wet (water content: 53.1%)) placed in a 100-ml autoclave was added a saturated solution of hydrogen chloride in ethanol (30 ml). After degassing with nitrogen for 3 times (5 kg/cm2 for each) and replacing nitrogen with hydrogen for 3 times (5 kg/cm2 for each) successively, the resulting mixture was stirred for 5 hours at 70° C. under a pressurized hydrogen atmosphere (5 kg/cm2). The reaction mixture was filtered to remove palladium on charcoal, which was washed with ethanol (45 ml). The filtrate and washing were combined and concentrated in vacuo, and after adding acetone (30 ml) to the residue, the resulting mixture was concentrated in vacuo once again. Subsequently, to the residue obtained were added acetone (30 ml), diisopropylethylamine (4.4 g, 3.0 equivalent) and acetyl chloride (0.81 ml, 1.0 equivalent) successively, and the resulting mixture was refluxed for 10 minutes. The reaction mixture was concentrated in vacuo. To the residue obtained were added water (30 ml) and ethyl acetate (60 ml) successively, and after stirring, the resulting mixture was filtered to remove insoluble precipitates, which were washed with water (30 ml) and ethyl acetate (30 ml) successively. The filtrate and washing were combined, and both organic and aqueous layers were separated by partitioning. The separated aqueous layer was extracted with ethyl acetate (30 ml) once again, and the extract was combined with the organic layer separated above. The organic layer was washed with water (30 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the title compound (2.86 g, yield: 91%) as colourless crystals.
Reaction SMILES: [H][H].[C:3]([O:7][C@@H:8]([C:11]1[C:12]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:13]2[C:18](=[CH:19][C:20]=1[CH3:21])[N:17]=[C:16]([CH:22]=[CH2:23])[CH:15]=[CH:14]2)[CH2:9][OH:10])([CH3:6])([CH3:5])[CH3:4]>C(O)C.O=[Al]O[Al]=O.[Rh]>[C:3]([O:7][C@@H:8]([C:11]1[C:12]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[C:13]2[C:18](=[CH:19][C:20]=1[CH3:21])[N:17]=[C:16]([CH2:22][CH3:23])[CH:15]=[CH:14]2)[CH2:9][OH:10])([CH3:4])([CH3:5])[CH3:6]
Reactant: C=Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1
Reactant: [H][H]
Agent: [Rh]
Agent: O=[Al]O[Al]=O
Solvent: CCO
Product: CCc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A balloon filled with hydrogen was connected to a degassed mixture of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-vinylquinolin-6-yl)ethanol (9 mg, 0.024 mmol) and Rhodium on activated alumina (2 mg, cat.) in ethanol. The mixture was stirred at room temperature for 2 hours, filtered and concentrated to dry. The obtained residue was used on next step reaction without purification. LCMS-ESI+ (m/z): 398.2, 400.2 (M+H)+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[CH:28]=[C:27]3[C:22]([CH2:23][CH2:24][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]3)=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>O1CCCC1.CO.[C].[Pd]>[C:32]([O:31][C:29]([N:25]1[CH2:24][CH2:23][C:22]2[C:27](=[CH:28][C:19]([O:18][CH2:17][CH:14]3[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]3)=[CH:20][CH:21]=2)[CH2:26]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(OCC3CCN(C(=O)OCc4ccccc4)CC3)cc2C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(OCC3CCNCC3)cc2C1
Yield: 87 %

Procedure:
4-(2-tert-Butoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidine-1-carboxylic acid benzyl ester (1.3 g) was hydrogenated using 7.5% palladium carbon (300 mg) in a mixture of tetrahydrofuran (10 ml) and methanol (20 ml) at 3 atm over 3 hours. After completion of the reaction, the reaction mixture was filtered through celite and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (815 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1[CH3:7].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[CH3:7][C:6]1[O:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([C:13]([F:24])([F:23])[F:12])[CH:19]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cc(Br)c(C)o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(C)o1
Yield: 61.6 %

Procedure:
By a method similar to that in Example 126c and using the compound (1.00 g) obtained in Example 128b, 3-(trifluoromethyl)phenylboronic acid (1.04 g), cesium carbonate (2.98 g, 3.6 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.19 g), the title compound (0.80 g) was obtained as a solid.