Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[C:15](=[O:18])(O)[O-].[Na+]>CO>[O:1]1[C:15](=[O:18])[CH2:6][O:5][CH2:4][CH2:3][CH2:2][O:8][C:7](=[O:9])[CH2:6][O:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)COCCCO
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: O=C1COCCCOC(=O)COCCCO1
Reaction time: 2 h
Yield: 99 %

Procedure:
271.2 Grams (2.02 moles) of crude 6-hydroxy-3-oxa-caproic acid, as prepared in Example 1, 3.5 liters (87 moles) of reagent grade methanol, and 0.2 grams (2 mmol) of concentrated sulfuric acid were charged into a five liter, round bottom flask containing some boiling chips. A reflux condenser connected to a dry stream of nitrogen gas via tubing was attached, and the solution was heated to reflux with an oil bath for twenty four hours. After the solution had cooled down, 5.00 grams (59.5 mmol) of sodium bicarbonate were added, and a distillation head was attached. The methanol was distilled off at atmospheric pressure. After the methanol was removed, the orangish brown residue was vacuum filtered into a tared, one liter round bottom flask containing a magnetic stirring bar. 297 grams of crude methyl 6-hydroxy-3-oxa-caproate were collected (99.0% yield). A still head was attached, and the crude product was vacuum distilled. Initially, a colorless liquid distilled over between 88° C. and 90° C. (0.01 mm Hg), but the distillation rate eventually slowed down. After two hours, some crystals of 1,5,8,12-tetraoxacyclotetradecane-7,14-dione formed in the condenser. The distillation was stopped. The collection flask was placed in the refrigerator overnight. Crystals of 1,5,8,12-tetraoxacyclotetradecane-7,14-dione formed in the collection flask and were removed by suction filtration. These crystals were washed with 100 mL of ethyl acetate and air dried. 4.11 grams of 1,5,8,12-tetraoxacyclotetradecane-7,14-dione and 67.5 grams of supernatent liquid A were isolated.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:24])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][CH2:28][C:3]1=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:48].Cl>>[ClH:48].[ClH:48].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:24])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:25][NH:26][CH2:27][CH2:28][C:3]1=2
Reactant: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCN(C(=O)OC(C)(C)C)C5)c(=O)c2)nn1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCNC5)c(=O)c2)nn1
Yield: 33 %

Procedure:
tert-Butyl 5-methyl-7-(4-(6-methylpyridazin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (200 mg, 0.42 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (57 mg, 33%) as an orange solid: mp 310-315° C.;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:14](Br)[C:15]#[CH:16].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:13])[C:11]=1[O:12][CH2:16][C:15]#[CH:14])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C#CCBr
Reactant: COC(=O)c1cc(F)c(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C#CCOc1c(F)cc(C(=O)OC)cc1F
Temperature: 25 °C
Yield: 101.7 %

Procedure:
To 80 ml of acetonitrile were added 4.5 g of methyl 3,5-difluoro-4-hydroxybenzoate, 3.5 g of propargyl bromide and 9.4 g of cesium carbonate, and the resulting mixture was heated to reflux for 2 hours. Thereafter, the reaction mixture which had been allowed to cool to near room temperature was filtered through Celite (registered trade mark). The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, and 5.5 g of methyl 3,5-difluoro-4-(2-propynyloxy)benzoate was obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].[Cl:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[CH2:11][N:12]=[C:13]=[O:14]>C1COCC1>[Cl:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[CH2:11][NH:12][C:13]([N:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7])=[O:14]
Reactant: OC[C@@H]1CCCN1
Reactant: O=C=NCc1ccccc1Cl
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1Cl)N1CCC[C@H]1CO
Reaction time: 1 h
Yield: 103.1 %

Procedure:
To a solution of (S)-pyrrolidin-2-ylmethanol (110 mg, 1.1 mmol) in THF (2.0 mL) was added 2-chlorobenzyl-isocyanate (167 mg, 1.0 mmol). The reaction mixture was stirred for 1 h and concentrated under reduced pressure to give (S)—N-(2-chlorobenzyl)-2-(hydroxymethyl)pyrrolidine-1-carboxamide as an oil (277 mg), which was used without further purification. LRMS (M+H+) m/z 269.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22](O)(=[O:26])[CH2:23][CH2:24][CH3:25].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O.CO.CCCCCC>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: CCCC(=O)O
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 50 %

Procedure:
Preparation of example 21 from the title compound of Example 7 (hydrochloride) (22 mg, 0.080 mmol), n-butyric acid (0.007 mL, 0.080 mmol), triethylamine (0.014 mL, 0.10 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (32 mg, 0.084 mmol) in CH2Cl2 (0.3 mL) and N,N-dimethylformamide (0.3 mL) was carried out analogously to Example 11. Silica gel chromatography (10:9:1 hexane:CH2Cl2:methanol followed by 9:5:1 CH2Cl2:hexane:methanol), also in an analogous manner, afforded the title compound (14 mg, 0.04 mmol) as a yellow powder in 50% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([C:16]([O:18]C(C)(C)C)=[O:17])[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[CH3:7]>CN1CCCC1=O>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([C:16]([OH:18])=[O:17])[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:14])([CH3:15])[CH3:13])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(F)c(C(=O)OC(C)(C)C)n1COCC[Si](C)(C)C
Solvent: CN1CCCC1=O
Product: Cc1c(Cl)c(F)c(C(=O)O)n1COCC[Si](C)(C)C
Temperature: 200 °C

Procedure:
tert-butyl 4-chloro-3-fluoro-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-2-carboxylate (Intermediate 264, 100 mg) was dissolved in N-methylpyrrolidinone (10 ml), heated to 200° C. for 30 minutes. The resulting solution was carried on to the next step without further purification.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([CH3:19])[C:17]=1Cl)=[O:12])[CH3:9].O>CN(C=O)C.C(OCC)(=O)C>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([CH3:19])[C:17]=1[N:3]1[CH:7]=[CH:6][CH:5]=[N:4]1)=[O:12])[CH3:9]
Reactant: c1cn[nH]c1
Reactant: CCOC(=O)c1cnn(C)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(C)c1-n1cccn1
Temperature: 40 °C
Yield: 9.1 %

Procedure:
Sodium hydride (60% in oil; 767 mg, 19 mmol) was added to a solution of pyrazole (1.36 g, 20 mmol) in dry DMF (40 mL) under nitrogen at 0° C. in an ice-water bath and the mixture was heated to 40° C. for 1 h. 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.89 g, 10 mmol) was added and the mixture was heated to 100° C. overnight and then cooled. Water and ethyl acetate were added, the organic layer was separated, and the aqueous phase was extracted three times with EtOAc. The combined organic phases were concentrated in vacuo and the residue was purified by flash silica chromatography eluting with a gradient of 0-20% ethyl acetate/hexanes, then 20% ethyl acetate/hexanes to give 2′-methyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid ethyl ester (0.2 g, 9%).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:28])[C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[C:16]([O:24][CH3:25])=[CH:15][C:14]=2[O:26][CH3:27])=[CH:6][CH:5]=1.[OH-].[Na+]>C1COCC1.CO.O>[CH3:27][O:26][C:14]1[CH:15]=[C:16]([O:24][CH3:25])[C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:18][C:13]=1[C:12]#[C:11][C:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:29])=[O:2])=[CH:9][CH:8]=1)=[O:28]
Reactant: COC(=O)c1ccc(C(=O)C#Cc2cc(-c3cccs3)c(OC)cc2OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)c(-c2cccs2)cc1C#CC(=O)c1ccc(C(=O)O)cc1
Reaction time: 1 h
Yield: 42.5 %

Procedure:
4-[3-(2,4-dimethoxy-5-thiophen-2-yl-phenyl)-propynoyl]-benzoic acid methyl ester (50 mg, 0.12 mmol) from Ex-1 was dissolved in THF (2 mL) and methanol (2 mL). Sodium hydroxide solution (1 N, 1 mL) was added and the resulting solution was stirred at room termperature under nitrogen for 1 h. The reaction was then diluted with water (10 mL) and washed with ethyl acetate (10 mL). The aqueous phase was acidified with conc. HCl and extracted with ethyl acetate (2×10 mL). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to afford 20 mg (42%) of the desired 4-[3-(2,4-dimethoxy-5-thiophen-2-yl-phenyl)-propynoyl]-benzoic acid as a yellow solid, m.p. 220° C. with decomposition. 1H-NMR (300 MHz, d6-DMSO) δ 8.30 (d, 2H, J=8.0 Hz), 8.14 (d, 2H, J=8.0 Hz), 8.01 (s, 1H), 7.58 (m, 1H), 7.50 (m, 1H), 7.08 (m, 1H), 6.88 (s, 1H), 4.04 (s, 3H), 4.02 (s, 3H); EIMS m/z 392 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:6][C:7]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[CH2:10][NH:9][C:8]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:34]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:6][C:7]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[CH2:10][NH:9][C:8]1=[S:34]
Reactant: CCOC(=O)C1(Cc2ccc(OC)c(OC)c2)C(=O)NCC1c1ccc(OC)c(OC)c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccccc1
Product: CCOC(=O)C1(Cc2ccc(OC)c(OC)c2)C(=S)NCC1c1ccc(OC)c(OC)c1
Reaction time: 1 h
Yield: 130.6 %

Procedure:
A mixture of 6 g of ethyl 3-(3,4-dimethoxybenzyl)-4-(3,4-dimethoxyphenyl)-2-oxo-3-pyrrolidinecarboxylate, 4 g of diphosphorus pentasulfide and 120 ml of anhydrous benzene is refluxed with stirring for one hour. While it is hot, the insoluble matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue is washed with water and recrystallized from ethanol to give 5.4 g of ethyl 3-(3,4-dimethoxybenzyl)-4-(3,4-dimethoxyphenyl)-2-thioxo-3-pyrrolidinecarboxylate as white crystalline powder, melting at 166°-169°C.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C:16]1[CH2:22][N:21](CC2C=CC(OC)=CC=2OC)[C:20](=[O:34])[C@H:19]([NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:18][CH:17]=1>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C:16]1[CH2:22][NH:21][C:20](=[O:34])[C@H:19]([NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:18][CH:17]=1
Reactant: COc1ccc(CN2CC(c3cccc(F)c3F)=CC[C@@H](NC(=O)OCc3ccccc3)C2=O)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CC=C(c2cccc(F)c2F)CNC1=O)OCc1ccccc1
Reaction time: 18 h
Yield: 66.4 %

Procedure:
Trifluoroacetic acid (60 mL) was added to a solution of benzyl (3R)-6-(2,3-difluorophenyl)-1-(2,4-dimethoxybenzyl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (3.70 g, 7.08 mmol) in dichloromethane (40 mL). After 18 h, the mixture was concentrated at 25° C., methanol (150 mL) was added, and the precipitate filtered. The filtrate was concentrated, diluted with dichloromethane (100 mL), washed with water (2×), saturated aqueous sodium bicarbonate (2×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (5% ethyl acetate/hexanes→65% ethyl acetate/hexanes) gave the title compound (1.75 g). MS 373.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:23]=1[C:24](O)=O>>[Cl:21][C:22]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:23]=1[C:24]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)[N:16]=1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc(Cl)ccc3Cl)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 2,5-dichlorobenzoic acid: MS (ES) m/z 438 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]=[N:19][C:20]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.CCOC(C)=O>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]=[N:19][C:20]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Cn1cc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc(N3CCC(n4ccc5ccc(F)cc54)CC3)nn2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-fluoro-1-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-yl)indoline (75 mg, 0.2 mmol) in THF (3 mL) was added DDQ (54 mg, 0.24 mmol). The resulting mixture was stirred at room temperature for 30 min and was poured into EtOAc (30 mL). The organic layer washed with Na2CO3(aq) (30 mL), H2O (30 mL), dried (Na2SO4), and filtered. The solvent was removed and the resulting residue purified by column using 80-90-100% EtOAc/(CH2Cl2/hexane=1/1) as the eluent to yield 6-fluoro-1-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-yl)-1H-indole, which was then converted to its corresponding HCl salt.
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][NH2:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[O-:20][C:21]#[N:22].[K+].O.C(OCC)C>Cl>[CH2:17]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][NH:16][C:21]([NH2:22])=[O:20])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:18][CH3:19]
Reactant: CCCN(CCC)C1CCc2cccc(CN)c2C1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCCN(CCC)C1CCc2cccc(CNC(N)=O)c2C1

Procedure:
2.6 g (10 mmol) of 2-dipropylamino-8-aminomethyl-1,2,3,4-tetrahydronaphthalene were dissolved in 22 ml of 1 N hydrochloric acid under nitrogen. A solution of 0.81 g (10 mmol) of potassium cyanate and 6 ml of water was subsequently added dropwise at a maximum of +25° C., and the batch was allowed to react for 4 h at room temperature. 20 ml of diethyl ether were then added. The aqueous phase was separated off and adjusted to pH 9 using 1 N sodium hydroxide solution. The precipitated reaction product was filtered off under suction and dried at +40° C. in vacuo. The product was purified by recrystallization from methanol.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:31][C:26]1[CH:25]=[C:24]([S:21]([N:18]2[CH2:19][CH2:20][CH:15]([C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=4)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[CH:14]=3)[CH2:16][CH2:17]2)(=[O:23])=[O:22])[CH:29]=[C:28]([Cl:30])[CH:27]=1
Reactant: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3cc(Cl)cc(Cl)c3)CC2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(C2CCN(S(=O)(=O)c3cc(Cl)cc(Cl)c3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.6 %

Procedure:
To a stirred solution of {4-[1-(3,5-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (75 mg, 0.15 mmol) in THF (6 mL) was added a solution of lithium hydroxide monohydrate (30 mg, 0.7 mmol) in water (1.5 mL) and the reaction mixture was stirred for 24 hours at room temperature. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether (3×5 mL). The washings were discarded. Water (5 mL) was added to the residue, and the mixture acidified (pH ˜2-3) with an aqueous solution of hydrochloric acid (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to give {4-[1-(3,5-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid (60 mg, 82%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.35 (br s, 1H), 8.10 (s, 1H), 7.86-8.01 (m, 2H), 7.82 (s, 2H), 7.69 (s, 1H), 7.31-7.44 (m, 2H), 3.85 (d, J=12.2 Hz, 2H), 3.72 (s, 2H), 2.62-2.73 (m, 3H), 1.93 (d, J=12.2 Hz, 2H), 1.69-1.83 (m, 2H); MS cald. for C23H19Cl2FNO4S [(M−H)−]: 494, obsd. 494.2.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3C(OC(C)(C)C)=O)=[CH:11][C:10]=2[C:29]([NH:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)=[CH:11][C:10]=2[C:29]([NH:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[O:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccnc1)c1cc(OC[C@@H]2CCCN2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of 1,1-dimethylethyl (2S)-2-[({4-[(phenylmethyl)oxy]-3-[(3-pyridinylamino)carbonyl]phenyl}oxy)methyl]-1-pyrrolidinecarboxylate (may be prepared as described in Description 74; 0.6 g, 1.19 mmol) in dichloromethane (15 ml) was added trifluoroacetic acid (2.0 ml, 26 mmol) dropwise. After stirred at 25° C. for 2 h, the pH of the solution was adjusted to 7-8 by adding aqueous NaHCO3 solution. The mixture was extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by prep-HPLC (Gilson GX-281, waters X-Bridge 5 μm, 100*19 mm; A: 0.04% NH3.H2O/water, B: CH3CN; 0-7 min, 35%-50%; 7-14 min, 95%; RT=7.0 min) to yield the title compound as a light yellow solid. 150 mg.
Reaction SMILES: [CH2:1]([SnH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH:10]([O:12][CH:13]=[CH2:14])=[O:11]>>[CH:10]([O:12][CH2:13][CH2:14][Sn:5]([CH2:14][CH2:13][O:12][CH:10]=[O:11])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])=[O:11]
Reactant: CCCC[SnH2]CCCC
Reactant: C=COC=O
Product: CCCC[Sn](CCCC)(CCOC=O)CCOC=O

Procedure:
The addition of dibutyltin dihydride to vinyl formate was carried out in a Pyrex® tube at 30°-35° C. by following the operating procedure of Example 5. The product was not isolated, because it decomposed as it was being formed.
Reaction SMILES: C(C1C=CC(CCC(C2C=CC=CC=2)=O)=CC=1)C.[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28]/[C:29](/[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:23][CH:22]=1)[CH3:20]>>[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28]/[C:29](/[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:30]\[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:23][CH:22]=1)[CH3:20]
Reactant: CCOC(=O)/C=C(/CCc1ccc(CC)cc1)c1ccccc1
Agent: CCc1ccc(CCC(=O)c2ccccc2)cc1
Product: CCOC(=O)/C=C(\CCc1ccc(CC)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.85.3, starting from 3-(4-ethylphenyl)-1-phenylpropan-1-one, (Z)-ethyl 5-(4-ethylphenyl)-3-phenylpent-2-enoate and (E)-ethyl 5-(4-ethylphenyl)-3-phenylpent-2-enoate were obtained as colourless oils.
Reaction SMILES: CO.[C:3]([C:6]1[CH:29]=[CH:28][C:9]([NH:10][C:11]2[CH:19]=[C:18]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)(=O)[CH3:4]>[C].[Pd].C(OCC)(=O)C>[CH2:3]([C:6]1[CH:29]=[CH:28][C:9]([NH:10][C:11]2[CH:19]=[C:18]([CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[CH3:4]
Reactant: CC(=O)c1ccc(Nc2cc(CCc3ccccc3)ccc2C(=O)O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1ccc(Nc2cc(CCc3ccccc3)ccc2C(=O)O)cc1
Temperature: 40 °C
Reaction time: 7 h
Yield: 100.9 %

Procedure:
To a mixed solution of methanol 1.0 mL and ethyl acetate 1.0 mL of 2-(4-acetylanilino)-4-phenethylbenzoic acid 10 mg was added 5% palladium-carbon 2.0 mg at room temperature, and it was stirred under hydrogen atmosphere at 40° C. for 7 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and the solvent was removed under reduced pressure to give 2-(4-ethylanilino)-4-phenethylbenzoic acid 9.7 mg of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=1)=[O:4].[Cl:20][C:21]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:22]=1[C:23]([N:25]=[C:26]=[O:27])=[O:24]>C(Cl)Cl>[Cl:20][C:21]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:22]=1[C:23]([NH:25][C:26]([N:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=1)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:27])=[O:24]
Reactant: COC(=O)c1ccc(NNC(=O)OC(C)(C)C)cc1
Reactant: O=C=NC(=O)c1c(F)cccc1Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2c(F)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a solution of tert-butyl 2-[4-(methoxycarbonyl)phenyl]hydrazinecarboxylate (Intermediate-7, 2.0 g, 7.54 mmol) in DCM (15 mL) was added 2-chloro-6-fluorobenzoyl isocyanate (Intermediate-8, 1.50 g, 7.54 mmol). The reaction mass was stirred at RT for 2 h. Excess of solvent was removed under vacuum to afford 3.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.42 (s, 9H), 3.83 (s, 3H), 7.24-7.46 (m, 5H), 7.94 (d, J=7.2 Hz, 2H), 9.91 (br s, 1H), 11.34-11.39 (br m, 1H); MS (m/z): 464.06 (M−H)−.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:8][C:7](=[O:9])[C@@:4]2([O:6][CH2:5]2)[C:3]21[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:5][C@@:4]1([OH:6])[C:3]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C@@H:2]([CH3:1])[CH2:8][C@@H:7]1[OH:9]
Reactant: C[C@H]1CC(=O)[C@]2(CO2)C12CCCCCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C[C@H]1C[C@H](O)[C@](C)(O)C12CCCCCC2
Yield: 76 %

Procedure:
(3R*,11S*)-11-Methyl-1-oxadispiro[2.0.6.3]tridecan-13-one (800 mg, 3.84 mmol) was reduced with lithium aluminum hydride (440 mg, 11.5 mmol) in Et2O (2 mL+4 mL) at ambient temp. for 16 h. Quenching with water (5 mL) and aq. HCl (5 N, 5 mL), usual extraction and purification by silica-gel FC (pentane/Et2O, 2:1, Rf=0.16) furnished (1R*,2R*,4S*)-/(1R*,2S*,4S*)-1,4-dimethylspiro[4.6]undecane-1,2-diol (620 mg, 76%).