Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:8]1[CH2:12][CH:11]([CH3:13])[O:10][C:9]1=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>[Pd].C(O)C>[CH2:1]([C@H:8]1[CH2:12][C@@H:11]([CH3:13])[O:10][C:9]1=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC=C1CC(C)OC1=O
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC[C@H]1C[C@@H](C)OC1=O
Yield: 98.4 %

Procedure:
Using the same general hydrogenation procedure described in Example I, 3-heptylidene-5-methyldihydro-2(3H)-furanone (10 g; 0.051 mole) was combined with 0.5 g 5% palladium on carbon catalyst and 10 ml ethanol. Hydrogen gas was bubbled into the mixture over a 12 hour period with stirring. After removal of the catalyst and evaporation of the solvent, 9.95 g (96% assay by GLC; 95% yield) cis-3-heptyl-5-methyldihydro-2(3H)-furanone was recovered. The proton nuclear resonance spectrum for the product was as follows:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[C:32]2[N:31]=[C:30]3[N:33]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=4[Cl:44])[CH2:34][CH2:35][CH2:36][N:29]3[C:28]=2[C:27]([CH:45]([OH:48])[CH2:46][CH3:47])=[CH:26][CH:25]=1>C(#N)C.C(=O)([O-])O.[Na+]>[Cl:23][C:24]1[C:32]2[N:31]=[C:30]3[N:33]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=4[Cl:44])[CH2:34][CH2:35][CH2:36][N:29]3[C:28]=2[C:27]([C:45](=[O:48])[CH2:46][CH3:47])=[CH:26][CH:25]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
Dess-Martin reagent (1.27 g, 3.00 mmol) was added to a stirred suspension of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (1.12 g, 2.73 mmol) in acetonitrile (23 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, concentrated in vacuo, and extracted with ethyl acetate/tetrahydrofuran. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 15-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with diisopropyl ether to give the title compound as a colorless powder (980 mg, 2.40 mmol, 88%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([Br:15])=[CH:8]2)=[O:4].O1CCCC1.CO.O.[OH-].[Li+:25]>O>[Li+:25].[Br:15][C:9]1[CH:10]=[N:11][C:12]2[C:7]([CH:8]=1)=[CH:6][C:5]([C:3]([O-:4])=[O:2])=[CH:14][CH:13]=2
Reactant: COC(=O)c1ccc2ncc(Br)cc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C([O-])c1ccc2ncc(Br)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-bromo-quinoline-6-carboxylic acid methyl ester described in Preparation Example 162 (26 mg, 0.098 mmol) and tetrahydrofuran (2 mL) were added methanol (0.2 mL), lithium hydroxide monohydrate (4.1 mg, 0.098 mmol) and water (0.2 mL), and the solution was stirred overnight at room temperature. The solvent was evaporated in vacuo, and the title compound (27 mg) was obtained.
Reaction SMILES: [K+].[K+].[C:3]1([S:13]([O-:16])(=[O:15])=[O:14])[C:4]([S:9]([O-:12])(=[O:11])=O)=[CH:5][CH:6]=[CH:7][CH:8]=1>S(=O)(=O)(O)O>[C:4]12[S:9](=[O:11])(=[O:12])[O:16][S:13](=[O:14])(=[O:15])[C:3]1=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=S(=O)([O-])c1ccccc1S(=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=S1(=O)OS(=O)(=O)c2ccccc21
Temperature: 72.5 °C
Yield: 49.7 %

Procedure:
A mixture of 1,2-benzenedisulfonic acid dipotassium salt (20 g, 0.064 mol) in fuming sulfuric acid (100 mL) was heated at 70-75° C. overnight. The reaction mixture was slowly poured onto ice and the precipitate was quickly collected by filtration. The solid was treated with benzene (500 mL) and dried over anhydrous sodium sulfate. The solvent was filtered and evaporated to give the title compound as a crystalline solid (7.0 g, 50% yield), mp 182-3° C. 1H-NMR (300 MHz, CDCl3) δ8.02-8.09 (m, 4H).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=1[NH2:6].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][C:16]=1[CH:25]1[CH2:29][CH2:28][N:27]([C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:26]1>N1C=CC=CC=1>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=1[NH:6][S:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[C:16]([CH:25]2[CH2:29][CH2:28][N:27]([C:30](=[O:35])[C:31]([F:34])([F:32])[F:33])[CH2:26]2)[CH:17]=1)(=[O:23])=[O:22]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C1CCN(C(=O)C(F)(F)F)C1
Reactant: Cc1ccc(OC(F)F)c(N)c1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cc(C)ccc2OC(F)F)cc1C1CCN(C(=O)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.1 %

Procedure:
0.093 g of 2-(difluoromethoxy)-5-methylaniline (0,538 mmol, purchased at Fluorochem) were dissolved in 10 mL of pyridin. 0.2 g of 4-methoxy-3-(1-(2,2,2-trifluoroacetyl)pyrrolidin-3-yl)benzene-1-sulfonyl chloride (0.538 mmol) were slowly added. The reaction mixture was stirred at room temperature for 18 h, and the solvent was evaporated and several times co-destilled with toluene. The oily brown residue was dissolved in dichloromethane and washed with a 5% aqueous ammonium chloride solution. After washing with saturated aqueous sodium chloride solution, the organic layer was dried over sodium sulphate, filtered, and the solvent evaporated. The crude product was purified via silica gel chromatography using a 40 g Redisep-column with dichloromethane/methanol 0-20% to yield 0.096 g of the title compound.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)=[O:5])C.[OH-].[K+].O>CO>[F:15][C:11]1[CH:10]=[C:9]([C@@H:7]2[CH2:8][C@H:6]2[C:4]([OH:5])=[O:3])[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1cccc(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1C[C@H]1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a solution of rac-trans 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid ethyl ester (13.0 g, 0.062 mol) in MeOH (310 mL) was added a solution of KOH (35.0 g, 0.625 mol) in MeOH (150 mL) at 0° C. After addition of the base the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into water and extracted with methylene chloride (2×50 mL). The aqueous layer was acidified with 10% HCl. The resulting mixture was extracted with methylene chloride (2×150 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness to give rac-trans-2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid as colorless crystals (9.5 g, 85%). Separation of the isomers by chiral SFC (Method D) gave the title compound (1S,2S)-2-(3-fluoro-phenyl)cyclopropanecarboxylic acid IM47 as colorless crystals (3.27 g, 17% overall yield from 3-fluorostyrene) sufficiently pure for the next step. Specific optical rotation +263.4° [α]D20 (C=1% MeOH)
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.O[CH2:16][CH2:17][N:18]1[C:27]2[C:26](=[O:28])[N:24]([CH3:25])[C:23](=[O:29])[N:22]([CH3:30])[C:21]=2[N:20]=[CH:19]1.O.C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([O:10][CH2:16][CH2:17][N:18]2[C:27]3[C:26](=[O:28])[N:24]([CH3:25])[C:23](=[O:29])[N:22]([CH3:30])[C:21]=3[N:20]=[CH:19]2)=[O:9])=[CH:13][CH:14]=1
Reactant: Cn1c(=O)c2c(ncn2CCO)n(C)c1=O
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: Cn1c(=O)c2c(ncn2CCOC(=O)C(C)(C)Oc2ccc(Cl)cc2)n(C)c1=O
Yield: 55.1 %

Procedure:
107.3 g (0.5 mol) 2-(p-chlorophenoxy) isobutyric acid and 56.0 g (0.25 mol) 7-hydroxyethyltheophylline were suspended together in 250 ml xylene and heated for 15 hours in a water separator after addition of 1.5 g p-toluenesulfonic acid. The solution was next agitated with dilute sodium bicarbonate solution (0.5 mol NaHCO3), waterwashed and evaporated in a rotary evaporator. The residue was crystallized from isopropanol, yielding 58.0 g (55% yield) 1-(7-theophyllinyl)-2-ethyl [2-(p-chlorophenoxy)-isobutyrate] with a melting point 131°-132°C.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)=O.C([Li])CCC.[Cl-].[Zn+2:18].[Cl-]>O1CCCC1.CCCCCC.C(O)C>[C:1]1([C:7]#[C:8][Zn:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: [Zn+2]
Agent: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCO
Product: [Zn]C#Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
The flask was charged with 120 mg (1.1 mmol) of phenylacetylene and 4 mL of tetrahydrofuran, and the flask was cooled to −78° C. in a cooling bath with ethanol and dry ice. Thereafter, 0.65 mL (1.0 mmol) of a 1.56 mol/L hexane solution of n-butyllithium was slowly added over a period of 20 minutes. After stirring the mixture at −78° C. for 30 minutes, a suspension of 140 mg (1.0 mmol) of zinc chloride in 1 mL of tetrahydrofuran was added thereto. The mixture was stirred at −78° C. for additional 1 hour, thereafter the cooling bath was removed, and the mixture was allowed to stand upto room temperature. The resulting solution was used as (phenylethynyl)zinc reagent [(Ph—C≡C—ZnCl].
Reaction SMILES: O[C:2]1([CH3:11])[CH:6]([CH2:7][C:8]#[CH:9])[C:5](=[O:10])[CH:4]=[CH:3]1.[OH-:12].[Na+].[Na+].[Cl-]>O>[CH2:7]([C:6]1[C:5](=[O:10])[CH2:4][CH:3]([OH:12])[C:2]=1[CH3:11])[C:8]#[CH:9]
Reactant: [OH-]
Reactant: C#CCC1C(=O)C=CC1(C)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C#CCC1=C(C)C(O)CC1=O
Reaction time: 4 h

Procedure:
Into a reaction vessel, a solution of 4-hydroxy-4-methyl-5-propargyl-2-cyclopentenone (3 g) and MgCl2.6H2O (4.0 g) in water (120 ml) was charged, and the temperature was elevated up to 100° C. The contents were adjusted to pH 6.8 with 0.1 N NaOH solution, and stirring was continued at 100° C. for 4 hours, during which the pH was maintained at 6.8 to 7.0. After cooling, NaCl (40 g) was added to the reaction mixture and extracted with ether (120 ml) 4 times. The extracts were combined together, dried over anhydrous magnesium sulfate and concentrated at 40° C. under reduced pressure to give an oily substance (2.5 g). The oily substance was chromatographed with silica gel (30 g), followed by development with a solvent mixture of ethyl acetate and hexane (1:2 by volume) to give 2-propargyl-3-methyl-4-hydroxy-2-cyclopentenone (2.3 g). Yield, 77%. N.M.R. (CDCl3, internal standard TMS, δ ppm, 90 MHz): 4.60 (broad d, 1H, 4-H); 3.95 (broad s, 1H, 4-OH); 3.04 (d, 2H, --CH2 --C≡H); 2.65 (d of d, 1H, 5-H); 2.38 (d of d, 1H, 5 -H); 2.20 (s, 3H, 3-CH3); 1.98 (s, 1H, C≡CH).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9](O)=[O:10].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]([Cl:15])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1sccc1OC(F)F
Solvent: Cc1ccccc1
Product: O=C(Cl)c1sccc1OC(F)F
Temperature: 90 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
At 80° C., a mixture of 4.2 g (0.022 mol) of 3-difluoromethoxy-thiophene-2-carboxylic acid in 45 ml of toluene is admixed with 3.1 g (0.026 mol) of thionyl chloride. After the addition has ended, the reaction mixture is heated to 90° C. and stirred at this temperature for another 2 hours. The reaction mixture is subsequently concentrated under reduced pressure at 60° C. This gives 4.6 (98.3% of theory) of 3-difluoromethoxy-thiophene-2-carbonyl chloride in the form of an oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:9]=[C:8]([Cl:10])[S:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12])=[O:4].B(Cl)([C@@H]1[C@@H](C)C2C(C)(C)C(C2)C1)[C@@H]1[C@@H](C)C2C(C)(C)C(C2)C1.[OH-].[Na+]>COC(C)(C)C>[CH2:2]1[NH:14][S:11](=[O:13])(=[O:12])[C:6]2[S:7][C:8]([Cl:10])=[CH:9][C:5]=2[CH:3]1[OH:4]
Reactant: NS(=O)(=O)c1sc(Cl)cc1C(=O)CBr
Agent: C[C@H]1C2CC(C[C@@H]1B(Cl)[C@H]1CC3CC([C@@H]1C)C3(C)C)C2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: O=S1(=O)NCC(O)c2cc(Cl)sc21
Temperature: -40 °C
Reaction time: 2 h

Procedure:
A 50-L, 5-necked flask equipped with a mechanical stirrer and a thermometer was flushed with nitrogen overnight. Working under nitrogen, the flask was charged with 3-bromoacetyl-5-chloro-2-thiophenesulfonamide (4, 855 g, 2.68 mol) and t-butyl methyl ether (12.5L). The stirred suspension was cooled to -40° C. using a dry-ice/2-propanol bath and (+)-β-chlorodiisopinocampheylborane (4.5L of a 1.2M solution in t-butyl methyl ether, 5.4 mol, 2 eq) was added via a cannula over 30 minutes, causing the temperature to rise to -32° C. The reaction mixture was maintained between -25° to -20° C. for 3.5 hours, after which TLC analysis indicated complete reduction. The mixture was warmed to 0° C. and 1M aqueous sodium hydroxide (11L) was added from an addition funnel over 10 minutes, causing the temperature to rise to 22° C. The biphasic mixture was stirred vigorously at ambient temperature for 2 hours, after which TLC analysis indicated complete cyclization. The phases were split and the dark aqueous layer was extracted with t-butyl methyl ether (3L), acidified to pH 1 using concentrated hydrochloric acid, and extracted with ethyl acetate (2×4L). The combined ethyl acetate extracts were washed with saturated aqueous sodium chloride (3L), dried over sodium sulfate (1 kg), filtered, and concentrated to a volume of about 1 liter by rotary evaporation, at which point toluene (2L) was added. As the remainder of the ethyl acetate was stripped, the product crystallized from toluene. It was collected by filtration, washed with toluene (2L) and methylene chloride (2L), and dried in air at ambient temperature to a constant weight of 498 grams (77%) of 5: mp 126°-127° C.; IR (KBr) 3550, 3230, 1430, 1410, 1320, 1170, 860, 720, 550, 470 cm-1 ; 1H NMR (DMSO-d6) δ 8.18-8.11 (m, 1H), 7.19 (s, 1H), 5.8 (br, 1H), 4.60-4.54 (m, 1H), 3.68-3.55 (m, 1H), 3.50-3.35 (m, 1H); [α]25D -5.9° (c=1, CH3OH); Analysis for C6H6ClNO3S2 ; Calcd: C, 30.06; H, 2.52; N, 5.84. Found: C, 30.14; H, 2.56; N, 5.80.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13](C(OC(C)(C)C)=O)[NH2:14])[CH:6]=[CH:7][C:8]=1[C:9]([O:11][CH3:12])=[O:10].[ClH:22]>O1CCOCC1>[ClH:22].[NH:13]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[NH2:14]
Reactant: COC(=O)c1ccc(N(N)C(=O)OC(C)(C)C)cc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(NN)cc1OC
Temperature: 20 °C
Reaction time: 5 h
Yield: 91.7 %

Procedure:
tert-butyl 1-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate (Intermediate#112) (4.86 g, 16.40 mmol) was added to a 4M solution of hydrogen chloride (61.5 mL, 246 mmol) in dioxane. The resulting solution was stirred at 20° C. for 5 hours. The reaction mixture was evaporated to dryness and the crude residue was triturated with Et2O to give a solid which was collected by filtration and dried under vacuum to give methyl 4-hydrazinyl-2-methoxybenzoate hydrochloride (3.50 g, 92%) as a pale green solid.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH3:26])=[CH:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:25])[C:13]3[C:18]([O:19][C:20]=2[C:21]=1[C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=[CH:15][CH:14]=3.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)C.O>[CH3:3][C:4]([CH3:26])=[CH:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:25])[C:13]3[C:18]([O:19][C:20]=2[C:21]=1[C:22](=[O:24])[CH:23]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1c(OCC=C(C)C)ccc2c(=O)c3ccccc3oc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)=CCOc1ccc2c(=O)c3ccccc3oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 3-(3-methylbut -2-enyloxy)-4-acetylxanthen-9-one (2.4 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.1 g of product m.p. 116-118° C., 1H-NMR (CDCl3)δ:1.69 (s, 3H); 1.72 (s, 3H); 4.71 (d, 2H, J=6.5); 5.38-5.40 (m, 1H); 7.05-7.10 (m, 2H); 7.08 (d, 1H, J=8.8 Hz); 7.10 (d, 1H, J=16 Hz); 7.30-7.48 (m, 6H); 7.50-7.58 (m, 2H); 7.65-7.60 (m, 1 H) 8.30-8.33(m, 1H); 8.42 (d, 1H, J=8.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2([C:24]([OH:26])=O)[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.S(Cl)([Cl:31])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2([C:24]([Cl:31])=[O:26])[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1C1(C(=O)O)CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc(Cl)cc1C1(C(=O)Cl)CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Yield: 100 %

Procedure:
To a stirred and refluxing mixture of 21 parts of 4-(5-chloro-2-methoxyphenyl)-1-(4-methylphenylsulfonyl)-4-piperidinecarboxylic acid and 270 parts of benzene are added dropwise 36 parts of thionyl chloride. Upon completion, the whole is stirred and refluxed for 4 hours. The reaction mixture is evaporated and the residue is washed twice with methylbenzene, yielding 22 parts (100%) of 4-(5-chloro-2-methoxyphenyl)-1-(4-methylphenylsulfonyl)-4-piperidinecarbonyl chloride.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:19][CH2:18][C:17]2[NH:16][C:15](=[O:20])[CH2:14][CH2:13][C:12]=2[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21]I.[H-].[Na+]>O1CCCC1>[CH3:21][N:16]1[C:17]2[CH2:18][CH2:19][CH:10]([O:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][C:12]=2[CH2:13][CH2:14][C:15]1=[O:20]
Reactant: CI
Reactant: O=C1CCC2=C(CCC(OC(=O)c3ccccc3)C2)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)CCC2=C1CCC(OC(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
46.5 g. of the isomer mixture containing about 60 percent of 6-benzoyloxy-3,4,5,6,7,8-hexahydro-1H-quinoline-2-one and 40% of the 3,4,4a,5,6,7-hexahydro isomer were dissolved in 400 ml. of tetrahydrofuran (THF). 80 ml. of methyl iodide were added and the resulting mixture cooled in an ice-water bath. 9.6 g. of sodium hydride (as a 50 percent suspension in mineral oil) were added in portions. After all of the sodium hydride suspension had been added, the cooling bath was removed and the reaction mixture stirred at ambient temperature under a nitrogen atmosphere for about 4 hours. The reaction mixture was then diluted with water and the aqueous mixture thoroughly extracted with chloroform. The chloroform extracts were combined and the combined extracts washed with saturated aqueous sodium chloride and then dried. The chloroform was removed by evaporation to dryness in vacuo leaving as a residue an orange oil weighing 47.3 g. Crystallization of the residue from an ether-hexane solvent mixture yielded crystals of 1-methyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone and the corresponding 3,4,4a,5,6,7-hexahydro isomer.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:49]=[CH:48][CH:47]=[CH:46][C:14]=1[C:15]([NH:17][C:18]1[CH:43]=[CH:42][C:21]([C:22]([N:24]([CH3:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=O)=[O:23])=[CH:20][C:19]=1[O:44][CH3:45])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:57][N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:49]=[CH:48][CH:47]=[CH:46][C:14]=1[C:15]([NH:17][C:18]1[CH:43]=[CH:42][C:21]([C:22]([N:24]([CH3:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:61]2[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]2)=[O:40])=[O:23])=[CH:20][C:19]=1[O:44][CH3:45])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCNCC1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)O)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Reaction time: 17 h
Yield: 74.7 %

Procedure:
A solution of 4-[2-[(3-tert-butoxycarbonylaminoprop-1-yl)oxy]benzoyl]amino-3-methoxy-N-methyl-N-[2-(5-carboxypent-1-yloxy)-4-methylphenyl]benzamide (3.5 g) in ethyl acetate (30 ml) was treated at ambient temperature with triethylamine (575 mg), N-methylpiperazine (569 mg), and diphenylphosphoryl azide (1.56 g). The reaction mixture was stirred at the same temperature for 17 hours. The reaction mixture was washed with brine and dried over magnesium sulfate. The crude product was purified by silica gel column chromatography (SiO2 100 g, 3% methanol in chloroform) to give 4-[2-[(3-tert-butoxycarbonylaminoprop-1-yl)oxy]benzoyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (2.93 g).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([N:58]5[CH2:63][CH2:62][O:61][CH2:60][CH2:59]5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:78]>CO.O>[ClH:78].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([N:58]5[CH2:63][CH2:62][O:61][CH2:60][CH2:59]5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(N5CCOCC5)cccc4c3=O)cc2)CCC1
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(N5CCOCC5)cccc4c3=O)cc2)CCC1
Yield: 75 %

Procedure:
Following the procedure of 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(8-morpholin-4-yl-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (7 mL), water (7 mL) and 1 M HCl (0.6 mL) and chromatographed on a 5 g C18 cartridge {gradient 10 to 50% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound as a white solid (23 mg, 75%). 1H NMR (400 MHz, DMSO-d6): δ 8.47 (bs, 3H), 7.67 (dd, J=7.5 and 2.1 Hz, 1H), 7.45-7.29 (m, 9H), 7.25 (d, J=8.3 Hz, 2H), 3.74 (t, J=4.1 Hz, 4H), 3.13 (t, J=3.6 Hz, 4H), 2.58-2.44 (m, 4H), 2.19-2.06 (m, 1H), 1.82-1.70 (m, 1H). LCMS (Method E): RT=3.44 min, [M+H]+=453.