Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.Br[C:27]1[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=1[O:29][C:30]1[N:35]=[C:34]([NH2:36])[CH:33]=[CH:32][N:31]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:27]2[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=2[O:29][C:30]2[N:35]=[C:34]([NH2:36])[CH:33]=[CH:32][N:31]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)OC1(C)C
Reactant: Nc1ccnc(Oc2ccccc2Br)n1
Product: Nc1ccnc(Oc2ccccc2-c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)n1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine and 2-(2-bromophenoxy)pyrimidin-4-amine. MS (ESI): mass calcd. for C23H16FN5O, 397.13; m/z found, 398.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.47 (s, 1H), 8.11 (d, J=2.1, 1H), 7.96 (d, J=5.7, 1H), 7.54-7.30 (m, 9H), 6.07 (d, J=5.7, 1H), 4.96-4.85 (m, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(OC(=O)[NH:35][C:36]([CH3:48])([CH3:47])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]=O)=[CH:41][CH:40]=1)(C)(C)C>>[NH2:35][C:36]([CH3:48])([CH3:47])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:41][CH:40]=1
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(COc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCC(C)(C)N)cc2)c1
Yield: 36.5 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (33 mg) and tert-butyl[2-(4-formylphenoxy)-1,1-dimethylethyl]carbamate (125 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (15 mg) was obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[S:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][C:21](=[O:25])[NH:22]2)=[CH:17][CH:16]=1.O>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[S:13])[NH:14][C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][C:21](=[O:25])[NH:22]3)=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc2c(c1)NC(=O)CC2
Reactant: CC(=O)Nc1ccc(N=C=S)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(NC(=S)Nc2ccc3c(c2)NC(=O)CC3)cc1
Temperature: 20 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
A mixture containing 1.92 g of 4-acetamidophenylisothiocyanate and 1.62 g of 7-amino-3,4-dihydro-2(1H)quinolone in 10 ml of DMF was stirred for 6 h at 20° C. Water was added and the product filtered and washed with water. Yield 85%.
Reaction SMILES: [C:1]([C:5]([C:7]1[N:12]2[C:13](=[S:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:19])(=[O:18])[CH:9]([C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)[C:8]=1[CH3:26])=[O:6])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CS(C)=O.C(OCC)(=O)C>[CH2:34]([C:9]1([C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)[C:8]([CH3:26])=[C:7]([C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[O:6])[N:12]2[C:13](=[S:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10]1(=[O:19])=[O:18])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CO[C@H]1C(=S)N2C(C(=O)C(C)(C)C)=C(C)C(c3nnnn3C)S(=O)(=O)[C@H]12
Reactant: BrCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CO[C@H]1C(=S)N2C(C(=O)C(C)(C)C)=C(C)C(Cc3ccccc3)(c3nnnn3C)S(=O)(=O)[C@H]12
Reaction time: 8 h

Procedure:
415 mg of 4-tert-butylcarbonyl-7α-methoxy-3-methyl-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-3-cephem 1,1-dioxide was dissolved in dimethyl sulphoxide (3 ml) and triethylamine (0.153 ml) and benzyl bromide (0.360 ml) were added. The reaction mixture was left overnight at room temperature, diluted with ethyl acetate, washed with a dilute solution of hydrochloric acid and eventually with brine. Drying over Na2SO4 and removal of the organic solvent left a residue which was then purified by flash chromatography affording the title compound as a white solid (270 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].C(=O)C1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:16](O[BH-](OC(=O)C)OC(=O)C)(=[O:18])[CH3:17].[Na+].[OH-].[Na+]>ClCCl>[C:2]1([CH2:1][N:3]2[CH2:6][CH2:7][CH2:17][C:16](=[O:18])[CH2:5][CH2:4]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCN(CC)CC
Reactant: O=Cc1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1CCCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(may be prepared as described in Synthetic Communications (1992), 22(9), 1249-58) was suspended in dichloromethane (100 ml) and triethylamine (9.31 ml, 66.9 mmol) added, followed by benzaldehyde (68 ml, 0.669 mol). The mixture was stirred at room temperature for 30 minutes under argon, then cooled in ice whilst sodium triacetoxyborohydride (17 g, 80 mmol) was added portionwise. The mixture was stirred and allowed to reach room temperature, then stirred for 2 hours. 2M sodium hydroxide solution (80 ml) was added, the layers separated and the aqueous layer extracted with dichloromethane (×2). The combined organic extracts were evaporated to half volume, then extracted with 2M hydrochloric acid (2×100 ml). The aqueous layer was made basic with 50% sodium hydroxide solution and extracted with dichloromethane (×2). The combined organic extracts were dried over magnesium sulphate and evaporated to afford the title compound (D2). 1H NMR (CDCl3) δ 1.82-1.88 (2H, m), 2.52-2.55 (2H, m), 2.59-2.62 (2H, m) 2.71-2.76 (4H, m) 3.65 (1H, s) 7.23-7.33 (5H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[C:30]1([C@H:36]2[CH2:40][CH2:39][CH2:38][C@@H:37]2[OH:41])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:41][C@H:37]2[CH2:38][CH2:39][CH2:40][C@@H:36]2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:12][C:11]=1[F:18])(=[O:8])=[O:9]
Reactant: O[C@H]1CCC[C@@H]1c1ccccc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC[C@@H]3c3ccccc3)cc2F)c(OC)c1
Yield: 33.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO 2010/079443; 500 mg, 1.12 mmol), (1S*,2R*)-2-phenylcyclopentanol (200 mg, 1.23 mmol), sodium hydride (63%; 100 mg, 2.63 mol) and DMSO (5.0 mL), to yield the title compound (220 mg, 33%) as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=O)[NH:11]2)(=[O:4])=[O:3].[BH4-].[Na+].C(O)(=O)C>O1CCOCC1>[CH3:1][S:2]([O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][NH:11]2)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1cccc2c1CCC(=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CS(=O)(=O)Oc1cccc2c1CCCN2
Yield: 44.8 %

Procedure:
4.5 g of 5-methanesulfonyloxy-3,4-dihydrocarbostyril was suspended in 90 ml of dioxane and 35 g of NaBH4 was added to the suspension, then 5.3 ml of acetic acid was added dropwise to the mixture. After heat-refluxing the resulting mixture for 1 hour, the solvent was removed under reduced pressure. Saturated aqueous solution of sodium bicarbonate was added to the residue to form precipitates which were filtered and washed with chloroform. The filtrate was extracted with chloroform and the chloroform layer was dried over Na4SO4 followed by removing the solvent. The residue was purified through a silica gel column chromatography (silica gel:Wako 200, a trade name for a product of Wako Junyaku Co., Ltdl; eluant:chloroform) and the eluate thus-obtained was crystallized from petroleum ether. Recrystallization of the crystals thus-obtained from methanol gave 1.9 g of 5-methanesulfonyloxy-1,2,3,4-tetrahydroquinoline as colorless prisms having a melting point of 74° to 76° C.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:31])([F:30])[C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:20](Cl)=[O:21].[NH:32]1[CH:36]=[CH:35][CH:34]=[CH:33]1>>[F:15][C:16]([F:31])([F:30])[C:17]1[CH:18]=[C:19]([C:20]([N:6]2[CH:7]([C:33]3[NH:32][CH:36]=[CH:35][CH:34]=3)[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:21])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: c1cc[nH]c1
Reactant: c1ccc2c(c1)cnc1ccccc12
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1c2ccccc2-c2ccccc2C1c1ccc[nH]1

Procedure:
(3,5-Bis-trifluoromethyl-phenyl)-[6-(1H-pyrrol-2-yl)-6H-phenanthridin-5-yl]-methanone was prepared from phenanthridine, 3,5-bis(trifluoromethyl)benzoyl chloride, and pyrrole according to GP 2. Yield, 12.5%. 1H-NMR (DMSO-d6): δ=5.21 (s, 1H), 5.79 (q, J=2.8 Hz, 1H), 6.59-6.63 (m, 1H), 6.64 (s, br., 1H), 6.84-7.09 (m, br., 2H), 7.21 (t, J=7.5 Hz, 1H), 7.43 (t, J=7.3 Hz, 1H), 7.51 (t, J≈7 Hz, 1H), 7.57 (d, J=7.1 Hz, 1H), 7.86 (s, br., 2H), 7.96 (d, J=7.8 Hz, 1H), 8.08 (d, J=7.5 Hz, 1H), 8.19 (s, 1H), 10.66 (s, 1H); (+)-ESI-MS: m/z=420 [M-pyrrole]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.O>S(Cl)(Cl)=O.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:9])=[CH:5][C:4]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: C1COCCN1
Reactant: CCCCCOc1cc(C(=O)O)ccc1OC
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCOc1cc(C(=O)N2CCOCC2)ccc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
4-Methoxy-3-pentyloxybenzoic acid (250 mg, 1.05 mmol, 1 eq) was dissolved in thionyl chloride (1.05 ml) in a stream of nitrogen, and the solution was stirred at 70° C. for 5 hours. The mixture was cooled to room temperature, and excess thionyl chloride was evaporated under reduced pressure. The residue was added to a solution of morpholine (274 mg, 3.15 mol, 3.0 eq) in DMF (3 ml) under ice-cooling. The mixture was stirred under ice-cooling for 30 minutes, and then further at room temperature for 1.5 hours. Water (30 ml) was added to this reaction mixture and the mixture was extracted twice with ethyl acetate (50 ml). The organic layers were combined, washed with saturated brine (50 ml) and dried over anhydrous sodium sulfate. The drying agent was fltered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give (4-methoxy-3-pentyloxyphenyl)morpholin-4-yl-methanone (219 mg, 67.9%) as an oil
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].S(=O)(=O)(O)O.[CH:11](O)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: OCCCCl
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: ClCCCOC(c1ccccc1)c1ccccc1
Yield: 96 %

Procedure:
To a solution of 3.85 g (40.7 mmol) of 3-chloro-1-propanol in benzene (4 ml) was added conc. sulfuric acid, followed by a solution of 5 g (27.2 mmol) of benzhydrol in benzene (6 ml), and the mixture was refluxed, under argon atmosphere, for 0.8 hours. The reaction mixture was diluted with benzene, washed with water and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and there was obtained 6.80 g (26.1 mmol) of benzhydryl 3-chloropropyl ether.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7](=O)[CH:8]=[CH:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])[CH3:2].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Na].[C:43]1([SH:49])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>COC(C)(C)C.CN(C=O)C.C(#N)C>[CH2:1]([O:3][C:4]([N:6]=[C:7]([S:49][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH:8]=[CH:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: Sc1ccccc1
Reactant: CCOC(=O)NC(=O)C=CSc1ccccc1
Agent: BrC(Br)(Br)Br
Agent: [Na]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)N=C(C=CSc1ccccc1)Sc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
N-ethoxycarbonyl-3-(phenylthio)acrylamide (1.20 g) was dissolved to acetonitrile (30 ml), then carbon tetrabromide (2.83 g) and triphenylphosphine (2.23 g) was added thereto and heat refluxing for three hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate 20:1) to obtain light yellow oil. It was dissolved to DMF (10 ml), then sodium salt of thiophenol (0.63 g) was added thereto under ice cooling and stirred at room temperature for two hours. t-Butyl methyl ether (100 ml) was added to the reaction mixture, washed successively with 1N aqueous sodium hydroxide solution, water and aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered off inorganic salt and concentrated under reduced pressure. The residue was purified by medium pressure preparative high performance liquid chromatography to obtain phenyl N-ethoxycarbonyl-3-(phenylthio)thioacrylimidate (0.40 g) as light yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[CH:9][C:8](C#CC3C=CC(C(OCC)=O)=CC=3)=[CH:7][C:6]=2[C:5]([C:25](C)(C)C)=[CH:4][CH2:3]1.FC(F)(F)S(OC1C2C=CC([C:48]#[C:49][C:50]3[CH:60]=[CH:59][C:53]([C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:52][CH:51]=3)=CC=2C(C)(C)CC=1)(=O)=O>>[CH3:25][C:5]1[C:6]2[CH:7]=[CH:8][C:9]([C:48]#[C:49][C:50]3[CH:60]=[CH:59][C:53]([C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:52][CH:51]=3)=[CH:10][C:11]=2[C:2]([CH3:1])([CH3:29])[CH2:3][CH:4]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C(C)(C)C)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3OS(=O)(=O)C(F)(F)F)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoate (Compound 71), 300 mg (0.63 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 87) was converted into the title compound (colorless oil) using 84 mg (0.94 mmol) of cuprous cyanide, 40 mg (0.94 mmol) of lithium chloride and 41 mg (1.54 ml, 1.88 mmol) of methyllithium (1.22M solution in Et2O).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH3:23])[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>O1CCCC1>[F:22][C:20]1[CH:19]=[CH:18][C:17]([CH3:23])=[C:16]([CH:11]2[C:10]([CH3:24])([CH3:25])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)ccc1C)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(F)cc1C1Nc2ccc(C(=O)O)cc2CC1(C)C
Temperature: 60 °C
Reaction time: 12 h
Yield: 40.5 %

Procedure:
A mixture of 2-(5-fluoro-2-methyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.70 g, 2.05 mmol), lithium hydroxide hydrate (0.86 g, 20.5 mmol), water (3 mL) in tetrahydrofuran (30 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-(5-fluoro-2-methyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (260 mg, 40%) as a white solid: LC/MS m/e calcd for C19H20FNO2 (M+H)+: 314.4, observed: 314.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:27][CH3:28])[CH2:22][S:23](O)(=[O:25])=[O:24])[C:11](=[O:29])[C@:10]([CH2:31][C:32]([O:34][CH3:35])=[O:33])([CH3:30])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[O:42]1[CH2:45][CH:44]([NH2:46])[CH2:43]1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:27][CH3:28])[CH2:22][S:23](=[O:24])(=[O:25])[NH:46][CH:44]3[CH2:45][O:42][CH2:43]3)[C:11](=[O:29])[C@:10]([CH2:31][C:32]([O:34][CH3:35])=[O:33])([CH3:30])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CS(=O)(=O)O)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: NC1COC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC[C@@H](CS(=O)(=O)NC1COC1)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of (S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-methoxy-2-oxoethyl)-3-methyl-2-oxopiperidin-1-yl)butane-1-sulfonic acid (189.8 mg, 0.35 mmol; Example 372, Step B) in dichloromethane (5.0 mL) was added oxalyl chloride (0.061 mL, 0.70 mmol), followed by DMF (2 drops). The reaction was stirred at room temperature for 3.5 hours, then concentrated in vacuo. The sulfonyl chloride intermediate was dissolved in dichloromethane (5.0 mL), then treated with 3-oxetanamine (50.0 mg, 0.684 mmol; Pharmablock R & D Co. Ltd., Nanjing, China) and N,N-diisopropylethylamine (0.122 mL, 0.699 mmol). After stirring at room temperature for 16 hours, the reaction was quenched with methanol (2.0 mL), then concentrated in vacuo. Purification of the residue by chromatography on silica gel (4 g SiO2, 0%-50% EtOAc in hexanes) provided the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]3[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>N1C=CC=CC=1>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][C:7]([CH:11]4[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]4)=[CH:8][CH:9]=3)[NH:4][N:3]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc3c(N)n[nH]c3c2)C1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc3c(NC(=O)c4ccc(F)cc4)n[nH]c3c2)C1
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
Tert-butyl 2-(3-amino-1H-indazol-6-yl)morpholine-4-carboxylate (43 mg, 0.135 mmol) was dissolved in pyridine (0.2 ml) and the solution was cooled to −5° C. 4-fluorobenzoyl chloride (21.4 mg, 0.135 mmo) was slowly added. After 5 min, the cooling bath was removed and stirring was continuing overnight. The reaction mixture was diluted with ethylacetate (2 ml) and washed with 1M citric acid solution (2 ml). The organic layer was dried over MgSO4 and concentrated in vacuo to give a brown oil which was further purified by flash column chromatography (silica gel, 50% to 100% ethyl acetate in heptane). The product was isolated as a yellow solid (40 mg, 67%), MS (ISP): 441.3 (100%, ([M-tBu+H]+), 385.2 (38%, [M+H]+).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:12]2[C@@H:13]([CH3:16])[CH2:14][CH2:15][C@@H:11]2[C:10]([CH2:17][OH:18])=[CH:9][O:8]1)[CH3:5])[CH3:2].N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(OCC)(=O)C>ClCCl>[C:25]([O:18][CH2:17][C:10]1[C@H:11]2[CH2:15][CH2:14][C@H:13]([CH3:16])[C@H:12]2[C@H:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[O:8][CH:9]=1)(=[O:27])[CH3:26]
Reactant: CCOC(C)O[C@@H]1OC=C(CO)[C@H]2CC[C@H](C)[C@@H]12
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(C)O[C@@H]1OC=C(COC(C)=O)[C@H]2CC[C@H](C)[C@@H]12
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.7 %

Procedure:
(1S, 4aS, 7S, 7aR)-1-[1-(ethoxy)ethoxy]-1,4a,5,6,7,7a-hexahydro-4-(hydroxymethyl)-7methylcycopenta[c]pyran (10.0 g, 0.039 mol) obtained in Example 5 was dissolved in 200 ml of dichloromethane. After 9.52 ml (0.12 mol) of pyridine, 11.2 ml (0.12 mol) of acetic anhydride and 100 mg of N, N-dimethylaminopyridine were added, the reaction mixture was stirred at room temperature for 5 hours. After 600 ml of ethyl acetate was added to the reaction mixture solution, the organic layer was washed with water (300 ml×2), 2N hydrochloric acid solution, saturated sodium bicarbonate solution (300 ml×2) and saturated sodium chloride solution (300 ml), and was thereafter dried by magnesium sulfate, filtered, and then concentrated under a reduced pressure. The residual substance was purified by chromatography using silica gel, and the fraction obtained from hexane:ether=1:1 eluent was concentrated. A colorless oily matter was thus obtained, i.e., (1S, 4aS,7S, 7aR)-4-(acetoxymethyl)-1-[1-(ethoxy)ethoxy]1,4a,5,6,7,7a-hexahydro-7-methylcyclopenta[c]pyran (9.27 g, yield=79.5%). This (1S, 4aS, 7S, 7aR)-4-(acetoxymethyl)-1-[1-(ethoxy)ethoxy]-l, 4a, 5, 6, 7, 7a-hexahydro-7-methylcyclopenta[c]pyran had the following physicochemical properties:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]([F:23])=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([F:24])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:26]([NH2:28])[CH3:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH2:26]([NH:28][C:18]([C:17]1[C:16]([F:24])=[CH:15][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[C:22]([F:23])[CH:21]=1)=[O:19])[CH3:27]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(F)c(C(=O)O)cc2F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1cc(F)c(N2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.5 %

Procedure:
4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,5-difluorobenzoic acid (0.021 g, 0.061 mmol) and ethylamine hydrochloride (7.50 mg, 0.092 mmol) were suspended in DMF (Volume: 0.7 mL) and treated with DIPEA (0.054 mL, 0.307 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.047 g, 0.123 mmol). The reaction mixture was stirred at room temperature for 15 min and diluted with water. The precipitate was filtered, washed with water and dried in vacuum to afford tert-butyl 4-(4-(ethylcarbamoyl)-2,5-difluorophenyl)piperazine-1-carboxylate (20.1 mg, 0.054 mmol, 89% yield). ESI-MS:m/z 370 (M+H)+.