Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(C=O)=CC3C4C=CC=CC=4C=CC=3C=2OC=1.[CH:20]([C:22]1[C:30]2[C:25](=[C:26]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[S:31][C:27]3=[CH:28][CH:29]=2)[N:24](C)[C:23]=1[C:39](OCC)=O)=[O:21]>>[CH3:39][C:23]1[NH:24][C:25]2[C:30]([C:22]=1[CH:20]=[O:21])=[CH:29][CH:28]=[C:27]1[S:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:26]=21
Reactant: CCOC(=O)c1c(C=O)c2ccc3sc4ccccc4c3c2n1C
Agent: O=Cc1cc2c3ccccc3ccc2c2occc12
Product: Cc1[nH]c2c(ccc3sc4ccccc4c32)c1C=O
Yield: 31.8 %

Procedure:
Using the procedure outlined in 15B, ethyl 3-formyl-1-methyl-1H-[1]benzothieno[2,3-g]indole-2-carboxylate gave a 31.8% yield of 2-methyl-1H-[1]benzothieno[2,3-g]indole-3-carbaldehyde, mp 192°-194°, (CH2Cl2 /petroleum ether), (C,H,N).
Reaction SMILES: [O:1]([CH2:9][C@H:10]1[C@@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:30])[O:11]1)[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:1][CH2:9][C@H:10]1[C@@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:30])[O:11]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C1COCCN1c1ccc2c(c1)OC[C@@H]1[C@H](CO)OC(=O)N21
Yield: 64 %

Procedure:
Using compound (3R,3 aR)-3-((t-butyldimethylsiloxy)methyl)-7-(3-oxomorpholin-4-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1(3H)-one (0.597 g, 1.38 mmol) prepared above in (a), and tetra-n-butylammonium fluoride (1M, 2.8 ml) as starting materials, preparation following the method as described in Example 1 (b) afforded 0.283 g of white solid, yield 64.3%.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:31])([C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:9])[CH2:3]1.[CH:33]([Sn](CCCC)(CCCC)CCCC)=[CH2:34]>O1CCOCC1>[F:1][C:2]1([F:32])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:31])([C:24]2[CH:29]=[CH:28][C:27]([CH:33]=[CH2:34])=[CH:26][CH:25]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(OC(=O)[C@](O)(c2ccc(Br)cc2)[C@@H]2CCC(F)(F)C2)CC1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: C1COCCO1
Product: C=Cc1ccc([C@@](O)(C(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)[C@@H]2CCC(F)(F)C2)cc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To a solution of 125 mg of the t-butyl 4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoyloxy)-tetrahydropyridine-1(2H)-carboxylate as obtained in Referential Example 52 in 4 ml of dioxane, 0.10 ml of vinyl tri-n-butyltin and 20 mg of tetrakistriphenylpalladium were added at room temperature, followed by 24 hours' heating under reflux at 110° C. in nitrogen atmosphere. Distilling the solvent off under reduced pressure, the resulting residue was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to provide 90 mg of the title compound.
Reaction SMILES: C1(O)C=CC=CC=1.[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([OH:26])=[CH:23]2)=[CH:18][C:17]=1[Br:27])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36]>>[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([O:26][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:23]2)=[CH:18][C:17]=1[Br:27])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Oc1ccc2cc(Br)c(OCc3ccccc3)cc2c1
Reactant: CC(C)(C)OC(=O)NCCCBr
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)NCCCOc1ccc2cc(Br)c(OCc3ccccc3)cc2c1
Yield: 3 %

Procedure:
Following GENERAL METHOD 5-1 for phenol alkylation using 7-(benzyloxy)-6-bromonaphthalen-2-ol (506.5 mg, 1.54 mmol) and tert-butyl 3-bromopropylcarbamate (409 mg, 1.72 mmol) and after column chromatography (eluting with 3-80% EtOAc/heptane) tert-butyl (3-((7-(benzyloxy)-6-bromonaphthalen-2-yl)oxy)propyl)carbamate was obtained as an off-white solid (706 mg, 94% yield). MS (M-Boc)=388.3. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.99 (s, 1H), 7.59 (d, J=9.60 Hz, 1H), 7.54 (d, J=8.08 Hz, 2H), 7.42 (t, J=7.58 Hz, 2H), 7.32-7.37 (m, 1H), 7.13 (s, 1H), 7.05-7.00 (m, 2H), 5.26 (s, 2H), 4.68 (br. s, 1H), 4.14 (t, J=6.06 Hz, 2H), 3.37 (q, J=6.40 Hz, 2H), 2.09-2.01 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Clc1nc(NCc2ccc(Cl)c(Cl)c2)c2c3c(sc2n1)CCCC3
Reactant: c1c[nH]cn1
Product: Clc1ccc(CNc2nc(-n3ccnc3)nc3sc4c(c23)CCCC4)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-dichlorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-dichlorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[C:25]([F:44])=[CH:26][CH:27]=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:48])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[C:25]([F:44])=[CH:26][CH:27]=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:46][CH2:47]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1c(F)cccc1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OC/C=C/C[C@H](C)Oc1c(F)cccc1-c1cccc-3c1
Agent: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OC/C=C/C[C@H](C)Oc1c(F)cccc1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1c(F)cccc1-c1cccc-3c1

Procedure:
Prepared in 95% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S,24E)-19-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.99 (d, J=7.7 Hz, 1H), 7.95 (s, 1H), 7.56 (t, J=7.5 Hz, 1H), 7.40 (d, J=7.7 Hz, 1H), 7.33-7.24 (m, 2H), 7.21 (dd, J=8.1, 5.1 Hz, 1H), 7.17 (s, 1H), 6.14 (dt, J=14.4, 7.3 Hz, 1H), 5.78 (d, J=14.7 Hz, 1H), 5.73 (br. s., 1H), 4.36 (br. s., 1H), 4.09 (t, J=11.0 Hz, 1H), 4.01-3.92 (m, 2H), 3.64-3.41 (m, 2H), 2.69 (d, J=10.6 Hz, 1H), 2.41 (s, 3H), 2.14-2.05 (m, 1H), 1.99-1.89 (m, 2H), 1.72-1.67 (m, 3H), 1.25 (s, 3H), 1.15 (s, 9H), 0.80 (d, J=5.9 Hz, 3H); LCMS (ESI, M): 641.3.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=2)[C:10]([C:22](O)=[O:23])=[C:9]1[CH:25]([CH3:27])[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:36][NH2:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=2)[C:10]([C:22](=[O:23])[NH:37][CH2:36][C:35]2[CH:38]=[CH:39][C:40]([F:41])=[C:33]([F:32])[CH:34]=2)=[C:9]1[CH:25]([CH3:26])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccc3)c2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
General Procedure E. To a solution of 1-benzyl-6-(ethoxylcarbonyl)-2-isopropyl-1H-indole-3-carboxylic acid (Compound 39, 1.00 g, 2.74 mmol) in CH2Cl2 (10 ml) was added EDC (1.04 g, 5.84 mmol) and DMAP (500 mg, 4.11 mmol), followed by 3,4-difluorobenzylamine (589 mg, 4.11 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→35% EtOAc-hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][N:6]([C:15]([N:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22]1)=[C:16]([C:19]#[N:20])[C:17]#[N:18])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[CH3:2].[H-].[Na+].O>O1CCCC1>[NH2:18][C:17]1[C:16]([C:19]#[N:20])=[C:15]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22]2)[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:35]
Reactant: CCOC(=O)CN(Cc1ccccc1Cl)C(=C(C#N)C#N)N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(N)c(C#N)c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n1Cc1ccccc1Cl
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A solution of N-(1-{(3R)-3-[(tertbutoxycarbonyl)amino]piperidin-1-yl}-2,2-dicyanovinyl)-N-(2-chlorobenzyl)glycine ethyl ester (320 mg) in tetrahydrofuran (5 ml) was cooled to 0° C., followed by adding thereto sodium hydride (33 mg), and the resulting mixture was stirred for 1 hour while being warmed to 25° C. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to obtain the title compound (300 mg).
Reaction SMILES: CC(N=C=NC(C)C)C.Cl.[CH3:11][O:12][C:13](=[O:23])[C@H:14]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH2:15].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([NH:15][C@@H:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([O:12][CH3:11])=[O:23])=[O:32])=[CH:26][CH:25]=1
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)Cc1ccc(C)cc1

Procedure:
DMAP (194 mg, 1.58 mmol) and DIC (N,N-diisopropylcarbodiimide) (740 μl, 4.76 mmol) were added to a solution of L-phenylalanine methyl ester hydrochloride (684 mg, 3.17 mmol) and p-tolylacetic acid (500 mg, 3.33 mmol) in dry DCM (35 ml). After 24 h at room temperature the solvent was removed under reduced pressure and the crude residue was purified by flash chromatography (DCM containing 1% EtOH) to afford (S)-methyl 2-[2-(4-methylphenyl)acetamido]-3-phenyl-propanoate in quantitative yield. The product was diluted with methanol (78 ml) and then an aqueous solution of NaOH (1N, 14.2 ml, 14.2 mmol) was added. The reaction mixture was stirred for 1 h at room temperature and concentrated. Then water and HCl 1N was added until pH 2. The organic product was extracted with DCM (3×50 ml), dried with Na2CO3 and concentrated under reduced pressure to afford (S)-2-[2-(4-methylphenyl)acetamido]-3-phenyl-propionic acid as a white solid (94% c.y.)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH:24]=[C:23]([Sn](CCCC)(CCCC)CCCC)[N:22]=[CH:21]1>C1(C)C=CC=CC=1.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>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:23]1[N:22]=[CH:21][N:20]([CH3:19])[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1cnc(-c2cc3nc(Cl)ccc3n2Cc2ccccc2)c1
Temperature: 110 °C

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.10 g, 0.31 mmol, from Example 62, Step 2) and 1-methyl-4-(tributylstannyl)-1H-imidazole (0.12 g, 0.31 mmol, Aldrich) in toluene (6.0 mL) was degassed. Tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.031 mmol) was added and the mixture was heated to 110° C. for 7 hours. Toluene was removed in vacuo and the mixture was dissolved in MeCN and filtered. Flash chromatography, eluting with a gradient from 0-70% EtOAc in hexanes afforded purified product (24 mg, 24%).
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[O:26])[O:24][C:23]([CH3:28])([CH3:27])[O:22][C:21]=3[CH:29]=2)[C:8](=[O:16])[CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH2:32]([C:35]1[CH:40]=[CH:39][C:38]([C:41]#[CH:42])=[CH:37][CH:36]=1)[CH2:33][CH3:34]>>[CH2:32]([C:35]1[CH:36]=[CH:37][C:38]([C:41]#[C:42][C:2]2[CH:31]=[CH:30][C:5]([CH2:6][N:7]([C:17]3[CH:18]=[CH:19][C:20]4[C:25](=[O:26])[O:24][C:23]([CH3:27])([CH3:28])[O:22][C:21]=4[CH:29]=3)[C:8](=[O:16])[CH2:9][CH2:10][CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)=[CH:4][CH:3]=2)=[CH:39][CH:40]=1)[CH2:33][CH3:34]
Reactant: CC1(C)OC(=O)c2ccc(N(Cc3ccc(Br)cc3)C(=O)CCC3CCCC3)cc2O1
Reactant: C#Cc1ccc(CCC)cc1
Product: CCCc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1

Procedure:
The titled compound was prepared following the procedure N using N-(4-bromobenzyl)-3-cyclopentyl-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)propanamide and 4-propylphenylacetylene as a white powder (40%). M+ (ESI): 550.1. HPLC, Rt: 6.33 min (Purity: 100%).
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].CC(C)([O-])C.[K+].[F:11][CH:12]([F:25])[N:13]([CH3:24])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1Cl)(=[O:16])=[O:15]>CN(C=O)C>[F:11][CH:12]([F:25])[N:13]([CH3:24])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:4][CH2:1][CH2:2][CH3:3])(=[O:16])=[O:15]
Reactant: CN(C(F)F)S(=O)(=O)c1ccccc1Cl
Reactant: CCCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1ccccc1S(=O)(=O)N(C)C(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 14.62 ml of n-propylmercaptan, 16.3 g of potassium t-butoxide and 400 ml of DMF at 0° C. was added 27.45 g (0.1076 mole) of N-difluoromethyl-N-methyl-2-chlorobenzenesulfonamide in 100 ml of DMF. The reaction mixture was stirred at room temperature for 2 days and then at 60° C. for 4 hours. The mixture was then concentrated and the residue was partitioned between 1N HCl solution and methylene chloride. The organic layer was separated, dried over MgSO4, and concentrated. The residue was chromatographed on silica gel (Hexane/chloroform 3:2) to yield 24.63 g of N-difluoromethyl-N-methyl-2-(n-propylthio)benzenesulfonamide as an oil.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[F:29][C:30]1[CH:31]=[C:32]([CH:38]=[C:39]([F:42])[C:40]=1[F:41])/[CH:33]=[CH:34]/[C:35](O)=[O:36]>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:35](=[O:36])/[CH:34]=[CH:33]/[C:32]4[CH:31]=[C:30]([F:29])[C:40]([F:41])=[C:39]([F:42])[CH:38]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Reactant: O=C(O)/C=C/c1cc(F)c(F)c(F)c1
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2cc(F)c(F)c(F)c2)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J, and trans-3,4,5-trifluorocinnamic acid, by the method of Example 1, step K, giving a yellow solid that was a mixture of cyclohexyl diastereomers by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C30H33F3N4O2: 539 (M+H). Found: 539
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][NH:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH2:3]1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28](=[O:42])[NH:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](O)=[O:38])=[CH:32][C:31]=1[O:40][CH3:41].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CCOC(C)=O.CN(C=O)C>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28](=[O:42])[NH:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([N:5]2[CH2:6][C:2]([F:1])([F:19])[CH2:3][CH:4]2[CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[O:38])=[CH:32][C:31]=1[O:40][CH3:41]
Reactant: COC(=O)c1ccc(OCC2CC(F)(F)CN2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CC(F)(F)CN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Cl)c(OC)c2)cc1
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture of methyl 4-(4,4-difluoro-2-pyrrolidinylmethoxy)benzoate (229 mg, 0.845 mmol), 4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (283 mg, 0.845 mmol), EDC.HCl (243 mg, 1.27 mmol), HOBt (cat.), DMAP (cat.), and DMF (10 ml) was stirred overnight. The mixture was diluted with EtOAc (300 ml). The solution was washed with brine (2×100 ml), dried over MgSO4, and concntrated in vacuo. The residue was chromatographed on silica gel with CHCl3-EtOAc (20:1 to 4:1) as eluent to give methyl 4-[1-[4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-4,4-difluoro-2-pyrrolidinylmethoxy]benzoate (482 mg, 97%) as a colorless viscous solid. 1H-NMR (CDCl3) δ2.50-2.67 (m, 2 H), 3.54-4.71 (series of m, 13 H), 6.69 (d, J=1.5 Hz, 1 H), 6.76 (d, J=8.3 Hz, 1 H), 6.84 (d, J=8.8 Hz, 2 H), 6.98 (dt, J=7.8, 1.5 Hz, 1 H), 7.23-7.27 (m, 1 H), 7.33 (d, J=8.3 Hz, 1 H), 7.39 (m, 2 H), 7.94 (d, J=8.8 Hz, 2 H), 8.00 (d, J=8.3 Hz, 1 H), 8.19 (dd, J=8.3, 1.5 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][O:8][CH:9]=[CH:10][C:11]([O:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH2:12]>C1(C)C=CC=CC=1>[CH3:6][O:5][C:1]([CH:2]1[CH2:3][CH2:12][C:11]([O:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]1[O:8][CH3:7])=[O:4]
Reactant: C=C(C=COC)O[Si](C)(C)C
Reactant: C=CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C1CCC(O[Si](C)(C)C)=CC1OC
Temperature: 80 °C

Procedure:
A mixture of methyl acrylate (5.23 mL, 58.0 mmol) and 1-methoxy-3-(trimethylsiloxy)-1,3-butadiene (from Aldrich, 10.0 g, 58.0 mmol) in toluene (100 mL) was heated at 80° C. for 2 d. The reaction solution was concentrated and purified on silica gel column to give the desired product as a mixture of trans- and cis-isomers (8.3 g, 55%). 1H NMR (500 MHz, CDCl3) δ 5.16 (1H, m), 4.97 (1H, m), 4.22 (1H, m), 4.08 (1H, m), 3.68 (3H, s), 3.67 (3H, s), 3.32 (3H, s), 3.24 (3H, s), 2.59 (1H, m), 2.51 (1H, m), 1.80-2.14 (8H, m), 0.18 (18H, s) ppm.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[NH:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[N:50]1([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]3=[O:12])=[CH:4][CH:3]=2)[CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(Cl)cc12
Reactant: C1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(N3CCCC3)cc12
Yield: 50.4 %

Procedure:
A mixture consisting of 500 mg (1.54 mmol) of the 7-chloro-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one prepared in Step B of Example 1; 45.0 mg (0.15 mmol) of 2-(di-t-butylphosphino)biphenyl; 17.0 mg (0.075 mmol) of palladium acetate; and 713 mg (7.42 mmol) of sodium t-butoxide, was suspended in 15 ml of toluene. Thereafter, 0.533 ml (6.39 mmol) of pyrrolidine was added to the above suspension, and the obtained mixture was then stirred under heating to reflux for 2 hours. Thereafter, the reaction solution was stood to cool, and water was then added thereto, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and was then concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5), so as to obtain 277.9 mg (50%) of 7-pyrrolidin-1-yl-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:44])([CH3:43])[CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C@H:8]([CH2:11][C:12](=[O:31])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:15][CH2:14]2)[S:7][CH:6]1[C:32]1[S:36][C:35]([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[N:34][CH:33]=1.[CH:45](=O)[CH:46]([CH3:48])[CH3:47].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]([CH3:44])([CH3:43])[CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C@H:8]([CH2:11][C:12](=[O:31])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:15][CH2:14]2)[S:7][CH:6]1[C:32]1[S:36][C:35]([CH:37]2[CH2:38][CH2:39][N:40]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:41][CH2:42]2)=[N:34][CH:33]=1
Reactant: CC(C)C=O
Reactant: CC(C)(C)CCN1C(=O)[C@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)SC1c1cnc(C2CCNCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CN1CCC(c2ncc(C3S[C@@H](CC(=O)N4CCC(N5CCc6ccccc6NC5=O)CC4)C(=O)N3CCC(C)(C)C)s2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.7 %

Procedure:
To a solution of (5S)-3-(3,3-dimethylbutyl)-5-(2-oxo-2-(4-(2-oxo-4,5-dihydro-1H-benzo[d][1,3]diazepin-3(2H)-yl)piperidin-1-yl)ethyl)-2-(2-(piperidin-4-yl)thiazol-5-yl)thiazolidin-4-one (30 mg, 0.04 mmol, 1 eq) in DCM (3 mL) was added isobutyraldehyde (6 mg; 0.08 mmol, 2 eq) and NaBH(OAc)3 (27 mg, 0.12 mmol, 3 eq). The reaction mixture was stirred at RT for 18 h, then quenched with MeOH (0.1 mL) and sat. NaHCO3 (1 mL). The reaction mixture was diluted with DCM (10 mL) and washed with water (5 mL), brine (5 mL), dried (MgSO4) and then concentrated in vacuo. The residue was purified by column chromatography over silica gel eluted with 2 to 10% MeOH in DCM to afford (5S)-3-(3,3-dimethylbutyl)-2-(2-(1-isobutylpiperidin-4-yl)thiazol-5-yl)-5-(2-oxo-2-(4-(2-oxo-4,5-dihydro-1H-benzo[d][1,3]diazepin-3(2H)-yl)piperidin-1-yl)ethyl)thiazolidin-4-one (23 mg, 79% yield). (M+1) 695. 1H NMR (CDCl3) δ 7.70 (m, 3H), 6.90 (t, J=7.2 Hz, 1H), 6.70 (d, J=7.5 Hz, 1H), 6.49 (NH, 1H), 5.65 (m, 1H), 4.74 (m, 1H), 4.44 (m, 1H), 3.93 (m, 1H), 3.65 (m, 1H), 3.45-3.35 (m, 3H), 3.17-2.59 (m, 9H), 2.09-1.41 (m, 15H), 1.35 (m, 1H), 1.00-0.85 (m, 15H) ppm.