Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([C:12]1[CH:16]=[C:15]([CH3:17])[S:14][C:13]=1Br)=[O:11].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:17][C:15]1[S:14][C:13]2[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=3[NH:9][C:10](=[O:11])[C:12]=2[CH:16]=1
Reactant: Cc1cc(C(=O)Nc2c(C)cccc2O)c(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc2c(s1)Oc1cccc(C)c1NC2=O
Temperature: 145 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
To a solution of N-(2-hydroxy-6-methylphenyl)-2-bromo-5-methyl-3-thiophenecarboxamide (3.0 g) in dimethyl sulfoxide (25 ml) was added potassium carbonate (2.5 g), and the mixture was stirred at 145° C. for 2 hours. The reaction system was cooled to room temperature and poured into ice water. The precipitated crystals were collected by filtration and the filtrate was extracted with chloroform, washed twice with water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue and the crystals obtained earlier were purified by silica gel column chromatography (chloroform:methanol=20:0-20:1). The obtained solid was collected by filtration from diisopropyl ether-hexane to give 2,6-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (700 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31]1([P:37](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[OH-].[Na+]>ClCCl>[C:31]1([P:37]([NH:1][C:2]2[CH:23]=[CH:22][C:5]([C:6]([N:8]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[CH2:12][N:11]4[CH:19]=[CH:20][CH:21]=[C:10]4[CH2:9]3)=[O:7])=[CH:4][CH:3]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:38])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(NP(=O)(c2ccccc2)c2ccccc2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A mixture of 0.10 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine 0.060 g of triethylamine and 0.12 g of diphenylphosphinyl chloride in 2 ml of dichloromethane is stirred at room temperature for 2 hours and then 1N NaOH is added. The mixture is extracted with ethyl acetate and the extract washed with brine and dried (Na2SO4). The solvent is removed and the residue triturated with ether-hexane to give 0.16 g of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[NH:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1C(O)=O>CS(C)=O>[Cl:14][C:13]1[C:6]2[C:7](=[O:9])[N:15]3[CH2:22][CH2:21][CH2:20][C@H:16]3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=[CH:3][C:2]=1[Cl:1]
Reactant: O=c1[nH]c2ccc(Cl)c(Cl)c2c(=O)o1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Product: O=C1Nc2ccc(Cl)c(Cl)c2C(=O)N2CCC[C@@H]12

Procedure:
A mixture of 22 g (94.8 mmol) of 5,6-dichloroisatoic acid anhydride, 10.85 g (94.8 mmol) of L-proline and 100 ml of dimethyl sulphoxide is heated to 90° for 0.5 hour, subsequently evaporated to dryness in a high vacuum and the residue is heated to 150° for 1 hour. By chromatography on silica gel while eluting with ethyl acetate and subsequent crystallization from ethyl acetate and hexane there is obtained (S)-6,7-dichloro-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione of melting point 203°-205° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:13][OH:14])[C:9]([O:11][CH3:12])=[O:10].[H-].[Na+].[CH3:17]I.O>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](=[CH:13]/[O:14][CH3:17])/[C:9]([O:11][CH3:12])=[O:10]
Reactant: CI
Reactant: COC(=O)C(=CO)c1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO/C=C(\C(=O)OC)c1ccccc1C
Reaction time: 1 h

Procedure:
A solution of 44 g of the product of Step B in 400 ml of tetrahydrofuran was introduced at 20°-25° C. into a solution of 700 ml of tetrahydrofuran and 11 g of sodium hydride (50% in oil). The reaction mixture was stirred for one hour and 150 ml of methyl iodide were added. The mixture was stirred for 5 hours and poured into water. Extraction was carried out with methylene chloride and the extracts were dried and brought to dryness to obtain 47.2 g of product which was chromatographed on silica and eluted with hexane-ethyl acetate mixture (7-3) to obtain the following:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:8]1[C:12]2([CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:15]2[CH2:16][CH2:17][C:12]3([O:11][CH2:10][CH2:9][O:8]3)[CH2:13][CH2:14]2)[CH2:4][CH2:3]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCN(C2CCC3(CC2)OCCO3)CC1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
1-Methyl-piperazine (128.27 g, 105.90 ml, 1.28 mol) was added in one portion to a stirred and cooled (3° C.) solution of 1,4-dioxaspiro[4.5]decan-8-one (200.00 g, 1.28 mol) in 1,2-dichloroethane (2.0 L). Then glacial acetic acid (76.90 g, 73.31 ml, 1.28 mol) was added in one portion followed by solid NaBH(OAc)3 (379.97 g, 1.79 mol) portionwise over 20 min. The reaction was slowly allowed to warm to RT and was stirred overnight. The reaction was quenched by addition of 10% aqueous NaOH (3×450 mL) with stirring over a period of 25 min. An exotherm of ca. 10° C. was observed. The mixture was stirred for 30 min. The organic layer was separated. Aqueous layer was further extracted with CH2Cl2 (3×1 L). Brine (1000 mL) was added to the aqueous layer and extracted with EtOAc (2×1000 mL). The combined organic solutions were dried (MgSO4) and concentrated to afford 9 (305.00 g, 1.27 mol, 99.10% yield) as brown/orange oil. 1H NMR (400 MHz, CDCl3) δ 1.45-1.68 (m, 4H), 1.72-1.90 (m, 4H), 1.99 (s, 3H), 2.45 (s, 2H), 2.56-2.67 (m, 1H), 2.87 (bs, 6H), 3.86-3.95 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][N:28]=1.C(#N)C.O>CN1CCCC1=O.C(OCC)(=O)C.O>[Br:1][C:2]1[C:3](=[O:19])[N:4]([C:27]2[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][N:28]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)nc1
Temperature: 106 °C

Procedure:
To a room temperature suspension of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (500.0 mg, 1.51 mmol) and Cs2CO3 (1.50 g, 4.60 mmol) in 1-methyl-2-pyrrolidinone (3.0 mL) was added ethyl 6-chloronicotinate (900 mg, 4.85 mmol). The resulting suspension was stirred and heated to 106° C. for 36 hours until complete consumption of starting material by LCMS analysis. The reaction mixture was then diluted with ethyl acetate (400 mL), water washed (3×200 mL). The resulting organic extract was separated, Na2SO4 dried, and concentrated. The resulting dark residue was subjected to SiO2 chromatography with ethyl acetate/hexanes (3:7) to furnish a solid. 1H NMR (400 MHz, d4-MeOH) δ 8.68 (app d, J=2.5 Hz, 1H), 8.39 (dd, J=8.7, 2.3 Hz, 1H), 7.62 (app q, J=8.2 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.08 (s, 1H), 7.08-6.99 (m, 2H), 5.31 (s, 2H), 4.37 (q, J=7.1 Hz, 2H), 2.43 (s, 3H), 1.37 (t, J=7.1 Hz, 3H); LC/MS C-18 column, tr=3.44 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 479 (M+H). ES-HRMS m/z 479.0401 (M+H calcd for C21H18BrF2N2O4 requires 479.0431).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6](O)/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20](O)=O)[C@H:12]2O[O:24][C@@H:10]1[CH2:11]2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOCC>[CH3:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[C@@H:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[O:24][CH2:10][CH2:11][CH2:12]1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H]2C[C@H]1OO2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOCC
Product: CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC

Procedure:
To a 12×75 mm tube containing [1-14C] PGH2 (2 μg, 0.01 μCi or 0.05 μCi) and inhibitor (1 mM final assay concentration, in 10 μl of ethanol) in 225 μl of phosphate buffer (0.1M, pH 7.5), was added to an aliquot of guinea pig lung microsomes (25 μl, containing 400 μg protein) or an aliquot of human platelet microsomes (25 μl, containing ≅130 g protein). The solution was incubated in a 22° water bath for 2 min.; ether (1 ml) and citric acid (25 μMoles) were added, and the tube plunged into an acetone-dry ice bath. The ether extract was transferred to a 1.0 ml Reacti-vial, and the volume reduced under nitrogen to ≅50 μl.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])#[CH:2].Br[CH2:20][CH2:21][CH2:22][CH2:23]CC.BrCCCCCCCCCC>>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:20][CH2:21][CH2:22][CH3:23])#[CH:2]
Reactant: CCCCCCBr
Reactant: C#Cc1c(CCCCCC)ccc2ccccc12
Agent: CCCCCCCCCCBr
Product: C#Cc1c(CCCCCCCCCC)ccc2ccccc12

Procedure:
1-Ethynyl-2-n-decylnaphthalene was prepared in a similar manner to 1-ethynyl-2-hexylnaphthalene, except that bromohexane was replaced by bromodecane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:28])[N:15]4[CH2:24][CH2:23]/[C:22](=[CH:25]\[O:26]C)/[CH2:21][CH2:20][C:16]4=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:28])[N:15]4[CH2:24][CH2:23][CH:22]([CH:25]=[O:26])[CH2:21][CH2:20][C:16]4=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CO/C=C1/CCc2nc3cc(C#Cc4cccc(F)c4)ccc3c(=O)n2CC1
Agent: Cl
Solvent: C1CCOC1
Product: O=CC1CCc2nc3cc(C#Cc4cccc(F)c4)ccc3c(=O)n2CC1
Temperature: 25 °C

Procedure:
A solution of (Z)-3-((3-fluorophenyl)ethynyl)-8-(methoxymethylene)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one (0.1 g, 0.8 mmol, 1 equiv) and 4N HCl (4 mL) in THF (20 mL) was heated at reflux for 4 h. After it was cooled to rt, the reaction mixture was quenched with Na2CO3 aqueous and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product. MS (ESI): 361 (MH+).
Reaction SMILES: C(OC1C=C(C=CC=1C)CN1CCC(NC2C=C(C=CN=2)C#N)CC1)C.Cl.Cl.[NH:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:36]2[CH:37]=[C:38]([CH:41]=[CH:42][N:43]=2)[C:39]#[N:40])[CH2:31][CH2:30]1.[CH2:44]([O:46][C:47]1[CH:48]=[C:49]([CH:52]=[C:53]([O:56][CH2:57][CH3:58])[C:54]=1[F:55])[CH:50]=O)[CH3:45]>>[CH2:44]([O:46][C:47]1[CH:48]=[C:49]([CH:52]=[C:53]([O:56][CH2:57][CH3:58])[C:54]=1[F:55])[CH2:50][N:29]1[CH2:30][CH2:31][CH:32]([NH:35][C:36]2[CH:37]=[C:38]([CH:41]=[CH:42][N:43]=2)[C:39]#[N:40])[CH2:33][CH2:34]1)[CH3:45]
Reactant: N#Cc1ccnc(NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Agent: CCOc1cc(CN2CCC(Nc3cc(C#N)ccn3)CC2)ccc1C
Agent: Cl
Product: CCOc1cc(CN2CCC(Nc3cc(C#N)ccn3)CC2)cc(OCC)c1F

Procedure:
The title compound was prepared in analogy to the synthesis of 2-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-isonicotinonitrile (example 189) from 2-(piperidin-4-ylamino)-isonicotinonitrile dihydrochloride (intermediate B15) and 3,5-diethoxy-4-fluoro-benzaldehyde (intermediate E5) in a yield of 4.3 mg (6%). MS (ISP): 399.3 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([Cl:10])=[CH:4][C:5]([Cl:9])=[C:6]([F:8])[CH:7]=1.[Cu][C:12]#[N:13]>>[Cl:10][C:3]1[CH:4]=[C:5]([Cl:9])[C:6]([F:8])=[CH:7][C:2]=1[C:12]#[N:13]
Reactant: N#C[Cu]
Reactant: Fc1cc(Br)c(Cl)cc1Cl
Product: N#Cc1cc(F)c(Cl)cc1Cl
Temperature: 150 °C
Reaction time: 4 h

Procedure:
48.8 g (0.2 mol) of 5-bromo-2,4-dichlorofluorobenzene and 17.9 g (0.2 mol) of copper(I) cyanide were introduced into a 100 ml 3-neck flask fitted with a reflux condenser and blade stirrer and stirred at 150° C. for 4 hours (no reaction). The reaction suspension was heated to 200° C. and stirred for a further 4 hours at this temperature: no reaction, 0 GC area-%.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(C(C)C)C(C)C)C.[CH3:14][S:15][C:16](=[O:29])[CH2:17][C@H:18]([NH:22][C:23](=[O:28])[CH2:24][CH2:25][CH:26]=[CH2:27])[C:19]([OH:21])=[O:20].[Cl-].[NH4+]>CN(C=O)C>[CH3:14][S:15][C:16](=[O:29])[CH2:17][C@H:18]([NH:22][C:23](=[O:28])[CH2:24][CH2:25][CH:26]=[CH2:27])[C:19]([O:21][CH2:2][C:3]#[N:4])=[O:20]
Reactant: N#CCBr
Reactant: C=CCCC(=O)N[C@@H](CC(=O)SC)C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCC(=O)N[C@@H](CC(=O)SC)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
2-Bromoacetonitrile (2.64 ml, 37.8 mmol) and N-ethyl-N-isopropylpropan-2-amine (3.29 ml, 18.9 mmol) were added to a solution of (S)-4-(methylthio)-4-oxo-2-(pent-4-enamido)butanoic acid (Compound 1f-IA) (1.17 g, 3.78 mmol) in DMF (5 ml), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution (3 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→30/70) to afford (S)-cyanomethyl 4-(methylthio)-4-oxo-2-(pent-4-enamido)butanoate (Compound 1g-IA) (368 mg, 34%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.C(O)CC.C(N(CC)CC)C>C(Cl)Cl.CS(C)=O.O>[Si:1]([O:8][CH2:9][CH:10]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:11][OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC(C=O)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(CO)Cc1ccccc1
Yield: 90 %

Procedure:
preparation of 3-(tert-Butyldimethylsilyloxy)-2-benzylpropanal (4). Dimethylsulfoxide (3 ml) was added dropwise to a solution of 1.10 g (8.67 mmol) of oxalyl chloride in 30 ml of methylene chloride at -78° C. This solution was stirred and a solution of 2.08 g (7.42 mmol) of the propanol it in 10 ml of dimethylsulfoxide was added. The resulting mixture was stirred for 20 minutes and then 7.6 ml (54.4 mmol) of triethylamine was added. After being stirred for an additional 20 minutes, the mixture was poured into 100 ml of water. The layers were separated. The aqueous phase was extracted with methylene chloride. The combined organic phases were dried and concentrated. The residue was purified on a silica gel column with 3:2 ether/hexane to give 1.84 g (90%) of 3 as a colorless liquid; 1H NMR (CDCl3) δ0.12 (s, 6H), 0.91 (s, 9H), 2.60 (m, 1H), 2.71 (m, 1H), 2.98 (m, 2H), 3.63 (m, 1H), 3.81 (m, 1H), 7.09 (m, 5H); IR (neat); 2931, 2860, 1730, 1471, 1255, 1100, 846 cm-1.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:35][N:36]([CH3:42])[CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][CH:37]([N:36]([CH3:42])[CH3:35])[CH2:38]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CN(C)C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(c2ccc3c(C(=O)NCC4(O)CCCC(F)(F)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxy-cyclohexylmethyl)-amide, DIPEA and 3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (m, 1H), 7.85 (1H), 7.48 (m, 2H), 6.69 (1H), 4.66 (s, 1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.26 (m, 2H), 2.85 (m, 1H), 2.54 (m, 4H), 2.22 (s, 6H), 2.15 (m, 1H), 2.06 (m, 2H), 1.85 (m, 3H), 1.74-1.76 (m, 5H). m/z: 467 [M+H]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([O:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(Cl)cc3)cc2)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(Oc2ccccc2)C(=O)O)cc1)c1ccc(-c2ccc(Cl)cc2)cc1
Yield: 74.7 %

Procedure:
In a similar manner to that described in Example 2, ethyl 3-[4-[2-(4′-chlorobiphenyl-4-carbonylamino)ethoxy]phenyl]-2-phenoxypropionate (900 mg), which is the product of Example 79, was reacted with aqueous sodium hydroxide solution (1N, 5.00 ml) and the reaction mixture was treated to give the title compound (638 mg) as a white powder.
Reaction SMILES: C([O:9][C@@H:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:18]=2)[N:13]([C:26](=[O:28])[CH3:27])[C@@H:12]([CH3:29])[CH2:11]1)(=O)C1C=CC=CC=1.[O-]CC.[Na+]>C(O)C>[C:26]([N:13]1[C:14]2[C:19](=[CH:18][C:17]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:16][CH:15]=2)[C@@H:10]([OH:9])[CH2:11][C@@H:12]1[CH3:29])(=[O:28])[CH3:27]
Reactant: CC(=O)N1c2ccc(N3CCOCC3)cc2[C@@H](OC(=O)c2ccccc2)C[C@@H]1C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)N1c2ccc(N3CCOCC3)cc2[C@@H](O)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
[Step 2] 180.6 mg of (2S,4S)-1-acetyl-2-methyl-6-morpholino-1,2,3,4-tetrahydroquinolin-4-yl benzoate was dissolved in 2 mL of ethanol, and 30.7 mg of sodium ethoxide was added to the solution. The mixture was stirred for 2 hours at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, water was added thereto, and the mixture was extracted three times with ethyl acetate. The extraction product was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (ethyl acetate:hexane=1:2). Thus, 97.8 mg (67.4%) of (2S,4S)-1-acetyl-4-hydroxyl-2-methyl-6-morpholino-1,2,3,4-tetrahydroquinoline was obtained as a white solid.
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C@H:12]3[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][C@H:13]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[CH:23](I)([CH3:25])[CH3:24]>>[CH:23]([N:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C@@H:13]4[CH2:14][NH:15][CH2:16][CH2:17][C@@H:12]4[N:10]([C:9]=23)[CH2:11][CH2:2]1)([CH3:25])[CH3:24]
Reactant: CC(C)I
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Product: CC(C)N1CCN2c3c(cccc31)[C@@H]1CNCC[C@@H]12

Procedure:
Utilizing the material from Example 255 Step A, the title compound was prepared in analogous fashion using isopropyl iodide as the alkyl halide and following the procedure of Step B–D of Example 255, as a viscous brown liquid. 1H NMR (CDCl3, 300 MHz) δ 1.18 (d, 6H), 1.60–1.67 (m, 1H), 1.71–1.94 (m, 2H), 2.63–2.75 (m, 2H), 2.81–2.95 (m, 2H), 2.99–3.20 (m, 2H), 3.30–3.55 (m, 3H), 3.99–4.12 (m, 1H), 6.45 (d, J=7.4 Hz, 2H), 6.65 (t, J=7.3 Hz, 1H) ppm. MS (CI): 258 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[NH2:9][C:10]1[CH:15]=[C:14]([NH:16][C:17]([O:19][CH3:20])=[O:18])[CH:13]=[CH:12][C:11]=1[NH:21][C:22](=[O:27])[CH2:23][N:24]([CH3:26])[CH3:25].O.[ClH:29]>CC(C)=O.C(O)C.C(OCC)C>[ClH:29].[CH2:1]([O:3][C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[C:14]([NH:16][C:17]([O:19][CH3:20])=[O:18])[CH:13]=[CH:12][C:11]=1[NH:21][C:22](=[O:27])[CH2:23][N:24]([CH3:26])[CH3:25])=[S:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)N=C=S
Reactant: COC(=O)Nc1ccc(NC(=O)CN(C)C)c(N)c1
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Solvent: CCOCC
Product: CCOC(=O)NC(=S)Nc1cc(NC(=O)OC)ccc1NC(=O)CN(C)C
Reaction time: 0.5 h

Procedure:
Ethoxycarbonyl isothiocyanate (5.6 g) was added dropwise, with cooling to maintain the temperature between 15° and 20° C., to a vigorously stirred solution of N-(2-amino-4-methoxycarbonylaminophenyl)-2-dimethylaminoacetamide (10.75 g) in dry acetone (200 ml). The resulting mixture was stirred for a further 30 minutes and then poured into an excess of water. The precipitated solid was filtered off to give crude 1-ethoxycarbonyl-3-(2-dimethylaminoacetamido-5-methoxycarbonylaminophenyl)thiourea, m.p. 171°-172° C, which was then dissolved in the minimum of ethanol. Diethyl ether (300 ml) was added, followed by an excess of a saturated solution of hydrogen chloride in diethyl ether. The precipitated solid was filtered off and recrystallised from methanol/ethanol to give 1-ethoxycarbonyl-3-(2-dimethylaminoacetamido-5-methoxycarbonylaminophenyl)thiourea hydrochloride (7.5 g), m.p. 211°-213° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([O:14]C)=O)[C:9](=[O:16])[S:8][C:5]2=[N:6][CH:7]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([N:21]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)=[O:14])[C:9](=[O:16])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: COC(=O)Cn1c(=O)sc2ncc(Cl)cc21
Product: CN1CCN(C(=O)Cn2c(=O)sc3ncc(Cl)cc32)CC1
Temperature: 130 °C
Yield: 15.8 %

Procedure:
A mixture of 6-chloro-1-methoxycarbonylmethyl-2-oxo-1,2-dihydrothiazolo[5,4-b]pyridine (2.0 g) and N-methyl-piperazine (1.6 g) was heated at 130° C. for 15 min. After cooling, the mixture was purified on a silica gel column chromatography using a mixture of chloroform and methanol (10:1). The desired fractions containing the objective compound were collected and evaporated. The crude crystals obtained were recrystallized from a mixture of chloroform and diethyl ether to give 6-chloro-2-oxo-1-[(4-methyl-1-piperazinyl)carbonylmethyl]-1,2-dihydrothiazolo[5,4-b]pyridine (0.4 g).