Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:4]=2[O:3]1.[OH-].[Na+].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:11][C:10]1[C:4]2[O:3][C:2]([CH3:12])([CH3:1])[CH2:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)Cc2cccc(O)c2O1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1cccc2c1OC(C)(C)C2
Yield: 94.6 %

Procedure:
2,3-Dihydro-2,2-dimethyl-7-benzofuranol (16.4 g, 0.1 mol) was dissolved in 100 ml of an aqueous solution of sodium hydroxide (6.0 g, 0.15 mol), and 12.8 g of acetic anhydride was dumped into the solution and thoroughly mixed, whereby a white solid substance was precipitated. This substance was collected by filtration and dried, whereby 19.5 g of 7-acetoxy-2,3-dihydro-2,2-dimethylbenzofuran was obtained. The melting point of this product was 48.5°-49.5° C. This phenol acetate was dissolved in 400 ml of chloroform, and 60 ml of 70% nitric acid was dropwise added at -5° C. Then, the stirring was continued at 10° C. for one hour. The reaction solution was washed with water, then dried over anhydrous sodium sulfate and concentrated. The solid substance thereby obtained was recrystallized from benzene-cyclohexane, whereby 19.6 g of 7-acetoxy-2,3-dihydro-2,2-dimethyl-5-nitrobenzofuran was obtained. The melting point of this product was 141°-142° C. The structure was confirmed by 1H-NMR spectrum and IR spectrum. Then, the product was added to a solution containing 35 g of sodium hydroxide in 200 ml of water and 50 ml of methanol, and heated at 40° C. for 15 minutes to complete hydrolysis. The reaction solution was neutralized by concentrated hydrochloric acid, and then extracted with ether. The extracted solution was washed with water, then dried over anhydrous sodium sulfate and concentrated, whereby 13.0 g of substantially pure 2,3-dihydro-2,2-dimethyl-5-nitro-7-benzofuranol was obtained. The melting point of this product was 97°-97.5° C. The phenol thus obtained, was reacted with O-ethyl-S-n-propyl-thiophosphoryl chloride in the same manner as in Example 1, whereby the compound (No. 4) identified in Table 1 was obtained as oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:15][CH2:14][C@H:13]([CH2:16][OH:17])[CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.CCN(CC)CC.[CH:25]([Si:28](OS(C(F)(F)F)(=O)=O)([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:15][CH2:14][C@H:13]([CH2:16][O:17][Si:28]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:25]([CH3:27])[CH3:26])[CH2:12]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: OC[C@H]1CCN(c2nnc3ccc(F)cn23)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](OC[C@H]1CCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of Intermediate 92a (667 mg, 2.83 mmol) and Et3N (630 μL, 4.53 mmol) in DCM (5 mL) was added triisopropylsilyltrifluoromethane sulfonate (950 μL, 3.54 mmol) and the mixture was stirred at RT for 1 h. The mixture was washed with sat. sodium hydrogen carbonate solution then brine, dried and concentrated in vacuo. The residue was purified by FCC, 2-6% MeOH in DCM, to give the title compound as a pale green viscous oil (1.11 g, quant.). LCMS (Method 3): Rt 4.76 min, m/z 393 [MH+].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]2[NH:21][C:20](=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:14](=[O:23])[C:13]3[C:24]([CH3:40])=[C:25]([O:38][CH3:39])[CH:26]=[C:27]([O:28][Si](C)(C)C(C)(C)C(C)C)[C:12]=3[CH2:11][S:10][CH2:9]2)[O:5][N:4]=1.[F-].[NH4+].[ClH:43]>CO.C(OCC)(=O)C.C(OCC)C>[ClH:43].[NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]2[NH:21][C:20](=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:14](=[O:23])[C:13]3[C:24]([CH3:40])=[C:25]([O:38][CH3:39])[CH:26]=[C:27]([OH:28])[C:12]=3[CH2:11][S:10][CH2:9]2)[O:5][N:4]=1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OCCCCC(=O)N[C@H](c1nc(CN)no1)CSC2
Agent: Cl
Agent: [F-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCOCC
Product: COc1cc(O)c2c(c1C)C(=O)OCCCCC(=O)N[C@H](c1nc(CN)no1)CSC2

Procedure:
(R)-4-(3-Aminomethyl-1,2,4-oxadiazol-5-yl) -16-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-14-methoxy-13-methyl-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-6,12-dione was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 1. The resulting product was dissolved in ethyl acetate. Upon addition of a 3N solution of hydrochloric acid in diethyl ether, a precipitate formed which was isolated to yield (R)-4-(3-aminomethyl-1,2,4 -oxadiazol-5-yl)-16-hydroxy-14-methoxy-13-methyl-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-6,12-dione hydrochloride as a white solid.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[C:18]2=[C:19]3[C:14](=[CH:15][CH:16]=[CH:17]2)[CH2:13][CH2:12][CH2:11][N:10]3[CH:9]=1)=[O:7])(=O)[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>CN(C)C=O.O1CCCC1>[C:8]1([C:6]2[O:7][C:1]([CH3:2])=[N:4][N:5]=2)[C:18]2=[C:19]3[C:14](=[CH:15][CH:16]=[CH:17]2)[CH2:13][CH2:12][CH2:11][N:10]3[CH:9]=1
Reactant: CC(=O)NNC(=O)c1cn2c3c(cccc13)CCC2
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nnc(-c2cn3c4c(cccc24)CCC3)o1
Temperature: 120 °C

Procedure:
N′-acetyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carbohydrazide was dissolved in 0.8 mL of mixture of N,N-dimethylformamide/tetrahydrofuran (9:1). To the solution was added Burgess Reagent (120 mg, 500 μmol). The reaction was heated at 120° C. for 24 hours. The solvent was removed under reduced pressure. residues were purified The crude product was purified using reverse phase chromatography (HPLC, C-18) using trifluoroacetic acid as a modifier to give 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-5-methyl-1,3,4-oxadiazole (56) as a yellow solid. Mp=70-72° C.; 400 MHz 1HNMR (DMSO-d6) δ 8.01 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.15 (t, J=7.6 Hz, 1H), 7.02 (d, J=7.2 Hz, 1H), 4.27 (t, J=5.6 Hz, 2H), 2.97 (t, J=6.0 Hz, 2H), 2.56 (s, 3H), 2.18-2.14 (m, 2H); LCMS [M+H]: 240.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:7]2[N:8]([CH2:15]CO)[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)=[N:5][N:6]=1.OCCN1C([N+]([O-])=O)=CN=C1C(NNC(=O)C)=N>>[CH3:1][C:2]1[NH:3][C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)=[N:5][N:6]=1
Reactant: Cc1nnc(-c2ncc([N+](=O)[O-])n2CCO)[nH]1
Agent: CC(=O)NNC(=N)c1ncc([N+](=O)[O-])n1CCO
Product: Cc1nnc(-c2ncc([N+](=O)[O-])n2C)[nH]1

Procedure:
Using the above procedure 2-(5-methyl-4H-1,2,4-triazol-3-yl)-1-(2-hydroxyethyl)-5-nitroimidazole (VI J) is prepared from 2-[1-(2-hydroxyethyl)-5-nitro-2-imidazolecarboximidoyl)-1-acetylhydrazine.
Reaction SMILES: [F:1][C:2]([F:9])([CH3:8])[C:3](OCC)=[O:4].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25]3[C:20](=[CH:21][C:22]([O:26][C@H:27]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=4)[C@@H:28]([NH2:30])[CH3:29])=[CH:23][CH:24]=3)[CH:19]=[N:18]2)=[CH:13][CH:12]=1>C(#N)C>[F:1][C:2]([F:9])([CH3:8])[C:3]([NH:30][C@@H:28]([CH3:29])[C@H:27]([O:26][C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[N:17]([C:14]1[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=1)[N:18]=[CH:19]2)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=1)=[O:4]
Reactant: CCOC(=O)C(C)(F)F
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Solvent: CC#N
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(C)(F)F)c1

Procedure:
Ethyl 2,2-difluoropropanoate (400 μl) and (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 135 mg, 0.34 mmol) was heated to 150° C. for 30 min. Then it was diluted with acetonitrile and purified by semiprep HPLC followed by flash chromatography on silica gel (n-heptane/ethyl acetate, 4:1) Yield 60 mg (36%).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([O:17][C:18]3[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=3)=[C:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH:35]([CH3:37])[CH3:36])[S:14][C:13]=2[CH:38]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:39][CH:40](O)[CH3:41].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOC(C)=O.CCCCCCC>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([O:17][C:18]3[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][CH:40]([CH3:41])[CH3:39])=[O:27])=[CH:20][CH:19]=3)=[C:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH:35]([CH3:36])[CH3:37])[S:14][C:13]=2[CH:38]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)O
Reactant: CC(C)c1ccccc1-c1sc2cc(O[Si](C)(C)C(C)(C)C)ccc2c1Oc1ccc(/C=C/C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)OC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3C(C)C)sc3cc(O[Si](C)(C)C(C)(C)C)ccc23)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 55 %

Procedure:
To a solution of (E)-3-(4-((6-((tert-butyldimethylsilyl)oxy)-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (59.6 mg, 0.109 mmol) in DCM (2.5 mL) was added i-PrOH (0.034 mL, 0.438 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (84 mg, 0.438 mmol) and 4-dimethylaminopyridine (8.02 mg, 0.066 mmol). The resulting mixture was stirred at room temperature for 75 min after which time the reaction was quenched by addition of water and diluted with DCM. The phases were separated and the aqueous layer was further extracted with DCM (3×). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO2, 0-30% EtOAc/Heptane) to (E)-isopropyl 3-(4-((6-((tert-butyldimethylsilyl)oxy)-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (35 mg, 0.060 mmol, 55% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.49 (d, J=16.0 Hz, 1H), 7.32-7.17 (m, 7H), 7.10-7.03 (m, 1H), 6.79 (d, J=8.8 Hz, 3H), 6.18 (d, J=16.1 Hz, 1H), 5.05 (p, J=6.2 Hz, 1H), 3.18 (p, J=6.8 Hz, 1H), 1.23 (d, J=6.4 Hz, 6H), 1.11 (d, J=6.8 Hz, 6H), 0.95 (s, 9H), 0.18 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][N:10]2[CH2:13][CH:12]([CH2:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:11]2)=[C:4]([O:26]C)[CH:3]=1.B(Br)(Br)Br.C(OCC)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][N:10]2[CH2:11][CH:12]([CH2:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)(=[O:16])=[O:17])[CH2:13]2)=[C:4]([OH:26])[CH:3]=1
Reactant: COc1cc(F)ccc1C(=O)CN1CC(CS(=O)(=O)c2ccc(F)cc2)C1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(CN1CC(CS(=O)(=O)c2ccc(F)cc2)C1)c1ccc(F)cc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-fluoro-2-methoxyphenyl)-2-(3-{[(4-fluorophenyl)sulfonyl]methyl}azetidin-1-yl)ethanone (Step 2, 49.4 mg, 0.125 mmol) in dichloromethane (1 mL) at 0° C. was added boron tribromide (1M in dichloromethane, 0.5 mL, 0.5 mmol). The reaction was stirred at 0° C. for 30 minutes. Diethyl ether (5 mL) was added and the resulting slurry partitioned between saturated sodium carbonate solution and ethyl acetate. Water was added to dissolve some of the resulting precipitate and the biphasic mixture was decanted from the remaining solid. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with ethyl acetate, to give the title compound which was treated with ethereal HCl to give the hydrochloride salt (10.5 mg, 20%). 1H NMR (500 MHz, d6-DMSO) δ 11.83 (1H, s), 10.34 (1H, s), 7.95 (2H, dd, J=5.3, 8.2 Hz), 7.83 (1H, dd, J=7.3, 8.5 Hz), 7.54 (2H, t, J=8.7 Hz), 6.91 (1H, dd, J=2.0, 10.7 Hz), 6.81–6.79 (1H, m), 4.83 (2H, s), 4.19 (2H, br s), 4.05–3.97 (2H, m), 3.87–3.78 (2H, m), 3.08–3.02 (1H, m); m/z (ES+) 382 (M+H)+.
Reaction SMILES: [O:1]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])S(C(F)(F)F)(=O)=O.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]3[CH:28]=[C:29](O)[CH:30]=[CH:31][C:25]=3[CH:24]=2)=[CH:19][CH:18]=1>N1C=CC=CC=1>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]3[CH:28]=[C:29]([O:1][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])[CH:30]=[CH:31][C:25]=3[CH:24]=2)=[CH:19][CH:18]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc2cc(-c3ccc(Br)cc3)sc2c1
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc2cc(-c3ccc(Br)cc3)sc2c1)C(F)(F)F

Procedure:
Tf2O was added slowly to a mixture of 2-(4-bromo-phenyl)-benzo[b]thiophen-6-ol (200 mg, 0.66 mol) in pyridine (3 mL) at 0° C. with stirring. The mixture was stirred at ambient temperature for 16 hours before quenched with NaHCO3 solution. The mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was used for next step reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:25]1(O)[CH2:34][CH2:33][C:28]2([O:32][CH2:31][CH2:30][O:29]2)[CH2:27][CH2:26]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10][CH:11]([CH:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[C:25]1[CH2:34][CH2:33][C:28]2([O:29][CH2:30][CH2:31][O:32]2)[CH2:27][CH:26]=1
Reactant: CCCCCC1CCC(C2CCC(c3ccc(C4(O)CCC5(CC4)OCCO5)c(F)c3)CC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1CCC(C2CCC(c3ccc(C4=CCC5(CC4)OCCO5)c(F)c3)CC2)CC1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
The compound (T-5) (29.4g), p-toluenesulfonic acid monohydrate (1.47 g) and toluene (800 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 120 minutes while water being distilled was removed. After cooling to room temperature, the reaction mixture was washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure and the residue was purified by means of column chromatography (silica gel; toluene), giving 8-[2-fluoro-4-(4′-pentyl-1,1′-bicyclohexane-4-yl)phenyl]-1,4-dioxaspiro[4,5]decan-7-ene (T-6) (20.5 g). The yield based on the compound (T-4) was 72%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:31])[CH2:13][CH2:12][N:11]([C:14](=[O:28])[C@H:15]([NH:19][C:20]([CH:22]3[CH2:26][CH2:25][C:24](=[CH2:27])[CH2:23]3)=[O:21])[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:30])[CH3:29])=[CH:4][CH:3]=1.C(=O)(O)[O-:33].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([OH:31])[CH2:13][CH2:12][N:11]([C:14](=[O:28])[C@H:15]([NH:19][C:20]([CH:22]3[CH2:26][CH2:25][C:24]4([O:33][CH2:27]4)[CH2:23]3)=[O:21])[CH:16]([CH3:17])[CH3:18])[CH2:10][C:9]2([CH3:29])[CH3:30])=[CH:6][CH:7]=1
Reactant: C=C1CCC(C(=O)N[C@@H](C(=O)N2CC[C@](O)(c3ccc(Cl)cc3)C(C)(C)C2)C(C)C)C1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)C1CCC2(CO2)C1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 5 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A mixture of N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-methylenecyclopentanecarboxamide (535 mg, 1.197 mmol) and sodium bicarbonate (141 mg, 1.676 mmol) in methylene chloride (4 mL) and water (2 mL) was cooled to 5° C. and treated with m-CPBA (318 mg, 1.436 mmol). The mixture was stirred at 5° C. for 1 hour, then allowed to warm to room temperature and stirred for 18 hours. The mixture was cooled to 5° C., treated with saturated sodium sulfite, and stirred at room temperature for 30 minutes. The layers were separated, and the aqueous phase was extracted 3× with methylene chloride. The organic phases were combined and concentrated in vacuo, and the residue was taken up in ethyl acetate. The solution was washed 3× with saturated sodium carbonate, once with water, and once with brine, then dried over sodium sulfate, and concentrated in vacuo to yield the title compound (535 mg, 1.155 mmol, 97% yield) as a glass and a mixture of diastereomers. 1H NMR (400 MHz, CD3OD) (NMR shows several rotomers) δ ppm 7.54-7.40 (m, 2 H), 7.37-7.26 (m, 2 H), 4.90-4.82 (m, 1 H+H2O), 4.63-4.48 (m, 0.6 H), 4.12-3.96 (m, 1 H+residual ethyl acetate), 3.68-3.46 (m, 1.6 H), 3.23-3.02 (m, 1.6 H), 2.98-2.90 (m, 0.4 H), 2.90-2.77 (m, 2 H), 2.76-2.53 (m, 1 H), 2.31-1.79 (m, 6 H+residual ethyl acetate), 1.79-1.64 (m, 1.6 H), 1.60 (bd, 0.4 H, J=14.1 Hz), 1.57-1.48 (m, 0.6 H), 1.04 (dd, 1.4 H, J=6.6, 3.1 Hz), 1.00 (t, 1.6 H, J=6.4 Hz), 0.96-0.90 (m, 3.2 H), 0.87-0.79 (dd, 3 H, J=5.5, 3.0 Hz), 0.79-0.71 (m, 3 H).
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]=1Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH:20]1(B(O)O)[CH2:22][CH2:21]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1CCC(P(C2CCCCC2)C2CCCCC2)CC1>C1(C)C=CC=CC=1.O.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([Si:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]=1[CH:20]1[CH2:22][CH2:21]1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(F)(F)F)c1Cl
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(F)(F)F)c1C1CC1

Procedure:
To a solution of tert-butyl-(2-chloro-3-trifluoromethyl-phenoxy)-dimethyl-silane (268 mg, 0.862 mmol), cyclopropyl boronic acid (96 mg, 1.12 mmol), K3PO4 (641 mg, 3.02 mmol), Pcy3 (24.2 mg, 0.086 mmol), and Pd(OAc)2 (9.7 mg, 0.043 mmol) in toluene/water (4 ml/0.2 ml) was stirred 3 hours at 110° C. and was diluted with Et2O. The residue was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the tert-butyl-(2-cyclopropyl-3-trifluoromethyl-phenoxy)-dimethyl-silane. To a suspension of tert-butyl-(2-cyclopropyl-3-trifluoromethyl-phenoxy)-dimethyl-silane in THF (5 mL) was added a solution of 1M-TBAF (1.12 mL, 1.3 eq), and then was stirred for 30 min at room temperature. The residue was diluted with EtOAc and water. The organic layer was washed with saturated ammonium chloride, water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give tert-butyl-(2-chloro-3-trifluoromethyl-phenoxy)-dimethyl-silane (53 mg, 30%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][CH:9]=[C:8]2[O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2)=[O:4].[OH-].[Li+].Cl>O1CCCC1>[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][CH:9]=[C:8]2[O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2)([OH:4])=[O:2]
Reactant: COC(=O)c1cc2c(Oc3ccc4[nH]ccc4c3)ccnc2cc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
After dissolving 6-methoxycarbonyl-7-methoxy-4-(indol-5-yloxy)quinoline (400 mg) in tetrahydrofuran (5 ml), a 1.5N aqueous lithium hydroxide solution (2.5 ml) was added and the mixture was stirred at room temperature for 3 hours. The reaction solution was adjusted to pH 4 with 1N aqueous hydrochloric acid, and the precipitated crystals were filtered out and washed with ethyl acetate to obtain the title compound (280 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:21]I>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Product: CN1CCN(c2ccc(Cc3ccc(F)cc3)cc2)CC1

Procedure:
The same procedure was followed as in Example 11 using the compound (10) synthesized in Example 3 and methyl iodide to produce the above.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH2:5][C:4]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[N:3]1[CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[CH:24][N:25]2[S:30]([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>CO.[Pd]>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:9][CH2:8]2)[N:3]1[CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[CH:24][N:25]2[S:30]([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)C=CCC45CCN(C(=O)OC(C)(C)C)CC5)cccc32)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)CCCC45CCN(C(=O)OC(C)(C)C)CC5)cccc32)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.8 %

Procedure:
To a solution of tert-butyl 2-oxo-1-((1-tosyl-1H-indol-4-yl)methyl)-1,9-diazaspiro[5.5]undec-3-ene-9-carboxylate (0.12 g, 0.218 mmol) in methanol (6.0 mL) was added 10% Pd/C and the reaction mixture was stirred for 6 h under hydrogen (1 atm. pressure) at rt. The reaction mixture was filtered through a pad of celite and washed with methanol. The filtrate was concentrated and the product was isolated as a white solid (0.120 g, 99%). [LCMS RtE=0.511 min, [M+H]+=551.9]
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][N:31]=1)[C:26](O)=[O:27]>>[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][N:31]=1)[C:26]([NH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[C:5]([CH3:21])=[CH:4][CH:3]=1)=[O:27]
Reactant: Nc1cc(C(=O)O)ccn1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)c2ccnc(N)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
2-Amino-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide and 2-aminoisonicotinic acid using method B. NMR; δH CDCl3 8.20,(1H, d), 7.93,(1H, s), 7.82,(2H, d), 7.60,(1H, d), 7.46,(1H, s), 7.39,(2H,d), 7.30-7.26,(2H, m), 6.96,(1H, s), 6.29,(1H, b), 4.67,(2H, s), 3.34,(2H, m), 2.24,(3H, s), 1.08,(1H, m), 0.59,(2H, m), 0.30,(2H, m). LCMS: retention time 2.75 min, MH+401.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:9]([CH2:17][CH2:18][CH:19]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:30][CH2:31][N:32]([CH2:19][CH2:18][CH2:17][C:9]2[CH:10]=[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:33][CH2:34]1
Reactant: O=CCCc1cc(-c2cccs2)n(-c2ccccc2)n1
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4cccs4)n(-c4ccccc4)n3)CC2)c1C

Procedure:
50 mg (71%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142 mmol), 1-(2,3-dimethylphenyl)piperazine (27 mg, 0.142 mmol), DIPEA (0.040 mL, 0.213 mmol) and NaBH(OAc)3 (90 mg, 0.573 mmol).