Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C@@H:10]([OH:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:18][CH:19]=2)[C@@H:10]([OH:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1COCCCCl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(O)cc2)[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2O)cc1
Temperature: 120 °C
Reaction time: 26 h
Yield: 95.8 %

Procedure:
A solution of 16.50 g (56.24 mmol) of (3R,4R)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester in 40 ml of N,N-dimethylformamide was treated in succession with 12.68 g (59.06 mmol) of 1-(3-chloro-propoxymethyl)-2-methoxy-benzene (WO 97/09311) and 12.44 g (90.00 mmol) of potassium carbonate. This mixture was stirred at 120° C. for 26 hours. Subsequently, the salts were filtered off and washed with dichloromethane. The filtrate was concentrated in a high vacuum to eliminate most of the N,N-dimethylformamide, poured into 300 ml of an ice/water mixture and the aqueous phase was extracted three times with 100 ml of dichloromethane. The combined organic phases were washed once with a small amount of water, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The thus-obtained crude product (31.64 g) was separated on silica gel using a 99:1 mixture of dichloromethane and methanol as the eluent and yielded 25.4 g (53.85 mmol, 95.8% of theory) of (3R,4R)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a slightly yellow oil; MS: 489 (M+NH4+)+.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12]O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]C(Br)(Br)Br>C(Cl)Cl>[Br:33][CH2:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]1
Reactant: BrC(Br)(Br)Br
Reactant: CCCCC[C@H]1CC[C@H](CO)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](CBr)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
A solution of 3.69 g of (trans-4-pentylcyclohexyl)methanol and 5.51 g of triphenylphosphine in 70 ml of methylene chloride at -30° C. was placed under argon gasification and treated portionwise within 15 minutes with 7.30 g of solid tetrabromomethane so that the internal temperature did not exceed -20° C. After completion of the addition, the cooling bath was removed and the mixture was stirred for a further 18 hours with gradual warming to room temperature. The mixture was then concentrated on a rotary evaporator and the semi-crystalline residue obtained was triturated with 200 ml of warm hexane, filtered and the concentrated filtrate was chromatographed with hexane on a column of silica gel. There were obtained 4.79 g (97%) of trans-1-(bromomethyl)-4-pentylcyclohexane as a colourless liquid which was purified further by distillation; b.p. 82° C./0.08 mmHg.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[C:8]1([C:14]#[C:15][C:16]2[CH:34]=[CH:33][C:19]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29](=[O:32])(=[O:31])[NH2:30])=[O:21])=[CH:18][CH:17]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:8]1([C:14]#[C:15][C:16]2[CH:34]=[CH:33][C:19]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29]([NH:30][C:5](=[O:7])[CH3:6])(=[O:31])=[O:32])=[O:21])=[CH:18][CH:17]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
In a stream of nitrogen and at 0° C., 0.15 ml (1.60 mmol) of acetic anhydride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 500 mg (1.30 mmol) of 4-phenylethynyl-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 10 and 320 mg (2.60 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was recrystallized from methanol to obtain 430 mg (yield: 77.6%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[NH:10][C:9]3[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:8]=3[N:7]([C:17]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([CH3:27])[CH:20]=3)=[O:18])[CH2:6][C:5]=2[CH:4]=[N:3]1.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.N1CCCC(=O)C2C=CC=CC1=2.[BH4-].[Na+].[NH4+].[Cl-]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[NH2:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([C:17]([N:7]2[CH2:6][C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:11]=3[NH:10][C:9]3[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:8]2=3)=[O:18])=[CH:20][C:21]=1[CH3:27]
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(C#N)c(C)c1
Agent: Cl[Co]Cl
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Agent: O=C1CCCNc2ccccc21
Solvent: CO
Solvent: O
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CN)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
A solution of 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-benzonitrile from Example E101.1 (1.42 g, 4.0 mmol) in methanol (50 ml) at 0° C. was treated with cobalt(II) chloride hexahydrate (1.90 g, 8.0 mmol). The mixture was stirred for 15 min at room temperature then sodium borohydride (1.51 g, 40.0 mmol) was added portionwise. The reaction mixture was stirred for 2 h then saturated NH4Cl was added. The mixture was stirred for 30 min then the solid was filtered off through Celite® filter agent and the filtrate concentrated in vacuo. The residue was re-dissolved in EtOAc and saturated NaHCO3. The layers were partitioned and the aqueous layer was extracted further with chloroform. Organics were combined, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 1% 35% ammonia:9% methanol:90% dichloro-methane) to yield the title compound (511 mg, 35%).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>>[CH2:25]([O:24][C:22]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)OCc1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6carboximidate and benzyl chloroformate, there is obtained ethyl N-benzyloxycarbonyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e:M+ 400 (6), 371 (6), 309 (32), 263 (20), 194 (35), 179 (15), 167 (27), 108 (12), 91 (100);
Reaction SMILES: [C:1]([N:6]1[C@H:10]([C:11]2[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][C:12]=2[F:19])[CH2:9][CH2:8][C@@H:7]1/[CH:20]=C/C(OCC)=O)(=[O:5])[CH2:2][CH:3]=C.C(N(CC)CC)C>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(Cl)Cl>[F:17][C:16]1[CH:15]=[C:14]([F:18])[CH:13]=[C:12]([F:19])[C:11]=1[C@H:10]1[N:6]2[C@@H:7]([CH:20]=[CH:3][CH2:2][C:1]2=[O:5])[CH2:8][CH2:9]1
Reactant: C=CCC(=O)N1[C@@H](/C=C/C(=O)OCC)CC[C@H]1c1c(F)cc(F)cc1F
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC=C[C@H]2CC[C@@H](c3c(F)cc(F)cc3F)N12
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
A solution of ethyl (E)-3-[(2R,5S)-1-(3-butenoyl)-5-(2,4,6-trifluorophenyl)pyrrolidin-2-yl]acrylate (1.35 g) and Grubbs catalyst 2nd generation (155 mg) in methylene chloride (70 mL) was heated under reflux for two hours. The reaction solution was left to cool to room temperature. Then, triethylamine (0.5 mL) was added to the reaction solution, and the mixture was stirred for one hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane->heptane:ethyl acetate=1:1->ethyl acetate) to obtain 548 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:27][C:28]1[CH:32]=[C:31]([CH2:33]OS(C)(=O)=O)[O:30][N:29]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:33][C:31]2[O:30][N:29]=[C:28]([CH3:27])[CH:32]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(COS(C)(=O)=O)on1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Product: Cc1cc(Cn2cc(C(=O)N3CCC4(CC3)OCc3ccccc34)c3ccc(Cl)cc32)on1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with methanesulfonic acid 3-methyl-isoxazol-5-ylmethyl ester (described in Heterocycles, 23(3), 571-83; 1985) gave the title compound. ES-MS m/e (%): 462.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.CN1C(=O)CCC1.[CH2:34]([CH2:36][NH2:37])[OH:35].Cl>CCO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:37][CH2:36][CH2:34][OH:35])=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Reactant: NCCO
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCO
Product: Cn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 110 °C

Procedure:
To a solution of ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (143.3 g, 0.402 mol) in EtOH (1.3 L) was added NMP (0.5 L) and ethanolamine (27.75 g, 0.454 mol). Distilled EtOH over a period of 2 h and the resulting reaction mixture was heated at 110° C. for 45 min. Cooled to 60° C. and added water dropwise (0.47 L), followed by addition of 1N HCl (0.2 L) to pH 2-3. Cooled to room temperature and diluted by dropwise addition of water (1.2 L). The solids which precipitated were collected by filtration, washed with water and dried under vacuum at 70° C. to afford a tan solid. 1H NMR (d6-DMSO) δ 10.41 (1H, t, J=5.5 Hz), 8.53 (1H, s), 8.00 (1H, s), 7.39-7.35 (2H, m), 7.15-7.10 (2H, m), 4.92 (1H, t, J=5 Hz), 4.15 (2H, s), 3.58 (3H, s), 3.55-3.53 (2H, m), 3.44-3.40 (2H, m); ES+ MS: 372 (M+H+, 100).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:33]4[CH2:38][CH2:37][N:36]([CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[CH2:35][CH2:34]4)=[N:21][N:22]3[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:47]>>[ClH:47].[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:22]2[C:23]3[C:19](=[CH:18][CH:17]=[C:16](/[CH:15]=[CH:14]/[CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:24]=3)[C:20]([CH:33]3[CH2:38][CH2:37][N:36]([CH2:39][C:40]([OH:42])=[O:41])[CH2:35][CH2:34]3)=[N:21]2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)CN1CCC(c2nn(Cc3ccc(F)cc3)c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Agent: Cl
Product: O=C(O)CN1CCC(c2nn(Cc3ccc(F)cc3)c3cc(/C=C/C4CCNCC4)ccc23)CC1
Reaction time: 4 h

Procedure:
A mixture of 4-{2-[3-(1-tert-butoxycarbonylmethyl-piperidin-4-yl)-1-(4-fluoro-benzyl)-1H-indazol-6-yl]-(E)-vinyl}-piperidine-1-carboxylic acid tert-butyl ester (400 mg, 0.63 mmol) in aqueous 5M hydrochloric acid (80 ml) was stirred at +23° under nitrogen for 4 h. The solution was evaporated in vacuo and the residue triturated with ether to give the title compound as a cream solid (299 mg).
Reaction SMILES: [NH2:1][CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[OH:4].[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35]([NH:1][CH:2]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=2)[CH:3]([OH:4])[C:5]2[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=2)=[O:36])=[CH:27][CH:26]=1
Reactant: COc1ccc(C(O)C(N)Cc2ccc(C(F)(F)F)cc2)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(O)C(Cc2ccc(C(F)(F)F)cc2)NC(=O)c2ccc(F)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-methoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.38 mmol) in acetonitrile (20 ml) was added 4-fluoronaphthalenecarboxylic acid (263 mg, 1.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (397 mg, 2.08 mmol) and 1-hydroxy-1H-benzotriazole (212 mg, 1.38 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (558 mg, 81%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:47])([F:46])[C:24]([F:45])([F:44])[C:25]([F:43])([F:42])[O:26][C:27]([F:41])([C:32]([F:40])([F:39])[O:33][C:34]([F:38])=[C:35]([F:37])[F:36])[C:28]([F:31])([F:30])[F:29]>C1COCC1>[F:37][C:35]([F:36])([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[CH:34]([F:38])[O:33][C:32]([F:39])([F:40])[C:27]([F:41])([O:26][C:25]([F:42])([F:43])[C:24]([F:44])([F:45])[C:23]([F:22])([F:46])[F:47])[C:28]([F:31])([F:30])[F:29]
Reactant: FC(F)=C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)cc(C(=O)OC)c1

Procedure:
Anhydrous THF (12 liters) and dimethyl 5-hydroxy-isophthalate (2100 g) were combined under nitrogen in an oil jacketed 22 liter RB flask equipped with a condenser, mechanical stirrer, pressure equalizing addition funnel. To this stirred solution was added anhydrous potassium carbonate (345 g), followed by 1,1,1,2,2,3,3-heptafluoro-3-(1,1,1,2,3,3-hexafluoro-3-(1,2,2-trifluorovinyloxy)propan-2-yloxy)propane (4750 g). Ca. 2 liters of additional THF was used to wash all the reagents into the reaction vessel. The resulting mixture was refluxed for 12.0 hours.
Reaction SMILES: C(Cl)(=O)C.[C:5]1([N:11]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:12](=[O:14])[CH3:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]([CH2:41][CH:42]=O)[CH2:30][N:31]([CH3:40])[C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:25]=[CH:26][C:27]=1[Cl:28].C([BH3-])#N.[Na+]>CO.O>[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]([CH2:41][CH2:42][N:18]2[CH2:17][CH2:16][CH:15]([N:11]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:12](=[O:14])[CH3:13])[CH2:20][CH2:19]2)[CH2:30][N:31]([CH3:40])[C:32](=[O:39])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: CN(CC(CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reactant: CC(=O)N(c1ccccc1)C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: O
Solvent: CO
Product: CC(=O)N(c1ccccc1)C1CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 0.33 h
Yield: 45.8 %

Procedure:
To a flask containing methanol (0.5 mL) at 0° C. was added acetyl chloride (0.085 mL), and the resulting solution was allowed to stir for 20 minutes. 4-(N-Phenylacetamido)piperidine (0.327 g) in methanol (1 mL) was added, followed by N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide (0.350 g) in methanol (2.5 mL) and, 15 minutes later, sodium cyanoborohydride (0.038 g). After being stirred at room temperature for 4 hours, the reaction mixture was diluted with water and extracted with dichloromethane. The organic extracts were washed (water), dried, and evaporated. The resulting material was chromatographed, with ethyl acetate:methanol (5:1) as the eluent, to give the title compound (0.253 g) as a white solid; MS: m/z=552(M+1). Analysis for C31H35Cl2N3O2.0.8 H2O: Calculated: C, 65.67; H, 6.51; N, 7.41; Found: C, 65.76; H, 6.37; N, 7.48.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:12])[CH:9]([F:11])[F:10])=[N:6][CH:7]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[F:10][CH:9]([F:11])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:7][N:6]=1)=[O:12]
Reactant: c1cn[nH]c1
Reactant: O=C(c1ccc(Br)cn1)C(F)F
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-n2cccn2)cn1)C(F)F
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(5-bromopyridin-2-yl)-2,2-difluoroethanone (7.064 g, 30 mmol), pyrazole (1.85 g, 27 mmol), CuI (0.273 g, 1.4 mmol), racemic trans-N,N′-dimethylcyclohexane-1,2-diamine (0.714 g, 5 mmol), K2CO3 (7.894 g, 57 mmol) was added to a sealed tube and dissolved in toluene (12 mL). The mixture was stirred vigorously overnight at 110° C. The mixture was cooled and filtered through Celite, washing with EtOAc. The combined filtrate and washings were concentrated, flash chromatography on silica gel afforded the title compound as a white solid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18](=[O:29])[CH:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[CH3:20])=[CH:9]1)=O)(C)(C)C.[F:30][C:31]([F:36])([F:35])C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.CCCC[N+](CCCC)(CCCC)CCCC.C1C=CC([Si-](F)(F)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[CH:19]([CH3:20])[C:18]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[NH:8][CH:9]=1)([OH:29])[C:31]([F:36])([F:35])[F:30]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C(=O)c1cn(C(=O)OC(C)(C)C)c2ccc(F)cc12)c1ccc(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F[Si-](F)(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC(c1ccc(Cl)cc1Cl)C(O)(c1c[nH]c2ccc(F)cc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.7 %

Procedure:
To a solution of crude 3-[2-(2,4-dichloro-phenyl)-propionyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester (81 mg) in tetrahydrofuran (0.8 ml) (trifluoromethyl)-trimethylsilane (2M in tetrahydrofuran, 0.23 ml) and tetrabutylammonium difluorotriphenylsilicate (20 mg) were added at 0° C. After being stirred at rt for 3 h, trifluoroacetic acid (127 mg) was added at 0° C. and stirred overnight. No deprotection was observed, so the mixture was neutralized with aq. 2M Na2CO3 solution and extracted with EtOAc. The combined organic layers were washed with water and dried over MgSO4. After evaporation of the solvent, the residue was dissolved in CH2Cl2 (0.8 mL) and trifluoroacetic acid was added at 0° C. After being stirred for 1 h at 0° C. and at room temperature for 8 h, the reaction mixture was poured into ice water, neutralized with aq. 2M Na2CO3 solution and extracted with CH2Cl2. The organic phase was washed with water and aq. sat. NaCl solution, and dried over MgSO4. MS: silylated product still present, the crude product was dissolved in 0.5 mL tetrahydrofuran and a solution of tetrabutylammonium fluoride (1M in tetrahydrofuran) was added at 0° C. After being stirred at room temperature for 1.5 h, the reaction mixture was poured into water, and extracted with EtOAc. The combined organic layers were washed with water and aq. sat. NaCl, and dried over MgSO4. The product was purified by preparative TLC (cyclohexane/EtOAc 2:1) to give 17.9 mg of the title product as colorless oil. MS (m/e, ISP neg. ion )=404.4 [M−H+].
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)=[O:4].[OH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH:12]1[C:10]2[CH2:11][N:5]([C:3](=[O:4])[CH2:2][O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=3)[C:6]3[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=3[O:8][C:9]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CBr)N1Cc2ccccc2Oc2ccccc21
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc(OCC(=O)N2Cc3ccccc3Oc3ccccc32)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 32.4 %

Procedure:
Title compound 455 (0.890 g, 2.81 mmol) and the methyl 4-hydroxybenzoate (0.512 g, 3.37 mmol) were dissolved in acetonitrile (10.0 mL) and the cesium carbonate (1.83 g, 5.62 mmol) was added. The reaction mixture was stirred at 100° C. in a sealed tube for 4 hours. The mixture was cooled down to room temperature and diluted with ethyl acetate. The organic layer was washed with water (2 times) and brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography (30-40% ethyl acetate in hexanes) to afford title compound 456 (355 mg, 32%) as white foam. MS (m/z): 390.3 (M+H).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[CH3:28][N:29]([CH3:36])[C:30](=[O:35])[C@@H:31]([NH:33][CH3:34])[CH3:32]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:33]([CH3:34])[C@@H:31]([CH3:32])[C:30]([N:29]([CH3:36])[CH3:28])=[O:35])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CN[C@@H](C)C(=O)N(C)C
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N(C)[C@@H](C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.64 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 71-2 (5.86 mmol, crude form) as starting materials, respectively 0.90 g (Isomer A, colorless amorphous) and 1.41 g (Isomer B, colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.[CH2:10]([NH:15][NH2:16])[CH2:11][CH2:12][CH2:13][CH3:14]>C(O)C>[NH2:9][C:8]1[N:15]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[N:16]=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: CCCCCNN
Reactant: CCOC=C(C#N)C#N
Solvent: CCO
Product: CCCCCn1ncc(C#N)c1N
Yield: 88 %

Procedure:
A warm solution of 6.02 g (49.3 mM) ethoxymethylenemalononitrile in 20 ml of ethanol was added via a cannula to a stirred solution of 6.04 g (59.1 mM)n-pentylhydrazine in 20 ml of ethanol at 50° C. The reaction mixture was then heated to reflux for 30 minutes, then cooled in a refrigerator for 18 hours. The off-white crystalline precipitate was filtered to yield 7.73 g (88%) of the title compound, mp=143°-144° C.; tlc, Rf =0.5, silica gel, methanol: chloroform (1:19).