Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4](I)[CH:3]=1.[CH3:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)(=[O:14])=[O:13].C([O-])([O-])=O.[Na+].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C:18]2[CH:17]=[CH:16][C:15]([S:12]([NH:11][CH3:10])(=[O:13])=[O:14])=[CH:20][CH:19]=2)[CH:3]=1
Reactant: Fc1ccc(Br)cc1I
Reactant: CNS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1ccc(-c2cc(Br)ccc2F)cc1
Temperature: 120 °C
Yield: 67 %

Procedure:
To a solution of 4-bromo-1-fluoro-2-iodobenzene (207 mg, 0.69 mmol) in anhydrous dioxane (3.4 mL) was added [4-(methylsulfamoyl)phenyl]boronic acid (148 mg, 0.69 mmol) and aqueous Na2CO3 solution (2M, 1.03 mL, 2.06 mmol). A stream of nitrogen gas was bubbled through the reaction mixture for 6 minutes. Tetrakistriphenylphosphine palladium(0) (24 mg, 0.021 mmol) was added and the mixture was heated under microwave irradiation at 120° C. for 12 minutes. The reaction mixture was cooled, diluted with EtOAc, treated with anhydrous Na2SO4 and filtered, washing the solids with EtOAc until the compound had completely eluted. The filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with heptane:EtOAc 100:0 to 60:40 to afford the title compound as clear, colorless residue in 67% yield, 159 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]=[C:18]([C:20](O)=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][NH:24][CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1.C(N=C=NCCCN(C)C)C.O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:23][N:24]([CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:20]([C:18]1[N:19]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:15]=[CH:16][CH:17]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)n2)CC1
Reactant: CNC1CCCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CN(C(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-[1-(tert-butoxycarbonyl)piperidin-4-yl]pyridine-2-carboxylic acid (247 mg) in dichloromethane (5 ml) are added, at room temperature, N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (130 mg), 4-dimethylaminopyridine (10 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (162 mg). The mixture is stirred at room temperature overnight, and then water is added. The aqueous phase is removed and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography. This gives tert-butyl 4-{6-[methyl(1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl]pyridin-2-yl}piperidine-1-carboxylate (219 mg).
Reaction SMILES: [Cl:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[C:18]([Cl:23])=[C:17](F)[C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH:14]1[CH2:16][CH2:15]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F-].[Na+].O>CN1CCCC1=O>[Cl:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[C:18]([Cl:23])=[C:17]2[C:3]=1[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][N:13]2[CH:14]1[CH2:16][CH2:15]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(Cl)c(F)c(F)c1Cl
Agent: [F-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)c(F)c(Cl)c2c1=O

Procedure:
19.1 g (0.05 mol) of ethyl 2-(2,5-dichloro-3,4,6-trifluorobenzoyl)-3-cyclopropylamino-acrylate are heated at 160°-170° C. together with 4.2 g (0.1 mol) of sodium fluoride in 100 ml of N-methyl-2-pyrrolidone for 5 hours. After cooling, the mixture is poured onto 200 ml of water. The solid which has precipitated is filtered off with suction, washed with water and dried at 80° C. in a drying cabinet.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:2]=1.O.[NH2:27][NH2:28]>CCO>[NH:27]([C:14]([C:13]1[CH:18]=[CH:19][C:10]([NH:9][C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:2][CH:3]=2)=[O:8])=[CH:11][CH:12]=1)=[O:15])[NH2:28]
Reactant: NN
Reactant: COC(=O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 66 %

Procedure:
To a suspension of methyl 4-[([1,1′-biphenyl]-4-ylcarbonyl)amino]benzoate (880 mg, 2.66 mmol) in EtOH (10 mL) was added hydrazine hydrate (1.8 mL). After stirring for 7 days at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (3×2 mL) and water (3×2 mL), and drying under vacuo at rt for 6 hrs gave 585 mg of the title compound (66%) as a white solid in 96.4% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.Cl.[NH2:17][CH2:18][CH2:19][C:20]1[CH:37]=[CH:36][C:23]2[N:24]([CH2:34][CH3:35])[C:25](=[O:33])[C:26]([CH3:32])([CH3:31])[C:27](=[O:30])[N:28]([CH3:29])[C:22]=2[CH:21]=1.[BH4-].[Na+]>CO>[CH2:34]([N:24]1[C:25](=[O:33])[C:26]([CH3:32])([CH3:31])[C:27](=[O:30])[N:28]([CH3:29])[C:22]2[CH:21]=[C:20]([CH2:19][CH2:18][NH:17][CH2:14][C:11]3[CH:10]=[CH:9][N:8]=[CH:13][CH:12]=3)[CH:37]=[CH:36][C:23]1=2)[CH3:35]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCN)ccc21
Reactant: O=Cc1ccncc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCNCc3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine(0.1 ml) and 4-pyridine carbaldehyde(0.094 ml) were added to a methanol solution (10 ml) of 7-(2-aminoethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine 2,4-dione hydrochloride(0.26 g). The mixture was stirred at room temperature for 1 hour. Sodium borohydride(0.11 g) was added, and the mixture was further stirred at room temperature overnight. The reaction liquid was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol=9:1→3:2). The purified product was condensed under reduced pressure to give the title compound(0.21 g) as a colorless oily matter.
Reaction SMILES: CC([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]1=[O:21])=C.S(=O)(=O)(O)O.[OH-].[Na+].O>C(O)C>[O:21]=[C:5]1[N:6]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:4]1
Reactant: C=C(C)n1c(=O)n(CCCC(=O)OCC)c2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCn1c(=O)[nH]c2ccccc21
Reaction time: 5 h
Yield: 81.4 %

Procedure:
31.4 g of the product of Step A were added at 0° to 5° C. to a mixture of 15.5 ml of sulfuric acid in 155 ml of ethanol and the mixture was stirred at 0° to 5° C. for 5 hours. The mixture was neutralized with sodium hydroxide and was poured into 1.5 liters of iced water. The mixture was stirred for 5 minutes and was vacuum filtered. The product was washed with water to obtain 22 g of ethyl 2,3-dihydro-2-oxo-1H-benzimidazol-1-butanoate melting at 88° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C@@H:19]2[C@H:10]([NH:11][CH2:12][C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:20][C@@H:19]2[C@H:10]([N:11]([C:29](=[O:31])[CH3:30])[CH2:12][C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2c1CN[C@@H]1CN(Cc3ccccc3)C[C@@H]21
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1Cc2c(C)cccc2[C@@H]2CN(Cc3ccccc3)C[C@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±)-trans-2-benzyl-6-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,4-c]isoquinoline from Example 105, Part A (28 mg, 0.1 mmol) in 1 mL of methylene chloride was added triethylamine (0.021 mL, 0.15 mmol) and acetyl chloride (0.009 mL, 0.15 mmol). The reaction was allowed to stir at ambient temperature for 2 h. The solution was concentrated and purified (ISCO, elution with 0-5% methanol/methylene chloride) to afford 25 mg of the title compound of Example 108 as an off-white solid. 1H NMR (CDCl3): δ 7.74-7.68 (m, 2H), 7.50-7.42 (m, 3H), 7.21-7.13 (m, 2H), 6.80-6.75 (m, 1H), 4.78 and 4.38 (ABq, 2H), 4.31-4.25 (m, 1H), 4.16-4.03 (m, 2H), 3.89-3.80 (m, 1H), 3.71-3.63 (m, 1H), 3.49 (s, 2H), 3.07-2.98 (m, 1H), 2.35 (s, 3H), 2.21 (s, 3H). LRMS (ESI): 321.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21]Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]([O:35][C:36](=[O:50])[NH:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][C@H:47]([NH2:49])[CH3:48])[CH:41]=1)([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:31]([O:35][C:36](=[O:50])[NH:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][C@H:47]([NH:49][CH2:21][C@@H:20]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16](=[O:19])[NH:17]3)[O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH3:48])[CH:41]=1)([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: C[C@@H](N)Cc1cccc(CCNC(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](Cc1cccc(CCNC(=O)OC(C)(C)C)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Yield: 63.5 %

Procedure:
A stirred solution of 8-benzyloxy-5-[(R)-2-bromo-1-(tert-butyldimethyl-silanyloxy)ethyl]-1H-quinolin-2-one (3.14 g, 6.43 mmol); {2-[3-((R)-2-aminopropyl)-phenyl]ethyl}carbamic acid tert-butyl ester (1.79 g, 6.43 mmol) and triethylamine (1.08 mL, 7.72 mmol) in DMF (21.0 mL) was microwaved (300 watts) at 80° C. for 15 h. Saturated aqueous sodium bicarbonate (10 mL) was added and the resulting mixture was extracted with DCM (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-5% MeOH in DCM) to give the title compound (2.8 g, 63% yield) as an off-white solid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)=[O:2].C(NC(C)C)(C)C.[Li].[CH3:17][Si:18](Cl)([CH3:20])[CH3:19]>C1COCC1>[CH3:17][Si:18]([CH3:20])([CH3:19])[C:5]1[S:6][CH:7]=[CH:8][C:4]=1[NH:3][CH:1]=[O:2]
Reactant: C[Si](C)(C)Cl
Reactant: O=CNc1ccsc1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)c1sccc1NC=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
3- Formylaminothiophene (Bull. Soc. Chim. Fr. 1976,151) (2 g), dissolved in dry THF (20 ml), was dropped into a freshly prepared solution of lithium diisopropylamine (0.035 mol) in THF (35 ml) at −70° C. The solution was warmed to −20° C. and stirred for 30 minutes, then cooled again to −70° C., whereupon trimethylsilylchloride (5 ml) was added. After stirring for an additional hour at this temperature the mixture was slowly warmed to room temperature and stirred for 4 hours. Quenching with a saturated solution of ammonium chloride, extracting with ethyl acetate, drying over sodium sulfate, removing the solvent and applying chromatography on silica gel (hexane:ethyl acetate 2:1) yielded 2-trimethylsilyl-3-formylaminothiophene (1.2 g) (m.p. 74-76° C.).
Reaction SMILES: C([Si]([O:8]/[C:9](/[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)=[CH:10]\[CH2:11][CH2:12][CH3:13])(C)C)(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:42]C)C=C4)N(CC2)C1.CS(N)(=O)=O>C(O)(C)(C)C.O>[Cl:20][C:16]1[CH:15]=[C:14]([C:9](=[O:8])[C@H:10]([OH:42])[CH2:11][CH2:12][CH3:13])[CH:19]=[CH:18][CH:17]=1
Reactant: CCC/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: CS(N)(=O)=O
Solvent: O
Solvent: CC(C)(C)O
Product: CCC[C@@H](O)C(=O)c1cccc(Cl)c1
Yield: 86.8 %

Procedure:
Compound 10k was synthesized by a procedure similar to that described for (R)-10a using (Z)-tert-butyl(1-(3-chlorophenyl)pent-1-enyloxy)dimethylsilane (9k, 4.1 g, 0.013 mol), AD-mix-β (18.5 g), and CH3SO2NH2 (1.3 g, 0.014 mol) in tert-butyl alcohol-water (50 mL:50 mL). The reaction was quenched with sodium sulfite (13.2 g). After purification, 2.4 g (77%) of the desired product was isolated: [α]20D +33.3° (c 1.1, CHCl3); 1H NMR (CDCl3) δ 7.91-7.87 (m, 1H), 7.80-7.75 (m, 1H), 7.63-7.17 (m, 1H), 7.45 (t, 1H, J=7.6 Hz), 5.08-5.00 (m, 1H), 3.58 (d, 1H, J=6.5 Hz), 1.89-1.75 (m, 1H), 1.61-1.35 (m, 3H), 0.93 (t, 3H, J=7.2 Hz); 13C NMR (CDCl3) δ 201.1, 135.4, 133.8, 130.2, 128.6, 126.5, 73.2, 37.8, 18.2, 13.8. C11H13ClO2.
Reaction SMILES: C(O[C:6](=[O:17])[NH:7][C:8]1[C:13]([CH:14]=[O:15])=[C:12]([Cl:16])[CH:11]=[CH:10][N:9]=1)(C)(C)C.[NH2:18][CH2:19][CH2:20]O.CC(O)=O>C1(C)C=CC=CC=1>[Cl:16][C:12]1[C:13]2[CH:14]3[O:15][CH2:20][CH2:19][N:18]3[C:6](=[O:17])[NH:7][C:8]=2[N:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C=O
Reactant: NCCO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C1Nc2nccc(Cl)c2C2OCCN12
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
tert-Butyl(4-chloro-3-formylpyridin-2-yl)carbamate (2.0 g, 7.79 mmol), 2-aminoethanol (0.57 g, 9.35 mmol), and AcOH (0.47 g; 7.79 mmol) were suspended in toluene (20 mL), and stirred overnight at room temperature. The reaction mixture was concentrated, and suspended in hexanes/ether (5/1, v/v). The resulting precipitate was filtered, suspended in NMP (3 mL) in 20 ml seal tube, and heated for 30 min. at 150° C. The crude product was purified directly via HPLC to provide 42 (270 mg, 10% yield) as a solid. LC-MS (M+H=226, obsd.=226).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[O:14][CH2:15][C:16]([F:19])([F:18])[F:17].[CH3:20][N:21]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:40].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH2:12]([S:9]([CH2:8][C:6]1[CH:5]=[CH:4][C:3]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:2]([C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:40])[N:21]([CH3:20])[CH:30]=2)[CH:7]=1)(=[O:11])=[O:10])[CH3:13]
Reactant: CCS(=O)(=O)Cc1ccc(OCC(F)(F)F)c(Br)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
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: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)Cc1ccc(OCC(F)(F)F)c(-c2cn(C)c(=O)c3ccccc23)c1
Temperature: 70 °C
Yield: 64.5 %

Procedure:
The title compound from Step 5 (200 mg, 0.58 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (197 mg, 0.69 mmol), Pd(PPh3)4 (67 mg, 58.0 umol) and Na2CO3 (184 mg, 1.74 mmol) in dioxane (6 mL) and water (6 drops) was degassed and then heated to 70° C. for 18 hours under N2. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (PE:EA=5:1˜1:1) followed by prep-HPLC purification to afford the title compound (164.44 mg, 67%) as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 8.52 (d, J=8.0 Hz, 1H), 7.58-7.48 (m, 3H), 7.40 (d, J=2.4 Hz, 1H), 7.22 (d, J=8.0, 1 H), 7.07 (t, J=8.0, 2 H), 4.30 (q, J=8.0 Hz, 2H), 4.23 (s, 2H), 3.67 (s, 3H), 2.98 (q, J=7.6 Hz, 2H), 1.43 (t, J=7.6 Hz, 3H). LCMS: 440.0 (M+1)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:30][CH2:31][CH2:32][OH:33])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CN=C1.[C:39]([Si:43](Cl)([CH3:45])[CH3:44])([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl>[Si:43]([O:33][CH2:32][CH2:31][CH2:30][C@@:8]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:45])[CH3:44]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CCCO[Si](C)(C)C(C)(C)C)(c2ccc(F)cc2)OC1=O
Reaction time: 8 h
Yield: 27.2 %

Procedure:
A mixture of (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (100 mg, 0.78 mmol), imidazole (142.8 mg, 2.1 mmol), and tert-butylchlorodimethylsilane (350 mg, 2.34 mmol) in CH2Cl2 (20 mL) was stirred overnight. The mixture was washed with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give crude (R)-6-(3-(tert-butyldimethylsilyloxy)propyl) -6-(4-fluorophenyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin -3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (120 mg), which was used for the next step without further purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([F:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl>[F:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: C1CNCCN1
Reactant: CC(=O)c1cc(F)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cc(F)c2cccnc2c1N1CCNCC1
Temperature: 65 °C
Yield: 10.1 %

Procedure:
A stirred mixture of 7-acetyl-5-fluoroquinolin-8-yltrifluoromethanesulfonate (1.00 g, 2.96 mmol, from Example 53, Step 2), piperazine (0.511 g, 5.93 mmol), and cesium carbonate (2.90 g, 8.90 mmol) in tetrahydrofuran (30 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over sodium sulfate and evaporated to dryness. The resulting residue was purified on silica gel, eluting with 0 to 20% methanol in dichloromethane, to give the desired product (82 mg, 10%). LCMS calculated for C15H17FN3O (M+H)+: m/z=274.1; Found: 274.1.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:14][CH2:15][CH2:16][CH2:17]Br.C(N(CC)CC)C.[Cl-].[Na+]>CN(C)C=O>[Cl:14][CH2:15][CH2:16][CH2:17][N:5]1[CH2:6][CH2:7][C:2]([OH:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:4]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: ClCCCBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1(c2ccccc2)CCN(CCCCl)CC1
Reaction time: 1 h

Procedure:
16.0 Grams of 4-hydroxy-4-phenylpiperidine, 24 g of 1-chloro-3-bromopropane and 15 g of triethylamine were mixed with 100 ml of dimethylformamide and stirred at 50°-60° C. for 1 hour. The reaction mixture was poured into 200 ml of saturated sodium chloride aqueous solution and the organic layer was extracted with chloroform, then the chloroform layer was washed with water, dried and the chloroform was removed by distillation. The residue thus obtained was purified by a silica-gel column chromatography (to obtain only the main product at the upper-most portion in the column). 14.3 Grams of 1-chloro-3-(4-hydroxy-4-phenyl-1-piperidyl)propane was obtained as in the form of colorless oily substance. Then this oily substance was distilled under a reduced pressure to obtain a fraction of distillate. The fraction of distillate was made as in the form of hydrochloride and recrystallized from ethanol to obtain 1-chloro-3-(4-hydroxy-4-phenyl-1-piperidyl)propane monohydrochloride having the melting point of 192°-195° C. as in the form of colorless needle-like crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C@H:7]2[N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[C:20]([NH2:25])=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:14][CH2:13]1.[C:26](N1C=CN=C1)(N1C=CN=C1)=[O:27].O>O1CCCC1>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C@H:7]2[N:12]1[CH2:13][CH2:14][CH:15]([N:18]2[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][C:26]2=[O:27])[CH2:16][CH2:17]1
Reactant: Cc1cccc2c1CCC[C@H]2N1CCC(Nc2ccccc2N)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc2c1CCC[C@H]2N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 60.9 %

Procedure:
(R)-N-[1-(5-Methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidin-4-yl]-benzene-1,2-diamine (1.83 g) was dissolved in tetrahydrofuran (100 ml), 1,1′-carbonyldiimidazole (973 mg) was added, and the mixture was stirred at room temperature for 10 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) and crystallized with hexane/ethyl acetate to give the title compound (1.2 g) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[C:12]([CH:20]2[S:24][CH2:23][CH2:22][S:21]2)[CH:11]=1)[NH:5][C:6](=[O:8])[CH3:7].O.[OH-].[Li+].Cl>C1COCC1.O>[S:21]1[CH2:22][CH2:23][S:24][CH:20]1[C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[CH2:16][C:17]([OH:19])=[O:18])[CH2:9][C@@H:4]([C:3]([OH:25])=[O:2])[NH:5][C:6](=[O:8])[CH3:7]
Reactant: COC(=O)[C@H](Cc1ccc(CC(=O)O)c(C2SCCS2)c1)NC(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N[C@@H](Cc1ccc(CC(=O)O)c(C2SCCS2)c1)C(=O)O
Reaction time: 0.75 h

Procedure:
To 3-(1,3-dithiolan-2-yl)4-(carboxymethyl)-N-acetyl-L-phenylalanine methyl ester (0.22 g, 0.57 mmol) in THF (10 mL) at 0° C. was added lithium hydroxide monohydrate (0.025 g, 0.60 mmol, 1 mL water). The mixture was stirred for 45 min., diluted with water, made acidic with 1 N HCl, and extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and concentrated to a glassy solid which was homogeneous by RP HPLC (0.18 g, 86%). MS [M−H]− 368.