Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:13][CH:2]1[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([NH:18][CH2:13][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN
Reactant: O=Cc1ccc(OCC2CO2)cc1
Product: CCCCNCC(O)COc1ccc(C=O)cc1

Procedure:
To 4-(2,3-epoxypropoxy)benzaldehyde (8.9 gms., 0.05 m) is added n-butylamine (30 ml.) and the resulting solution is refluxed 17 hours. The excess n-butylamine is removed under reduced pressure (20 mm). The oil is dissolved in 6N hydrochloric acid (30ml.) and the solution is heated on a steam bath for 40 minutes. The hot acidic solution is poured into a hot saturated aqueous sodium carbonate solution with nitrogen bubbling through it. The basic solution is extracted with chloroform. The chloroform is dried over sodium sulfate and concentrated to yield 4-(3-n-butylamino-2-hydroxypropoxy) benzaldehyde, as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[C:13]([C:14]#[N:15])=[C:12]([S:16][CH3:17])[S:11][C:10]=1[C:18]([O:20]CC)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1>[C:14]([C:13]1[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:10]([C:18]([OH:20])=[O:19])[S:11][C:12]=1[S:16][CH3:17])#[N:15]
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSc1sc(C(=O)O)c(NC(=O)OC(C)(C)C)c1C#N
Temperature: 50 °C
Yield: 101.9 %

Procedure:
A mixture of ethyl 3-bis(t-butoxycarbonyl)amino-4-cyano-5-(methylthio)thiophene-2-carboxylate (10 g, 22 mmol), tetrahydrofuran (250 ml) and 4N sodium hydroxide (25 ml) was heated at 50° C. for 16 hours. The mixture was evaporated, and water (50 ml) was added followed by acidification with acetic acid (pH=4) at 0° C. The precipitate was filtered off and dried to afford 7.05 g (99%) of 4-cyano-5-methylthio-3-(t-butoxycarbonylamino)thiophene -2-carboxylic acid. 1H-NMR (DMSO-D6, δ): 1.45 (s, 9H), 2.70 (s, 3H), 9.20 (s, 1H).
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[CH3:15][NH:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C>[N:1]1([CH2:6][C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N+:16]([O-:17])[CH3:15])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(Cn1ccnc1)c1cccs1
Reactant: CNO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C[N+]([O-])=C(Cn1ccnc1)c1cccs1
Temperature: 50 °C
Reaction time: 96 h
Yield: 89.7 %

Procedure:
Under a nitrogen, a mixture of 22.00 g (0.114 mol) of 2-(1H-imidazol-1-yl)-1-(2-thienyl)ethanone (3), 11.49 g (0.138 mol) of N-methylhydroxylamine hydrochloride, and 22.55 g (0.275 mol) of sodium acetate in 250 ml of ethanol is heated to 50° C. and stirred for 4 days. The reaction mixture is filtered while hot and the filtrate concentrated in vacuo. Crystallization from ethanol gives 22.62 g (89%) of compound 4, melting point 162°-164° C. Anal. Calcd. for C10H11N3OS: C, 54.28; H, 5.01; N, 18.99. Found: C, 54.16; H, 5.06; N, 18.86.
Reaction SMILES: [NH3:1].C[O:3][C:4]([C:6]1[C:14]2[O:13][CH2:12][CH2:11][C:10]=2[C:9]([NH:15][C:16](=[O:18])[CH3:17])=[CH:8][CH:7]=1)=O>CO>[C:16]([NH:15][C:9]1[C:10]2[CH2:11][CH2:12][O:13][C:14]=2[C:6]([C:4]([NH2:1])=[O:3])=[CH:7][CH:8]=1)(=[O:18])[CH3:17]
Reactant: COC(=O)c1ccc(NC(C)=O)c2c1OCC2
Reactant: N
Solvent: CO
Product: CC(=O)Nc1ccc(C(N)=O)c2c1CCO2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Ammonia gas was bubbled through a solution of 4-acetylamino-2,3-dihydro-benzofuran-7-carboxylic acid methyl ester (12 g, 51 mmol, prepared as described in Takuji Kakigami et al, Chem. Pharm. Bull, 46 (1), 42-52, (1998)) in CH3OH (200 mL) in a pressure bottle at 0-5° C. until the solution was saturated. The bottle was sealed and stirred at 60° C. overnight. After cooling to 0-5° C., the reaction mixture was charged one more time with NH3 gas, then the sealed bottle stirred at 60° C. for another 24 h. After cooling to rt, white precipitates were collected by filtration, and dried under vacuum to furnish the title compound (10.5 g) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[C:13]1(OB(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][CH:6]=1)[CH3:2]
Reactant: OB(O)Oc1ccccc1
Reactant: CCOC(=O)c1ccc(Cl)nc1
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: CCOC(=O)c1ccc(-c2ccccc2)nc1
Yield: 86.8 %

Procedure:
Under nitrogen atmosphere, 6-chloronicotinic acid ethyl ester (24.0 g) and phenylboric acid (23.6 g) were dissolved in dioxane (200 mL) and aqueous sodium carbonate solution (2M, 100 mL), tetrakis(triphenylphosphine)palladium (7.0 g) was added, and the mixture was refluxed for 8 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=7:1 to 5:1) to give the title compound (25.5 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1.[Li]C(C)(C)C.[Br:17]C(Cl)(Cl)C(Cl)(Cl)Br.[NH4+].[Cl-]>C1COCC1>[Br:17][C:6]1[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][N:9]=[C:8]([CH3:11])[CH:7]=1
Reactant: COCOc1ccc(C)nc1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCOc1cnc(C)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
A solution of 1000 mg (6.53 mmol) 5-methoxymethoxy-2-methyl-pyridine (J.-P. Behr et al. Bioorg. Med. Chem. Lett. 2003, 13(10), 1713) in 10 mL THF was cooled to −78° C., where 4.03 mL (6.85 mmol) t-BuLi (1.7M solution in pentane) was added. The resulting mixture was stirred under argon for 1 h, then 2.126 g (6.53 mmol) 1,2-dibromotetrachloroethane (in 5 mL THF) was added. Stirring was continued for 1 h at −78° C. and the reaction mixture was warmed to rt. Saturated NH4Cl solution was added and the aqueous mixture was extracted with EtOAc (2×). The combined organic layers were washed with H2O and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to leave a residue that was purified on silica gel (EtOAc/hexane=1:1) to afford 920 mg of the title compound as an oil. LCMS: tR=0.29 min, M+H=232 (79Br), 234 (81Br) (method J).
Reaction SMILES: [Cl:1][C:2]([F:6])=[C:3]([F:5])[F:4].[CH2:7]=[CH:8][CH:9]=[CH2:10]>>[Cl:1][C:2]1([F:6])[C:3]([F:5])([F:4])[CH2:10][CH:9]=[CH:8][CH2:7]1
Reactant: FC(F)=C(F)Cl
Reactant: C=CC=C
Product: FC1(F)CC=CCC1(F)Cl

Procedure:
4-chloro-4,5,5-trifluorocyclohexene was prepared in the same manner as in Example 12 except that chlorotrifluoroethylene (CTFE) and 1,3-butadiene were continuously injected into the flow reactor at the rates of 65.2 g/hr and 30.3 g/hr, respectively. Then, 8.6 g of unreacted chlorotrifluoroethylene (CTFE) was recovered. The resultant was purified by steam distillation, and then the water layer was removed to give 64.9 g of the mixture (GC%=61%).
Reaction SMILES: N1C=CN=C1.[I:6]I.[Si:8]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]O)([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[C:21]([Si:8]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][I:6])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:23])([CH3:24])[CH3:22]
Reactant: II
Reactant: CC(C)(C)[Si](OCCCCCO)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCCCCI)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 0.1 %

Procedure:
Imidazole (310 mg, 4.40 mmol), iodine (440 mg, 3.5 mmol), and a solution of 2 (1 g, 2.98 mmol) in CH2Cl2 (2 mL) were added sequentially to a 0° C. solution of PPh3 (450 mg, 3.5 mmol) in CH2Cl2 (15 mL) and kept in the dark. After 2 h, the reaction mixture was quenched by adding 20% aq. Na2S2O3 (5 mL). The aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, and the solvent was removed in vacuo. The residue was purified by careful column chromatography using 5% EtOAC/hexane to afford iodide 3 (1.25 mg, 92%). TLC: 10% EtOAc/hexane, Rf˜0.85; 1H NMR (CDCl3, 400 MHz) δ 7.67-7.62 (m, 4H), 7.45-7.35 (m, 6H), 3.67 (t, 2H, J=6.0 Hz), 3.41 (t, 2H, J=6.7 Hz), 2.03-1.93 (m, 2H), 1.72-1.64 (m, 4H), 1.04 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](OC1C=CC=CC=1)=[N:7][CH:6]=[CH:5]2.C([O-])(=O)C.[NH4+:23].[OH-].[Na+]>>[NH2:23][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Brc1ccc2c(Oc3ccccc3)nccc2c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: Nc1nccc2cc(Br)ccc12
Temperature: 150 °C
Yield: 71.8 %

Procedure:
A mixture of 12 g of 1c and 27 g of ammonium acetate was heated at 150° C. for 14 hours. After cooling to room temperature aqueous 3N NaOH was added and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with brine and aqueous 2N hydrochloric acid was added until pH2-3. The acid aqueous layer was separated, made basic (pH10) with aqueous 2N NaOH and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried (MgSO4) and concentrated to give 6.4 g of 1d. 1H-NMR 200 MHz (CDCl3) δ: 5.1 (2H, br s), 6.96 (1H, dd, J=6 Hz and J=1 Hz), 7.54-7.70 (2H, m), 7.88 (1H, d, J=2 Hz), 7.98 (1H, d, J=6 Hz).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]([OH:31])[CH2:16][N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])[CH2:19][CH2:18]3)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[BH4-].[Na+].CC(C)=O>C(O)C>[OH:3][CH:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]([OH:31])[CH2:16][N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])[CH2:21][CH2:22]3)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)[CH3:2]
Reactant: COc1ccccc1N1CCN(CC(O)COc2cccc3cc(C(C)=O)oc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: COc1ccccc1N1CCN(CC(O)COc2cccc3cc(C(C)O)oc23)CC1
Reaction time: 1 h

Procedure:
There was dissolved 4.3 g (0.01 mole) of 2-acetyl-7-{2-hydroxy-3-[4-(2-methoxyphenyl)piperazinyl]propoxy}benzofuran in 50 ml of ethanol, and thereto 0.35 g of sodium borohydride was gradually added with cooling with ice. After stirring 1 hour, aceton was added to decompose the excess sodium borohydride and the solvent was distilled away under reduced pressure. The residue was extracted from ethyl acetate and the obtained extract was dried with magnesium after washing with water. Ethyl acetate was distilled away under reduced pressure and the obtained residue was crystallized from ethyl acetate.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[N:30]1([CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])[S:14][N:13]=1
Reactant: NCCCCN1CCCC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Solvent: C1CCOC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CCCC3)c2C(N)=O)cc1F
Temperature: 47.5 °C
Reaction time: 24 h
Yield: 81.9 %

Procedure:
A mixture of [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester (0.34 g, 0.81 mmol), 4-pyrrolidinobutylamine (0.12 g, 0.81 mmol) and tetrahydrofuran (2.8 mL) was shaken at 45-50° C. for 24 hours. The mixture was concentrated and purified by radial chromatography (4 mm plate, CH3OH—CHCl3—NH4OH (10:89:1) to (15:84:1)), affording 0.31 g of the title compound as a colorless solid. The material was dissolved in ca. 10 mL of 4:1 methanol-chloroform at −10° C. and was treated with a solution of methanesulfonic acid (0.043 mL in 0.5 mL of CH3OH). After stirring for 5 minutes, the mixture was concentrated in vacuo, and the residue was triturated with methanol-ether, affording 0.35 g of the title compound (82%) as a colorless solid. HPLC ret. time: 3.3 minutes. 1H NMR (400 MHz, D2O) δ 6.74 (dd, 1H, J=6.0, 9.6 Hz), 6.63 (dd, 1H, J=6.4, 10.4 Hz), 4.61 (s, 2H), 3.44 (m, 2H), 3.05-2.98 (m, 4H), 2.98-2.81 (m, 2H), 2.62 (s, 3H), 1.95-1.93 (m, 4H), 1.83-1.80 (m, 2H), 1.6-1.5 (m, 2H), 1.4-1.3 (m, 2H) ppm; MS (APCI, m/z): 468 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[CH2:17]O)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([NH:27][CH2:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2CO)CC1
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2CNC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To [2-(4-methylpiperazin-1-yl)-5-nitrophenyl]methanol prepared in step A of example 1 (0.150 g, 0.60 mmol) in 5 mL of THF at 0° C. was added thionyl chloride (0.22 mL, 5 eq). The reaction mixture was refluxed for 45 minutes and then the solvent and the excess of thionyl chloride were evaporated. The residue was suspended in 5 mL of acetonitrile and tert-butylamine (0.62 mL, 10 eq) was added at 0° C. The solution was stirred 48 h at room temperature, evaporated and the residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of Na2CO3. The aqueous layer was extracted with ethyl acetate and then the combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was thoroughly washed with pentane and filtered off to yield expected compound as an orange powder (0.192 g, quantitative yield) m/z (ESI) 307.2 [M+H]+.
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C([Li])CCC.[C:16]([C:18]1([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:26]=2)[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)#[N:17].[Cl-].[Na+]>O1CCCC1.O>[C:16]([C:18]1([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:26]=2)[CH2:19][CH2:20][C:21](=[C:3]2[S:8][CH2:7][CH2:6][CH2:5][S:4]2)[CH2:22][CH2:23]1)#[N:17]
Reactant: C[Si](C)(C)C1SCCCS1
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2(C#N)CCC(=C3SCCCS3)CC2)cc1OC1CCCC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 272 %

Procedure:
To a solution of 2-trimethylsilyl-1,3-dithiane (9.25 mL, 48.7 mmol) in dry tetrahydrofuran (80 mL) at 0°C. under an argon atmosphere was added rapidly n-butyllithium (2.5M in hexanes, 19.2 mL, 48 mmol). After 10 min, the mixture was cooled to -78°C. and a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (7.53 g, 23 mmol) in tetrahydrofuran (40 mL) was added. After 10 min, aqueous sodium chloride was added, the mixture was allowed to warm to room temperature and was diluted with water. This mixture was combined with the product of three substantially similar reactions conducted on ketone (3.04, 6.01 and 6.1 g, 48.3 mmol total), the combined mixture was extracted three times with methylene chloride, the extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 10% ethyl acetate/hexanes, provided a white solid (26 g, 87%): m.p. 115°-116° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([O:18][CH3:19])[CH2:4][NH:5][C:6]1[CH:15]=[C:14]([O:16]C)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.[ClH:20]>>[ClH:20].[ClH:20].[NH2:1][CH2:2][CH:3]([O:18][CH3:19])[CH2:4][NH:5][C:6]1[CH2:15][C:14](=[O:16])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: COc1cc(NCC(CN)OC)nc2ccccc12
Agent: Cl
Product: COC(CN)CNC1=Nc2ccccc2C(=O)C1
Yield: 85 %

Procedure:
A solution of 2-(3-amino-2-methoxyprop-1-ylamino)-4-methoxyquinoline (0.84 g, 0.00321 mol) in hydrochloric acid (10M, 30 ml) was stirred at reflux for 24 h. After cooling the mixture was concentrated to give the title compound as a light brown solid (0.88 g, 85%). δH (CD3OD) 3.00-3.90 (5H, m, 2CH2, CHOCH3), 3.36 (3H, s, CHOCH3), 6.48 (1H, s, 3-H), 7.47-8.15 (4H, m, ArH). MS (ES+) 248 (M+H).
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:3]=1[NH:4][C@H:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:3]=1[NH:4][CH:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)[C@@H](C)Nc1ccc(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Nc1ccc(F)c(F)c1F
Temperature: 110 °C
Reaction time: 19 h
Yield: 85 %

Procedure:
Methyl (2R)-2-(2,3,4-trifluoroanilino)propionate (50 mg, 57% ee) was dissolved in N,N-dimethylformamide (DMF; 1 ml) and potassium carbonate (63.2 mg) was added thereto at room temperature. Then the liquid reaction mixture was stirred at 110° C. for 19 hours. After adding water to the liquid reaction mixture, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography (ethyl acetate-normal hexane=1:4) to thereby give the title compound (42.5 mg) as colorless crystals. The optical purity of this product was 0% ee. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 5.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].Br[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][C:26]([CH:32]4[CH2:34][CH2:33]4)=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[N:13][CH:14]=1>>[CH:29]1([C:28]2[C:23]([N:20]3[CH2:21][CH2:22][N:17]([C:15]([C:12]4[N:13]=[CH:14][C:9]([N:4]5[CH2:5][CH2:6][N:2]([CH3:1])[C:3]5=[O:7])=[CH:10][CH:11]=4)=[O:16])[CH2:18][CH2:19]3)=[N:24][CH:25]=[C:26]([CH:32]3[CH2:34][CH2:33]3)[CH:27]=2)[CH2:31][CH2:30]1
Reactant: CN1CCNC1=O
Reactant: O=C(c1ccc(Br)cn1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: CN1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C4CC4)CC3)nc2)C1=O
Yield: 34.6 %

Procedure:
Using 1-methyl-2-imidazolidinone (181 mg) and (5-bromopyridin-2-yl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (700 mg) described in Preparation Example 142 and by the reaction and treatment in the same manner as in Example 1, the title compound (253 mg) was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1>CC(C)=O.O=[Mn]=O>[CH:2]([C:3]1[CH:4]=[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)=[O:1]
Reactant: NS(=O)(=O)c1cccc(CO)c1
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: NS(=O)(=O)c1cccc(C=O)c1
Reaction time: 50 h
Yield: 76.4 %

Procedure:
A solution of 3-(hydroxymethyl)benzenesulfonamide (307 mg, 1.64 mmol) in acetone (16 mL) was added to a round bottom flask containing MnO2 (1.43 g, 16.4 mmol). The mixture was stirred for 50 hours until the starting material was consumed, then filtered though a pad of celite. The filtrate was evaporated to afford the product (232 mg, 76%) as a white solid. MS (ES+) m/z 186 [M+H]+.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:30][C:29]([CH:31]=O)=[N:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:33][CH2:34][CH2:35][OH:36].[BH4-].[Na+].C(=O)([O-])O.[Na+]>CO>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:30][C:29]([CH2:31][NH:33][CH2:34][CH2:35][OH:36])=[N:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: O=Cc1nnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Reactant: NCCO
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3nnc(CNCCO)s3)[nH]2)cc1)C1CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of 5-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3,4-thiadiazole-2-carbaldehyde (300 mg) in methanol (10 mL) was added 2-aminoethanol (250 μL) at room temperature, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was cooled to room temperature, sodium tetrahydroborate (72 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography to give a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-methanol (9:1, volume ratio). The pale-yellow amorphous solid was subjected to silica gel column chromatography, and the title compound (188 mg, yield 57%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-methanol (8:2, volume ratio). MS: 517 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:34])[C:9]([CH2:21][CH2:22][CH2:23][CH2:24][B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)([CH2:17][CH2:18][CH:19]=C)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:35]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]([CH3:34])[C:9]([CH2:17][CH2:18][CH:19]=[O:35])([CH2:21][CH2:22][CH2:23][CH2:24][B:25]1[O:26][C:27]([CH3:32])([CH3:33])[C:28]([CH3:30])([CH3:31])[O:29]1)[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=[O+][O-]
Reactant: C=CCCC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)OC(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C(CCC=O)(CCCCB1OC(C)(C)C(C)(C)O1)C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 70 %

Procedure:
A solution of tert-butyl 2-(tert-butoxycarbonyl(methyl)amino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hex-5-enoate (1.10 g, 2.29 mmol) in dichloromethane (30 mL) was cooled to −78° C. and treated with ozone until a pale blue-gray color appeared. After TLC indicated the absence of starting material, the ozone inlet tube was replaced with nitrogen and nitrogen was bubbled through the solution for 20 min to remove any excess ozone. Triphenylphosphine (1.50 g, 5.72 mmol, 2.5 equiv) was added in one portion, the cooling bath was removed and the mixture was stirred for 4 h. The solution was concentrated and purified by MPLC (0-40% ethyl acetate in heptane) gave tert-butyl 2-(tert-butoxycarbonyl(methyl)amino)-2-(3-oxopropyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as a colorless oil (780 mg, 70%). Rf 0.40 (30% ethyl acetate in heptane). ESI MS found for C25H46BNO7 m/z [484.3 (M+1)].