Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](OC)=[O:25])=[CH:15][C:13]=2[N:14]=1.[F:28][C:29]1[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:31][C:30]3[CH:32]=[CH:33][CH:34]=[C:35]([C:36]([F:37])([F:38])[F:39])[C:29]=3[F:28])=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: COC(=O)c1cc2nc(Nc3c(C)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: Nc1cccc(C(F)(F)F)c1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3cccc(C(F)(F)F)c3F)c3c(c2[nH]1)CC(C)(C)O3
Yield: 22.7 %

Procedure:
The title compound was prepared by following the procedure as described for Example-137 using methyl 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-35, 0.100 g, 0.207 mmol) and 2-fluoro-3-trifluoromethyl aniline (0.044 g, 0.301 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) and dry toluene (5.0 mL) to afford 0.025 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 2.25 (s, 3H), 3.14 (s, 2H), 7.23-7.33 (m, 2H), 7.39-7.49 (m, 3H), 7.54 (s, 1H), 8.77 (m, 1H), 9.11 (s, 1H), 10.22 (s, 1H), 11.01 (s, 1H): MS [M−H]−: 531.08.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[OH-].[K+].[CH2:11](Cl)[C:12]#[CH:13].O>CS(C)=O>[CH3:8][C:5]1[N:4]=[CH:3][C:2]([O:1][CH2:13][C:12]#[CH:11])=[CH:7][CH:6]=1
Reactant: C#CCCl
Reactant: Cc1ccc(O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C#CCOc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.1 %

Procedure:
To a solution of 25.0 g (0.229 mole) 3-hydroxy-6-methylpyridine in 200 ml DMSO there was added 12.8 g (0.22 mole) powdered potassium hydroxide and 20.0 g (0.266 mole) propargyl chloride. The mixture was stirred at room temperature for 6 hrs. and then poured into an equal volume of water. This mixture was extracted with ether. The ether extract was dried, filtered and concentrated to have 20.5 g crude product. Distillation gave 16.2 g 6-methyl-3-(2-propynyloxy)-pyridine. Yield 48% theory; b.p. 75° C. (1.0 mm); mp 32°-34° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[NH:12][CH:13]=[C:14]([C:16](=[O:27])[NH:17][CH:18]2[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]2)[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=1)=[O:37]>CN(C=O)C>[CH2:1]([O:8][C:9]([C:11]1[N:12]([CH2:35][C:36](=[O:37])[NH:38][C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=2)[CH:13]=[C:14]([C:16](=[O:27])[NH:17][CH:18]2[CH2:23][CH2:22][N:21]([CH:24]([CH3:25])[CH3:26])[CH2:20][CH2:19]2)[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: CC(C)N1CCC(NC(=O)c2c[nH]c(C(=O)OCc3ccccc3)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(NC(=O)c2cc(C(=O)OCc3ccccc3)n(CC(=O)Nc3ccc(Cl)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 39.1 %

Procedure:
To a solution of 4-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1H-pyrrole-2-carboxylic acid benzyl ester (50 mg) in DMF (2 mL) was added Cs2CO3 (176 mg), followed by 2-bromo-N-(5-chloro-pyridin-2-yl)-acetamide (34 mg). The mixture was stirred for 20 h at RT whereupon it was filtered. The filtrates were directly subjected to preparative HPLC(CH3CN/H2O gradient+0.05% TFA). Pure 1-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-pyrrole-2-carboxylic acid benzyl ester (28.5 mg) was obtained as its trifluoroacetate salt. MS (ESI+): m/e=538 [M+H]+, chloro pattern.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([CH:16]=[O:17])[C:11](OCC)=O)=[CH:5][CH:4]=1)#[N:2].[NH2:18][C:19]([NH2:21])=[S:20]>C(O)C>[O:17]=[C:16]1[C:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:11][NH:21][C:19](=[S:20])[NH:18]1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(C=O)Cc1ccc(C#N)cc1
Solvent: CCO
Product: N#Cc1ccc(Cc2c[nH]c(=S)[nH]c2=O)cc1
Temperature: 90 °C
Yield: 69.4 %

Procedure:
To a solution of ethyl 3-(4-cyanophenyl)-2-formylpropanoate (1.3 g, 5.62 mmol) in Ethanol (60 mL) was added thiourea (1.712 g, 22.49 mmol) under argon. The mixture was heated at 90° C. for 3 h. After removing the solvent, the residue was dissolved in water (80 mL), washed with ether twice. The aqueous solution was acidified to pH 4-5 with acetic acid, and the resulting precipitate was collected by filtration, washed with water until the wash waters were neutral to afford the title compound (0.95 g, 3.90 mmol, 69.5% yield). LCMS: rt=1.86 min, [M+H+]=224
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([O:8][C:9]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:31])[C:27]([O:29]C)=O)=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CCO>[NH:2]([C:27](=[O:29])[C:26]([NH:25][C:22]1[CH:21]=[CH:20][C:19]([C@H:16]2[CH2:17][CH2:18][C@H:13]([CH2:12][NH:11][C:9](=[O:10])[O:8][C:4]([CH3:6])([CH3:7])[CH3:5])[CH2:14][CH2:15]2)=[CH:24][CH:23]=1)=[O:31])[NH2:3]
Reactant: NN
Reactant: COC(=O)C(=O)Nc1ccc([C@H]2CC[C@H](CNC(=O)OC(C)(C)C)CC2)cc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1

Procedure:
Prepared using hydrazine hydrate in EtOH from methyl {[4-(trans-4-{[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)phenyl]amino}(oxo)acetate as described for Intermediate 18.1 1H NMR δ 0.99-1.06 (2H, m), 1.37-1.42 (12H, m), 1.77-1.80 (4H, m), 2.39-2.49 (1H, m), 2.81 (2H, t), 4.60 (2H, s), 6.80 (1H, t), 7.19 (2H, d), 7.68 (2H, d), 10.21 (1H, s), 10.45 (1H, s)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)Cl>[N:25]1([C:11](=[O:13])[CH2:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1cccc([N+](=O)[O-])c1)N1CCOCC1
Reaction time: 0.33 h
Yield: 72.4 %

Procedure:
To a stirred suspension of (3-nitro-phenyl)-acetic acid (2 g) in CH2Cl2 (40 ml, with a catalytic amount of DMF) at 0° C. under N2 was added oxalyl chloride (1.1 ml) drop wise. The reaction mixture was stirred for 40 min morpholine (2.5 g) was added. After stirring for 20 min, the reaction mixture was filtered. The filtrate was concentrated in vacuo to yield 1-morpholin-4-yl-2-(3-nitro-phenyl)-ethanone as a solid (2 g). A mixture of 1-morpholin-4-yl-2-(3-nitro-phenyl)-ethanone (2 g) and 10% Pd on activated carbon (0.2 g) in ethanol (30 ml) was hydrogenated at 30 psi for 3 h and filtered over Celite. Removal of the volatiles in vacuo provided 2-(3-amino-phenyl)-1-morpholin-4-yl-ethanone (1.7 g). A solution of 2-(3-amino-phenyl)-1-morpholin-4-yl-ethanone (1.7 g, 7.7 mmol) was dissolved in 6 N HCl (15 ml), cooled to 0° C., and vigorously stirred. Sodium nitrite (0.54 g) in water (8 ml) was added. After 30 min, tin (II) chloride dihydrate (10 g) in 6 N HCl (30 ml) was added. The reaction mixture was stirred at 0° C. for 3 h. The pH was adjusted to pH 14 with solid potassium hydroxide and extracted with EtOAc. The combined organic extracts were concentrated in vacuo provided 2-(3-hydrazin-phenyl)-1-morpholin-4-yl-ethanone (1.5 g). 2-(3-Hydrazinophenyl)-1-morpholin-4-yl-ethanone (3 g) and 4,4-dimethyl-3-oxopentanenitrile (1.9 g, 15 mmol) in ethanol (60 ml) and 6 N HCl (1 ml) were refluxed for 1 h and cooled to RT. The reaction mixture was neutralized by adding solid sodium hydrogen carbonate. The slurry was filtered and removal of the volatiles in vacuo provided a residue that was extracted with ethyl acetate. The volatiles were removed in vacuo to provide 2-[3-(3-tert-butyl-5-amino-1H-pyrazol-1-yl)phenyl]-1-morpholinoethanone (4 g), which was used without further purification.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:20](=[CH:21][CH:22]=2)[O:19][C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:12][C:11]3=[O:23])[CH:5]=[N:4]1.[CH2:24]([O:26][C:27]1[CH:32]=[C:31]([C:33](O)=[O:34])[CH:30]=[C:29]([O:36][CH2:37][CH3:38])[C:28]=1[C:39]1[CH:44]=[CH:43][C:42]([C:45]([O:47][CH3:48])=[O:46])=[C:41]([F:49])[CH:40]=1)[CH3:25]>>[CH2:24]([O:26][C:27]1[CH:32]=[C:31]([C:33]([N:16]2[CH2:15][CH2:14][C:13]3([CH2:12][C:11](=[O:23])[C:10]4[C:20](=[CH:21][CH:22]=[C:8]([C:6]5[CH:5]=[N:4][N:3]([CH3:2])[CH:7]=5)[CH:9]=4)[O:19]3)[CH2:18][CH2:17]2)=[O:34])[CH:30]=[C:29]([O:36][CH2:37][CH3:38])[C:28]=1[C:39]1[CH:44]=[CH:43][C:42]([C:45]([O:47][CH3:48])=[O:46])=[C:41]([F:49])[CH:40]=1)[CH3:25]
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)cn1
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1ccc(C(=O)OC)c(F)c1
Agent: Cl
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cnn(C)c4)ccc2O3)cc(OCC)c1-c1ccc(C(=O)OC)c(F)c1

Procedure:
In the same manner as in Reference Example 3-1, the intended compound was obtained as a colorless solid using 6-(1-methyl-1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride and 2,6-diethoxy-3′-fluoro-4′-(methoxycarbonyl)biphenyl-4-carboxylic acid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:25]=[CH:24][C:11]2[NH:12][C:13]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][N:16]=3)=[N:14][C:10]=2[CH:9]=1)=[O:7])#[N:2].[N:26]([Sn](CCCC)(CCCC)CCCC)=[N+:27]=[N-:28].C(#N)C.O1CCCC1>C(O)(=O)C>[N:2]1[NH:26][N:27]=[N:28][C:1]=1[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:25]=[CH:24][C:11]2[NH:12][C:13]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][N:16]=3)=[N:14][C:10]=2[CH:9]=1)=[O:7]
Reactant: N#CCCNC(=O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C(NCCc1nn[nH]n1)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Temperature: 25 °C

Procedure:
A stirred solution of 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-cyano-ethyl)-amide [150 mg, Example 246(s)] and azidotributyltin (2 ml) was heated at 95° C. for 24 hours. The reaction was cooled to ambient temperature and stirred for 2 hours with acetonitrile (20 ml), tetrahydrofuran (10 ml) and acetic acid (20 ml). The reaction mixture was washed with iso-hexane (6×80 ml) and concentrated in vacuo. The residue was subjected to preparative HPLC to give 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid [2-(2H-tetrazol-5-yl)-ethyl]-amide (35.9 mg) as a brown solid. LC-MS (Method L): RT=9.80 minutes, 374.21 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([C@@H:15]2[CH2:17][C@H:16]2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32]([NH2:34])=[O:33])[CH2:27][CH2:26]1>CN1C(=O)CCC1.CS(C)=O.CO>[CH3:11][C:9]1[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([CH:15]3[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][CH:28]([NH:31][C:32]([NH2:34])=[O:33])[CH2:27][CH2:26]3)[N:7]2[N:8]=1
Reactant: NC(=O)NC1CCNCC1
Reactant: Cc1cc2nc(NC(=O)[C@@H]3C[C@H]3c3ccncc3)cc(Cl)n2n1
Agent: Cl
Solvent: CS(C)=O
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cc1cc2nc(NC(=O)C3CC3c3ccncc3)cc(N3CCC(NC(N)=O)CC3)n2n1
Temperature: 25 °C
Yield: 5.9 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-(pyridin-4-yl)cyclopropanecarboxamide (7E, 154 mg, 0.469 mmol) and 1-(piperidin-4-yl)urea hydrochloride (169 mg, 0.939 mmol) in NMP (1.5 mL) was stirred at room temperature overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (10-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (12 mg, 2%). 1H NMR (DMSO-d6) δ: 10.97 (s, 1H), 8.33-8.52 (m, 2H), 7.07-7.37 (m, 4H), 6.08 (s, 2H), 5.41 (s, 2H), 4.24 (br. s., 2H), 3.65 (br. s., 2H), 3.16 (br. s., 2H), 2.35 (s, 3H), 1.89 (br. s., 2H), 1.50 (br. s., 4H). ESI-MS: m/z 435.0 (M+H)+.
Reaction SMILES: CC1(C)N([O])C(C)(C)CCC1.[OH:12][CH2:13][CH2:14][C:15]1([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[CH:13]([CH2:14][C:15]1([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)=[O:12]
Reactant: OCCC1(CCN2CCOCC2)CCCCC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: ClCCl
Product: O=CCC1(CCN2CCOCC2)CCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 143.5 %

Procedure:
After adding 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (32 mg, 0.20 mmol) to a solution of 4-[2-[1-(2-hydroxyethyl)cyclohexyl]ethyl]morpholine (439 mg, 1.82 mmol) and iodobenzene diacetate (644 mg, 2.00 mmol) in methylene chloride (10 mL), the mixture was stirred at room temperature for 14 hours. The reaction mixture was washed with saturated aqueous sodium hydrogencarbonate and saturated brine in that order and dried (anhydrous sodium sulfate), and then the solvent was distilled off under reduced pressure to obtain the title compound as a brown oil (625 mg). This was used without purification for the following step.
Reaction SMILES: CCN(/[CH:6]=[C:7](/[C:11]([O:13][CH2:14][CH3:15])=[O:12])\[C:8]([CH3:10])=O)CC.Cl.[C:17]([NH:21][NH2:22])([CH3:20])([CH3:19])[CH3:18]>CCO>[C:17]([N:21]1[C:8]([CH3:10])=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[N:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)NN
Reactant: CCOC(=O)/C(=C/N(CC)CC)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(C(C)(C)C)c1C
Temperature: 25 °C
Yield: 96 %

Procedure:
A stirred solution of diethylaminomethylene ethyl acetoacetate (552 mg, 2.8 mmol, see R. A. Fecik, P. Devasthale, S. Pillai, A. Keschavarz-Shokri, L. Sehn, and L. A. Mitscher; J. Med. Chem. 2005, 48, 1229) and tert-butyl hydrazine hydrochloride (387 mg, 3.1 mmol) in EtOH (5 mL) was heated to reflux for 15 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc and saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure to provide ethyl 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylate (560 mg, 96%) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:7]([S:8][C:9]([F:12])([F:11])[F:10])=[C:6](C=O)[N:5]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[Cl:26])[N:4]=1)#[N:2].[CH3:27][O:28][CH:29](OC)[O:30][CH3:31].C(OCC)C>CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:3]1[C:7]([S:8][C:9]([F:10])([F:12])[F:11])=[C:6]([CH:29]([O:30][CH3:31])[O:28][CH3:27])[N:5]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:23])[F:24])=[CH:17][C:16]=2[Cl:26])[N:4]=1)#[N:2]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(C=O)c1SC(F)(F)F
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: COC(OC)c1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 76.2 %

Procedure:
The product of Example 3 (2.0 g, 0.005 mol) was combined with trimethylorthoformate (10 ml, 0.09 mol) and para-toluenesulfonic acid monohydrate (50 mg, catalytic) in anhydrous methanol. The mixture was refluxed for 72 hours, cooled to room temperature, poured into diethyl ether, washed with a 1:1 mixture of 10% aqueous sodium hydroxide solution and concentrated aqueous sodium chloride solution (100 ml), water (100 ml) and saturated aqueous sodium chloride solution (100 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to leave an oil that was purified by silica gel chromatography using a 3:1 hexane:dichloromethane solvent mixture. This provided the title compound as a white solid (1.83 g), m.p. about 93° C. Also prepared by this method: Compound 18.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:41])=[C:4]([C@H:8]2[CH2:12][N:11]([CH2:13][C:14]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[O:15])[C@@H:10]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C@@:9]2([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[F:40])[C:31]#[N:32])[CH:5]=[CH:6][CH:7]=1.N.C[N:44](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:41])=[C:4]([C@H:8]2[CH2:12][N:11]([CH2:13][C:14]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:44])=[O:22])=[CH:19][CH:18]=3)=[O:15])[C@@H:10]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C@@:9]2([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[F:40])[C:31]#[N:32])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)C[C@@H]1N(CC(=O)Nc2ccc(C(=O)O)cc2)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N(CC(=O)Nc2ccc(C(N)=O)cc2)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Yield: 100.1 %

Procedure:
A mixture of rac-4-{2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetylamino}-benzoic acid (0.33 g, 0.55 mmol), a solution of ammonia (0.5 M in dioxane, Aldrich, 2 mL, 1 mmol), HATU (0.3 g, 0.79 mmol) and iPr2NEt (0.3 g, 2.33 mmol) in CH2Cl2 (20 mL) was stirred at room temperature for 20 h. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by chromatography (EtOAc) to give rac-4-{2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetylamino}-benzamide as a white solid (0.33 g, 100%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([CH3:19])=[C:13]([Br:18])[C:14]([CH3:17])=[C:15]([CH3:16])[C:10]=2[O:9][CH:8]=1)(=O)=O.[CH2:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)[CH3:23].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.O.C1(C)C=CC=CC=1>[Br:18][C:13]1[C:14]([CH3:17])=[C:15]([CH3:16])[C:10]2[O:9][CH:8]=[C:7]([C:27]3[CH:28]=[CH:29][C:24]([CH2:22][CH3:23])=[CH:25][CH:26]=3)[C:11]=2[C:12]=1[CH3:19]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: Cc1c(Br)c(C)c2c(OS(=O)(=O)C(F)(F)F)coc2c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccc(-c2coc3c(C)c(C)c(Br)c(C)c23)cc1
Yield: 92 %

Procedure:
A mixed solution of 5-bromo-4,6,7-trimethyl-1-benzofuran-3-yl trifluoromethanesulfonate obtained in Reference Example 261 (1.35 g, 3.49 mmol), 4-ethylphenyl boronic acid (523 mg, 3.49 mmol), tetrakis(triphenylphosphine)palladium(0) (81 mg, 0.07 mmol) in a 2 N aqueous sodium carbonate solution (4 mL)-ethanol (4 mL)-toluene (15 mL) was reacted under argon atmosphere at 80° C. for 5 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The combined organic layer was washed with a saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane) to obtain 1.10 g (yield 92%) of the title compound. Oily matter.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:7]1[CH2:12][O:11][CH:10]=[CH:9][CH2:8]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>ClCCl.C1COCC1>[O:11]1[CH2:12][CH2:7][CH2:8][CH2:9][CH:10]1[O:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C(O)CCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a mixture of 3-hydroxypropanoic acid (7.2 g, 80 mmol, TCI, TOKYO KASEI) and DHP (13.4 g, 160 mmol, Alfa) in dichloromethane (100 mL) and THF (100 mL) was added PPTS (2 g, 8 mmol, Aldrich) in portions. The reaction mixture was stirred at rt overnight, and was quenched with 50 mL of saturated NaHCO3 aqueous solution. The resulted mixture was extracted with dichloromethane (50 mL×5). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (1:1 (v/v) petroleum ether/EtOAc) to give colorless oil (7.8 g, 56%).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[HeH]O.C[O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#N)=[CH:12][CH:11]=1.O>C1C=CC=CC=1.CCOCC>[O:9]1[CH:12]2[CH2:11][CH:10]1[CH2:17][C:16]1[C:13]2=[CH:14][CH:3]=[CH:2][CH:1]=1
Reactant: [Li]CCCC
Reactant: COc1ccc(C#N)cc1
Agent: [HeH]O
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: c1ccc2c(c1)CC1CC2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Butyl lithium (1.6M hexane solution: 36 ml) was added dropwise to a solution of helioalcohol (4.0 g) in benzene (100 ml) at room temperature. The mixture was stirred at room temperature for one hour, followed by addition of 4-methoxybenzonitrile (3.85 g) in benzene (20 ml). The mixture was stirred at room temperature overnight, followed by addition of water and extraction with ether. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in toluene (75 ml), followed by addition of dimethyl fumarate (7.58 g) and trichloroacetic acid (0.3 g). The mixture was refluxed for 3 hours and concentrated under reduced pressure. The reside was dissolved in ethyl acetate and washed with water, an aqueous saturated sodium hydrogen carbonate solution and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (silica gel: 50 g. eluent:ethyl acetate−hexane=1:2) to yield tetrahydro-2,4-epoxynaphthalene derivative (2.84 g) as a mixture of diastereoisomers. This was dissolved in a mixture of THF (5 ml) and methanol (5 ml), followed by addition of an aqueous NaOH (1.1 g) solution (5 ml). The mixture was stirred overnight and concentrated under reduced pressure. After being diluted with water, the mixture was washed with ethyl acetate. Conc. HCl was added to the aqueous layer until its pH becomes about 2.The mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ether (50 ml), followed by addition of conc. HCl. The mixture was refluxed for 10 minutes and concentrated under reduced pressure, followed by addition of water. The resulting precipitate was collected by filtration and washed with methanol and ether to yield the title compound (2.64 g).