Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])[O:2]1.[BrH:12]>O>[Br:12][CH2:1][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:4][C:3]([OH:2])=[O:11]
Reactant: O=C1Cc2ccccc2CO1
Reactant: Br
Solvent: O
Product: O=C(O)Cc1ccccc1CBr
Reaction time: 0.17 h

Procedure:
3-Isochromanone (30 g), Mann, F. G. and Stewart, F. H., Journal of the Chemical Society 2819 (1954) is added with swirling to 150 ml of hydrobromic acid (48%) at 80° C. The resulting mixture is then heated on a steam bath with occasional swirling for 10 min and thereafter poured into a mixture of crushed ice and water (750 g). The resulting mixture is then extracted with ethyl acetate and the ethyl acetate extracts washed with a mixture of water and brine (1:1) and dried over magnesium sulfate. Concentration under reduced pressure yields a residue of crude o-(bromomethyl)phenylacetic acid. (Crystallization of the crude product from methylene chloride yields a product with melting point 130°-131° C. and a C:H ratio of 46.90:4.09). The crude o-(bromomethyl)phenylacetic acid, 400 ml of benzene and 38 g of triphenylphosphine is stirred at 80° C. for 5 hr and cooled and filtered to yield 57 g of title product, melting point 248°-249° C. The C:H:Br:P ratio is 66.22:4.94:16.16:6.49.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:24][C:23]=2[CH:33]=1.Cl[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].C1(C)C=CC=CC=1>C(Cl)Cl.O>[F:8][C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:16])=[O:17])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH2:29][CH2:28]3)=[N:24][C:23]=2[CH:33]=1
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-c2ccc3oc(C4CCNCC4)nc3c2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(S(C)(=O)=O)cc4F)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl 4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate (200 mg, 0.42 mmol) dissolved in DCM and added Trifluoroacetic acid (0.75 ml). This mixture was stirred at rt for 2 h. DCM removed from the reaction mixture to obtain 5-(2-fluoro-4-(methylsulfonyl)phenyl)-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (190 mg). 5-(2-fluoro-4-(methylsulfonyl)phenyl)-2-(piperidin-4-yl)-benzo[d]oxazole 2,2,2-trifluoroacetate (190 mg, 0.39 mmol) was dissolved in DCM (20 ml) and added TEA (0.43 ml, 3.12 mmol). This mixture stirred at rt for 30 mins and added isopropyl chloroformate in toluene (0.095 g, 0.78 mmol). After 1 h, reaction mass diluted with water and extracted with DCM. Removal of DCM afforded crude. Crude was purified by combiflash using a mixture of EtOAc and Petether (35:65) as eluent to afford the titled compound (120 mg) as a pale-yellow solid. M.P.: 96.5-101.2° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.87 (s, 1H), 7.81 (dd, J 1.7, 8, 1H), 7.80-7.75 (m, 1H), 7.67 (t, J 7.5, 1H), 7.59 (d, J 8.4, 1H), 7.50 (d, J 8.5, 1H), 4.94 (septet, J 6.2, 1H), 4.19 (d, J 10.9, 2H), 3.22-3.13 (m, 1H), 3.12 (s, 3H), 3.04 (t, J 10.9, 2H), 2.22-2.14 (m, 2H), 2.00-1.88 (m, 2H), 1.26 (d, J 6.2, 6H).
Reaction SMILES: [O:1]([CH2:8][CH2:9]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2>>[O:1]([CH2:8][CH2:9][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: BrCCOc1ccccc1
Product: c1ccc(OCCOc2ccc3[nH]ccc3c2)cc1

Procedure:
The title compound was prepared by a method analogous to that described in Example 1 from 2-phenoxyethyl bromide and 5-hydroxyindole. MS ES (MH+)=254.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4](=[N:8][O:9][CH2:10][C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[C:5]([OH:7])=[O:6].[NH2:20][C:21]([NH2:23])=[S:22].C([O-])(=O)C.[Na+]>O>[NH2:23][C:21]1[S:22][CH:2]=[C:3]([C:4](=[N:8][O:9][CH2:10][C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[C:5]([OH:7])=[O:6])[N:20]=1
Reactant: NC(N)=S
Reactant: O=C(CON=C(C(=O)O)C(=O)CBr)OCC(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Nc1nc(C(=NOCC(=O)OCC(Cl)(Cl)Cl)C(=O)O)cs1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 18.6 %

Procedure:
To a solution of 4-bromo-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyric acid (20 g) in tetrahydrofurna (50 ml) was added a solution of thiourea (3.9 g) and sodium acetate (4.2 g) in water (50 ml), and the mixture was stirred at 40° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure to half of the original volume, which was adjusted to pH 7.5 with a saturated aqueous sodium bicarbonate and then washed with ethyl acetate. After the aqueous solution was further adjusted to pH 2.0 with 10% hydrochloric acid, the water was removed by decantation. The residual substance was dissolved in tetrahydrofuran (200 ml), followed by drying over magnesium sulfate. Removal of the solvent gave an oil, which was triturated with diisopropyl ether to give 2-(2-aminothiazol-4-yl)-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)acetic acid (syn isomer) (3.5 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:10].[CH3:11][C:12](=O)[CH:13]=[CH2:14]>C(O)C.[Fe](Cl)(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[Cl:9][C:8]1[C:3]([Cl:2])=[C:4]2[C:5]([C:13]([CH3:14])=[CH:12][CH:11]=[N:10]2)=[CH:6][CH:7]=1
Reactant: Nc1cccc(Cl)c1Cl
Reactant: C=CC(C)=O
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Product: Cc1ccnc2c(Cl)c(Cl)ccc12
Temperature: 65 °C

Procedure:
A mixture of 2,3-dichlorobenzenamine monohydrochloride (0.308 mol), iron(III) chloride (0.52 mol) and zinc chloride (0.0308 mol) in ethanol (800 ml) was heated at 65° C. for 30 minutes. 3-butenone (0.308 mol) in ethanol (200 ml) was added dropwise at 65° C. over a 1 hour period and the mixture was stirred and refluxed overnight. The mixture was cooled to room temperature and evaporated. The residue was taken up in water, basified with NH4OH, filtered off and extracted with ethyl acetate. The organic layer was extracted with 3N HCl. The aqueous layer was basified with NH4OH and extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated, yielding 38g (58%) of 7,8-dichloro-4-methylquinoline (interm. 1).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:14]([O:16][CH3:17])=[O:15])=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].[CH3:24][Si:25]([CH3:32])([CH3:31])[CH2:26][CH2:27][O:28][CH2:29]Cl>CN(C=O)C.C1COCC1>[CH3:24][Si:25]([CH3:32])([CH3:31])[CH2:26][CH2:27][O:28][CH2:29][N:9]1[C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([C:14]([O:16][CH3:17])=[O:15])[N:6]=[C:5]1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(=O)OC)c(C(=O)OC)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCc1nc(C(=O)OC)c(C(=O)OC)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 106 %

Procedure:
The diester 1 from Step (a) (23 g, MW 240, 0.096 mol) was dissolved in 300 ml DMF. Potassium t-butoxide (100 ml of a 1M solution in dry THF) was added through a syringe. The solution was stirred for 15 min at 25° C. [2-(trimethylsilyl)ethoxy]methyl chloride (SEM-chloride, 18.6 ml, 1.1 eq, MW 166, d 0.94) was added and a precipitate instantly formed. The reaction was stirred for 90 min at 25° C. The solvent was removed and the residue partitioned between ethyl acetate and water. The organic extract was dried over K2CO3 and concentrated. By TLC (SiO2, MeOH-CHCl3 /1-10) a single major spot was observed. This crude product (38 g, 106% yield) was used in subsequent steps without further purification.
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Cl:14][C:15]1[C:16]([CH3:41])=[C:17]([NH:23][C@H:24]([CH2:39][OH:40])[C:25]([NH:27][NH:28][C:29](=[O:38])[C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)=[O:26])[CH:18]=[CH:19][C:20]=1[C:21]#[N:22].O>CN(C=O)C>[Si:10]([O:40][CH2:39][C@@H:24]([NH:23][C:17]1[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[C:15]([Cl:14])[C:16]=1[CH3:41])[C:25]([NH:27][NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=1)=[O:26])([C:7]([CH3:9])([CH3:8])[CH3:6])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(N[C@H](CO)C(=O)NNC(=O)c2ccc(C#N)cc2)ccc(C#N)c1Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(N[C@H](CO[Si](C)(C)C(C)(C)C)C(=O)NNC(=O)c2ccc(C#N)cc2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.7 %

Procedure:
Imidazole (1.3 g, 19.1 mol) and TBDMS-Cl (1.73 g, 11.46 mmol) were added sequentially to a pre-cooled (0° C.) solution of (R)-N′-(2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxypropanoyl)-4-cyanobenzohydrazide (1.52 g, 3.82 mmol) in DMF (145 mL). The reaction mixture was allowed to warm to room temperature and stirred for 20 h, whereupon the solution was poured into H2O (200 mL). The white precipitate was filtered, washed with H2O (35 mL) and taken up in CH2Cl2 (300 mL). This organic layer was washed with brine (1×160 mL), dried (Na2SO4), tittered and concentrated to provide the title compound (1.52 g, 78%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 9.6 (br s, 1H), 7.97 (d, J=8.0 Hz, 2 H), 7.80 (d, J=9 Hz, 2 H), 7.41 (d, J=8 Hz, 1H), 6.63 (d, J=8 Hz, 3H), 5.45 (d, J=8 Hz, 1H), 4.29-4.23 (m, 1H), 4.05-4.02 (m, 2H), 2.21 (s, 3 H), 0.79 (s, 9H), 0.01 (s, 6 H).
Reaction SMILES: BrBr.[OH-:3].[Na+].[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[O:13][CH:12]([CH3:17])[CH2:11]2)(=[O:7])C.BrO.Cl>O.O1CCOCC1>[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[O:13][CH:12]([CH3:17])[CH2:11]2)([OH:7])=[O:3]
Reactant: CC(=O)c1ccc2c(c1)CC(C)O2
Reactant: [OH-]
Agent: BrBr
Agent: Cl
Agent: OBr
Solvent: C1COCCO1
Solvent: O
Product: CC1Cc2cc(C(=O)O)ccc2O1
Temperature: 0 °C
Yield: 57.4 %

Procedure:
On an ice-common salt bath, 6.25 ml of bromine was added dropwise to a solution of 15.1 g of sodium hydroxide in 100 ml of water under stirring and cooling. To a solution of 6.50 g of 5-acetyl-2-methyl coumaran (Ml) in 100 ml of dioxane, the above mixture (i.e., hypobromous acid solution) was added dropwise at 3°-8° C. under cooling on an ice bath. The ice bath was removed after the addition. The resultant mixture was stirred for 3.5 hours at room temperature. After the reaction, the reaction mixture was poured into 500 ml of ice water, followed by addition of 30 ml of hydrochloric acid to precipitate a crystal. The crystal was recovered by filtration and washed with water. The resultant crystal was dried under reduced pressure, followed by washing with hexane and isopropyl ether successively to obtain 3.77 g of 5-carboxy-2-methylcoumaran (M2) (Yield: 57.4%).
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[C:14]([Cl:17])[N:13]=[N:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=O)(C)(C)C.Cl.CCOC(C)=O>CCOC(C)=O>[Cl:17][C:14]1[N:13]=[N:12][C:11]2[C:10]([CH3:19])([CH3:18])[CH2:9][NH:8][C:16]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2nnc(Cl)cc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1(C)CNc2cc(Cl)nnc21
Yield: 125.7 %

Procedure:
3-Chloro-7,7-dimethyl-6,7-dihydro-pyrrolo[3,2-c]pyridazine-5-carboxylic acid tert-butyl ester (75 mg) suspended in EtOAc (0.5 mL) was stirred under a N2 atmosphere. 4M HCl/EtOAc (5 mL) was added slowly and after complete addition the mixture was stirred for 8 h. LC analysis indicated 10% starting material remaining. The reaction mixture was concentrated in vacuo and the following morning taken up in 4M HCl/EtOAc (5 mL). The solution was stirred for 1 h after which point LC analysis indicated complete consumption of the starting material. The reaction mixture was concentrated in vacuo and azeotroped with MeOH (2×5 mL) to provide the title compound (61 mg) as a white solid. 1H NMR (270 MHz, D4-MeOH): 6.92 (1H, s), 3.79 (2H, s) and 1.44 (6H, s). MS: [M+H]+=184.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:19])=[C:15]([Cl:18])[N:16]=3)[C:11](=[O:20])[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]2)[CH:7]=1.Cl[CH2:29]CCl.CO.C=O>[Pd].C(O)(=O)C>[Cl:18][C:15]1[N:16]=[C:17]2[C:12]([C:11](=[O:20])[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9][N:8]2[C:6]2[CH:7]=[C:2]([NH:1][CH3:29])[C:3]([F:27])=[CH:4][C:5]=2[F:26])=[CH:13][C:14]=1[F:19]
Reactant: ClCCCl
Reactant: CCOC(=O)c1cn(-c2cc(N)c(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Agent: [Pd]
Agent: C=O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1cn(-c2cc(NC)c(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Reaction time: 16 h

Procedure:
Ethyl 1-(5-amino-2,4-difluorophenyl)-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (500 mg) was added to a mixture of 10 ml of 1,2-dichloroethane, 5 ml of methanol and 0.5 ml of acetic acid together with 100 mg of 37% formalin. Using 0.08 g of 10% palladium on carbon, hydrogenation was carried out for 16 hours. After the catalyst was filtered off, the filtrate was concentrated in vacua. The residue was dissolved in 50 ml of chloroform, washed with an aqueous solution of 50% sodium carbonate, dried over anhydrous magnesium sulfate, and then concentrated in vacua. The residue was subject to chromatography using 20 g of silica gel (eluting solution: chloroform) to give 150 mg of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]([C:38](=[O:44])[NH:39][C:40]([CH3:43])([CH3:42])[CH3:41])([CH2:25][CH2:26][CH2:27][CH2:28][B:29]1[O:33][C:32]([CH3:35])([CH3:34])[C:31]([CH3:37])([CH3:36])[O:30]1)[CH2:6][CH2:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][N:9]1C(OC(C)(C)C)=O)(=[O:3])[CH3:2].Cl>C(OCC)(=O)C>[C:1]([NH:4][C:5]([CH2:6][CH2:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][NH:9]1)([CH2:25][CH2:26][CH2:27][CH2:28][B:29]1[O:30][C:31]([CH3:36])([CH3:37])[C:32]([CH3:34])([CH3:35])[O:33]1)[C:38]([NH:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:44])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(CCC1Cc2ccccc2CN1C(=O)OC(C)(C)C)C(=O)NC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(CCC1Cc2ccccc2CN1)C(=O)NC(C)(C)C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 3-(3-acetamido-3-(tert-butylcarbamoyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)heptyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate in ethyl acetate was treated with a solution of HCl (g) in ethyl acetate (approximately 2 M). After stirring for 30 min the reaction was concentrated to dryness and the crude hydrochloride product was used without further purification.
Reaction SMILES: [OH:1][CH:2]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=[CH:4][CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:11][C:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[BH4-].[Na+]>C(O)C>[OH:1][CH:2]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=[CH:4][CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:11][CH:12]([OH:20])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCCCCC(O)C=CC1CCC(=O)N1CC(=O)CCCCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCC(O)C=CC1CCC(=O)N1CC(O)CCCCC(=O)O
Reaction time: 2 h
Yield: 139.2 %

Procedure:
To a solution of 14 (over 100 mg) in 3 mL of ethanol at 0° was added 45 mg of sodium borohydride. After stirring two hours at 0°, it was quenched with a few drops of acetic acid. Saturated sodium chloride was added, followed by extraction with methylene chloride three times. The combined organic layer was then dried over magnesium sulfate. Removal of the solvent gave 140 mg of 7-[2-(3-hydroxy-1-octen-1-yl)-5-oxopyrrolidin-1-yl]-6-hydroxy-1-heptanoic acid (15). IR (CH2Cl2): 3500-2600 (br), 1720, 1665 cm-1 ; PMR (CDCl3): δ6.33-5.40 (m, 5H, including --CO2H and 2--OH), 4.23-3.00 (m, 5H), 2.66-2.20 (m, 4H), 1.90-1.13 (m, 16H), and 0.93 (t, 3H); MS: m/z 338.2313 (M+ --OH), calcd. for C19H32O4N, 338.2330.
Reaction SMILES: [CH:1]1([S:7]([CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O>Cl>[CH:1]1([S:7]([CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=3)[O:14][C:15]=2[CH3:16])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)C3CCCCC3)c(C)o2)cc1
Agent: Cl
Solvent: O
Product: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)C1CCCCC1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A solution of methyl 4-(4-(cyclohexylsulfonylmethyl)-5-methyloxazol-2-yl)-benzoate (1.0 g, 2.65 mmol, 1.00 equiv) in 6N hydrochloric acid (20 mL) was refluxed overnight. The reaction mixture was cooled to room temperature and 30 mL of water and ice were added. The precipitate ws collected by filtration, washed with 3×20 mL of hexane and dried in a vacuum oven to give 0.85 g (88%) of 4-(4-(cyclohexylsulfonylmethyl)-5-methyloxazol-2-yl)benzoic acid as a white solid. LC-MS: (ES, m/z): 365 [M+H]+, 341, 257, 216, 189, 146, 115.
Reaction SMILES: [H-].[Na+].COP([CH2:9][C:10](=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)(=O)OC.[CH2:20]([O:22][C:23](=[O:39])[CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:35](=[O:36])[CH2:34][CH2:33][CH2:32][C@@H:31]1[CH:37]=O)[CH3:21]>C1COCC1>[CH2:20]([O:22][C:23](=[O:39])[CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:35](=[O:36])[CH2:34][CH2:33][CH2:32][C@@H:31]1/[CH:37]=[CH:9]/[C:10](=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[CH3:21]
Reactant: CCOC(=O)COCCCCN1C(=O)CCC[C@@H]1C=O
Reactant: COP(=O)(CC(=O)Cc1cccc(Cl)c1)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
Sodium hydride (60% dispersion in oil, 35 mg, 0.88 mmol) was added to a solution of [3-(3-chlorophenyl)-2-oxopropyl]-phosphonic acid dimethyl ester (221 mg, 0.80 mmol) in THF (2.0 mL) at 0° C. After 1 h at 0° C., [4-((R)-2-formyl-6-oxo -piperidin-1-yl)-butoxy]-acetic acid ethyl ester (0.88 mmol, crude) in THF (2 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with aqueous acetic acid (50%, 10 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (20%→40% EtOAc/CH2Cl2, gradient) afforded 117 mg (34%) of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-oxo-but-1-enyl]-6-oxo-piperidin-1-yl}-butoxy)-acetic acid ethyl ester.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: BrCc1ccccc1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccccc2)c1
Yield: 79 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (300 mg, yield: 79.0%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.[Cl:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](Cl)=[O:23])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:23])=[CH:18][CH:17]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Product: O=C(COc1ccc(Cl)cc1)N1Cc2cccn2Cc2ccccc21

Procedure:
This compound was prepared from 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 4-chlorophenoxyacetyl chloride in the manner of Example 75, step B, m.p. 120-122° C. MS [(+)ESI, m/z]: 353 [M+H]+ Anal. Calcd for C20H17CIN2O2:C, 68.09; H, 4.86; N, 7.94. Found: C, 67.82; H, 4.87; N, 7.87.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH:17]=[C:18]([C:20]([Cl:22])=[O:21])[S:19][C:9]1=2)C1C=CC=CC=1.CN1C2C(=CC=CC=2)C2C=C(C(O)=O)SC1=2>O=S(Cl)Cl>[CH3:1][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH:17]=[C:18]([C:20]([Cl:22])=[O:21])[S:19][C:9]1=2
Reactant: O=C(Cl)c1cc2c3ccccc3n(Cc3ccccc3)c2s1
Agent: Cn1c2ccccc2c2cc(C(=O)O)sc21
Solvent: O=S(Cl)Cl
Product: Cn1c2ccccc2c2cc(C(=O)Cl)sc21

Procedure:
Preparation as described for (10) from (9) (2.0 g) and 20 ml SOCl2 gave 2.1 g (26) which was used without further purification.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[ClH:12].N([O-])=O.[Na+]>>[Cl:12][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: Cl
Reactant: Nc1cccc2cnccc12
Agent: O=N[O-]
Agent: [Na+]
Product: Clc1cccc2cnccc12

Procedure:
5-Aminoisoquinoline is reacted with hydrochloric acid, sodium nitrite and cuprous chloride to afford 5-chloroisoquinoline, which was then reduced with diborane in tetrahydrofuran. The resultant 5-chlorotetrahydroisoquinoline was then acetylated with acetic anhydride and chlorosulfonated with chlorosulfonic acid at low temperature, for example -50° C., to afford the desired chlorosulfonyl tetrahydroisoquinoline.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][CH:28]=[CH:27]3)=O)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O(C1SC(CNC(C2C=C3CCNC3=NC=2)=O)=CC=1)C1C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][CH2:22][C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][CH:28]=[CH:27]3)=[CH:19][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)c1ccc2ncccc2c1
Agent: O=C(NCc1ccc(Oc2ccccc2)s1)c1cnc2c(c1)CCN2
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: c1ccc(COc2ccc(NCc3ccc4ncccc4c3)cc2)cc1
Yield: 33 %

Procedure:
To a solution of lithium aluminum hydride (52 mg, 1.37 mmol) in tetrahydrofuran (10 mL) was added a solution of quinoline-6-carboxylic acid (4-benzyloxyphenyl)-amide described in Preparation Example Z+-2 (194 mg, 19%) in tetrahydrofuran, and the solution was stirred under reflux for 3 hours. The reaction solution was allowed to room temperature, an aqueous solution of saturated ammonium chloride was added thereto, the solution was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate), and the title compound (62 mg, 33%) was obtained as a pale yellow solid.