Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:28])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH:23]=[CH:22]3)[CH:5]=[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:29](OC(=O)C)(=[O:31])[CH3:30].CCN(CC)CC>CC#N>[C:29]([N:24]1[C:25]2[C:21](=[CH:20][C:19]([CH2:18][N:4]3[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=4[F:17])=[C:2]([Cl:1])[C:3]3=[O:28])=[CH:27][CH:26]=2)[CH:22]=[CH:23]1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1c(Cl)c(OCc2ccc(F)cc2F)ccn1Cc1ccc2[nH]ccc2c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)n1ccc2cc(Cn3ccc(OCc4ccc(F)cc4F)c(Cl)c3=O)ccc21
Temperature: 86 °C
Reaction time: 6 h

Procedure:
To a solution of 3-chloro-4-(2,4-difluorobenzyloxy)-1-(1H-indol-5-ylmethyl)-1H-pyridin-2-one (Step 5, synthesis of Example 86) (0.22 g, 0.57 mmol) in CH3CN (10 mL) was added acetic anhydride (0.06 mL, 0.58 mmol) and Et3N (2 mL), and the reaction mixture was stirred at 86° C. for 6 h. The reaction mixture was cooled to room temperature, and partitioned between 1 N HCl and EtOAc. The organic solution was separated, washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. 1H NMR (300 MHz, MeOD) δ 8.35 (d, J=9 Hz, 1H), 7.77 (d, J=9 Hz, 1H), 7.70 (d, J=3 Hz, 1H), 7.54 (s, 2H), 7.31 (d, J=9 Hz, 1H), 7.01-6.99 (m, 2H), 6.66 (d, J=3 Hz, 1H), 6.59 (d, J=9 Hz, 1H), 5.29 (s, 4H), 2.63 (s, 3H). ES HRMS m/z 443.0965 (M+H C23H18ClF2N2O3 requires 443.0969).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]1[CH2:14][N:13](C(OCC2C=CC=CC=2)=O)[CH2:12]1.[H][H]>CO.[Pd]>[NH:13]1[CH2:14][CH:11]([C:3]2[N:2]([CH3:1])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N:4]=2)[CH2:12]1
Reactant: Cn1c(C2CN(C(=O)OCc3ccccc3)C2)nc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cn1c(C2CNC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.6 %

Procedure:
A solution of 1-3 (3.32 g, 10.33 mmol) in MeOH (52 mL) was subjected to 2 cycles of the evacuation/backfilling with nitrogen and then treated with 10% Pd/C (1.1 g). The evacuation/backfilling with nitrogen procedure was repeated two times and then the nitrogen atmosphere was exchanged for a hydrogen atmosphere by evacuation/backfilling with a balloon of hydrogen. After stirring for 3 hours under hydrogen at ambient temperature, the reaction mixture was filtered through celite, and washed with additional MeOH (20 mL). The filtrate was concentrated to yield Intermediate 1 as brown solid (2.1 g, 100%). MS: m/z=188.2 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2(O)[C:21]3[CH:20]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:17][C:16]=3[O:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:4][CH2:3]1.S(C1C=CC=CC=1C(OC(=O)C1C=CC=CC=1S(O)(=O)=O)=O)(O)(=O)=O.C(O)(=O)CC.[OH-].[Na+]>O>[CH3:1][N:2]1[CH2:3][CH2:4][C:5](=[C:8]2[C:21]3[CH:20]=[C:19]([C:22]([F:25])([F:23])[F:24])[CH:18]=[CH:17][C:16]=3[O:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][CH2:7]1
Reactant: CN1CCC(C2(O)c3ccccc3Oc3ccc(C(F)(F)F)cc32)CC1
Agent: O=C(OC(=O)c1ccccc1S(=O)(=O)O)c1ccccc1S(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCC(=O)O
Product: CN1CCC(=C2c3ccccc3Oc3ccc(C(F)(F)F)cc32)CC1
Temperature: 100 °C

Procedure:
Dehydration of the xanthene-9-ol (88.2 g., 0.24 m.) is accomplished by refluxing with 88.1 g. (0.48 m.) of sulfobenzoic anhydride and 1.2 1. of propionic acid for two hours. The reaction mixture is heated in vacuo at 100° C. and the residual syrup is dissolved in water and made strongly basic with 40% sodium hydroxide solution. Extraction with ether gives 1-methyl-4-(2-trifluoromethyl-9-xanthenylidene)-piperidine, m.p. 82°-83° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[CH3:25][C:26](=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27](O)=[O:28].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:25][C:26](=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:28]
Reactant: CC(=Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C(C)=Cc1ccccc1
Yield: 93.7 %

Procedure:
The same procedures as in Example 146 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), α-methylcinnamic acid (2.3 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (4.0 g, 94%) as an oily product.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[NH2:20][CH2:21][CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[OH:23]>>[OH:23][CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:21][NH:20][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: NCC(O)c1ccccc1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCC(O)c3ccccc3)s2)c(C)[nH]c1=O
Yield: 58 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 2-amino-1-phenylethanol as described in Step 5, Example 24 to give the title compound as a yellow solid (58% yield). LC/MS: RT 2.68 min; m/e 419 (M+H); 1H NMR (CDCl3, δ, ppm): 11.30 (1H, br), 7.58 (1H, d), 7.40 (5H, m), 6.90 (1H, d), 5.33 (1H, br), 4.90 (1H, m), 3.47 (1H, m), 3.22 (1H, m), 2.60 (2H, q), 2.44 (3H, s), 1.22 (3H, t).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][N:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CC(O)C.O.[OH-].[Na+]>[C:12]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)Cc1ccc(Cl)nc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)Cc1ccc(-c2ccccc2)nc1
Temperature: 67.5 °C

Procedure:
2-chloropyridine-5-acetic acid (0.2 gm, 1.21 mmole), phenylboronic acid (0.16 gm, 1.3 mmole) and 50% water wet 10% Palladium carbon (0.08 gm, 0.036 mmole Pd) were added to 10 ml of 5:1 water isopropanol mixture, then Na2CO3 (0.15 gm, 1.4 mmole) dissolved in 3 ml of water was added to the above mixture, the reaction was heated at 65-70° C. overnight, the reaction was cooled to room temperature, diluted with 20 ml of 70:15:1 i-PrOH/H2O/10% NaOH, filtered, the catalyst was washed with 20 ml×3 using the above mixture, the filtrate was dried under vacuum and crude mixture was used without any purification in the next step.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]1[C:23](=[O:29])[N:24]([CH3:28])[CH:25]=[CH:26][CH:27]=1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:21][C:22]2[C:23](=[O:29])[N:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Reactant: Cn1cccc(CBr)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.5 %

Procedure:
3-Bromo-4-nitro-1H-indazole (Preparation B; 0.49 g, 2.04 mmol) was dissolved in dimethyl formamide (5 mL). Potassium carbonate (1.13 g, 8.15 mmol) was added followed by 3-(bromomethyl)-1-methylpyridin-2(1H)-one (0.41 g, 2.04 mmol). The mixture was stirred at ambient temperature for two days. The mixture was diluted with ethyl acetate (8 mL) and concentrated under vacuum to give a dark solid which was dried overnight under high vacuum. This material was dissolved in ethyl acetate (80 mL) and washed with water (40 mL). The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under vacuum to give a green solid. This material was triturated with diethyl ether and the solids were collected by filtration and dried under high vacuum to give 3-((3-bromo-4-nitro-1H-indazol-1-yl)methyl)-1-methylpyridin-2(1H)-one as a beige solid (552 mg).
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].CO[CH2:16][N:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:18][Si](C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH2:23]([N:17]1[CH2:16][CH:3]([CH3:4])[CH:2]([C:1]([O:6][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:5])[CH2:18]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C/C=C/C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(Cc2ccccc2)CC1C(=O)OCc1ccccc1
Yield: 105.9 %

Procedure:
Benzyl (2E)-but-2-enoate obtained in Example 1e (20.5 g, 116 mmol) was dissolved in dichloromethane (5 ml), and the mixture was cooled in an ice bath with stirring. Trifluoroacetic acid (257 μl, 3.47 mmol) was added, and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (33.1 g, 139 mmol) was added dropwise to the reaction liquid over 15 minutes so that the internal temperature did not exceed 62° C., while washing with dichloromethane (25 ml). The reaction liquid was left to stand until it reached mom temperature and was stirred for 15 hours. The reaction liquid was concentrated and purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane) to give the title compound (38 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]=[C:11]([C:17](OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:17]1[C:5]2[C:6](=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=CNc1ccc(OC)cc1)C(=O)OCC
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1Cl
Yield: 94.8 %

Procedure:
Diethyl {[(4-methoxyphenyl)amino]methylene}malonate (63.5 g, 0.22 mol) was dissolved into POCl3 (300 mL, 3.0 mol), and the reaction mixture was heated at reflux for 16 h. After removal of solvent, toluene was added and the mixture was concentrated to remove remaining POCl3. The residue was diluted with DCM, washed with aqueous Na2CO3 and brine, dried over Na2SO4 and concentrated to give ethyl 4chloro-6methoxyquinoline-3-carboxylate (55.4 g, 96% yield) as a yellow solid which was used without further purification. LCMS: (FA) ES+ 266.1.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH2:22]Br)[CH:16]=1>C(O)C>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH2:22][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=1
Reactant: Oc1ccccc1
Reactant: Clc1ccc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Clc1ccc(Br)cc1COc1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of phenol (7.1 g) and potassium carbonate (11.1 g) in ethanol (100 mL) is added 4-bromo-2-bromomethyl-1-chloro-benzene (19.5 g). The mixture is stirred at ambient temperature over night. The ethanol is evaporated, and water is added to the residue. The resulting mixture is extracted with ethyl acetate, the combined extracts are dried over sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 70:30).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:65][C:66]([CH3:70])([CH3:69])[CH2:67][NH2:68]>C(Cl)Cl>[OH:65][C:66]([CH3:70])([CH3:69])[CH2:67][NH:68][C:28]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]1)=[O:30]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCC(C)(C)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80 mg, 0.14 mmol) in methylene chloride (10 mL), HATU (Aldrich, 105 mg, 0.28 mmol) was added followed by the addition of DIPEA (0.34 mmol) and 2-hydroxy-2-methyl-propylamine (Matrix, 25 mg, 028 mmol). The mixture was stirred at rt 1 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 35-50% EtOAc/hexanes) to give a white solid. 50 mg.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][C:18]([NH2:24])([C:21](=[O:23])[NH2:22])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[NH2:24][C:18]1([C:21]([NH2:22])=[O:23])[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(N)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)C1(N)CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Trifluoroacetic acid (6.17 mL, 83.0 mmol) was added to a solution of 4-amino-4-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (2.02 g, 8.30 mmol) in dichloromethane (16.6 mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in methanol (2.00 mL), repeatedly concentrated under reduced pressure twice and dried under reduced pressure to give 4-amino-piperidine-4-carboxylic amide 2TFA salt as a colorless substance (3.25 g).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].O>CN(C=O)C>[C:3]1([C:9]2[CH:13]=[CH:12][N:11]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CBr
Reactant: c1ccc(-c2cc[nH]n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1ccc(-c2ccccc2)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a slurry of 8g (0.2 mol) of sodium hydride in 100 mL of DMF at room temperature was added 23g (0.16 mol) of 3-phenylpyrazole. The mixture was stirred 1 hr and 17.8 mL (0.16 mol) of ethyl bromoacetate was added. The reaction was heated at about 100° C. for 2 hr, cooled, poured into water, extracted into methylene chloride, dried over magnesium sulfate and stripped. The resulting oil was chromatographed on silica gel HPLC using 25% ethyl acetate in hexane. The first, and major, component to elute was the 3-isomer. It was recrystallized from ether-hexane to yield 6.0g of ethyl 3-phenyl-1H-pyrazole-1-acetate having an Rf of 0.66 on silica gel in 1:1 ethylacetate-hexane. The third component to elute from the HPLC separation was a minor fraction containing the 5-isomer. Upon stripping the solvent one obtained 1.0g of ethyl 5-phenyl-1H-pyrazole-1-acetate as an oil having an Rf of 0.51 on silica gel in 1:1 ethyl acetate-hexane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])=[O:10])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].C(OO)(=[O:23])C>C(O)(=O)C>[N+:18]([C:3]1[CH:4]=[C:5]([CH2:8][S:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])(=[O:23])=[O:10])[CH:6]=[CH:7][C:2]=1[CH3:1])([O-:20])=[O:19]
Reactant: Cc1ccc(CS(=O)c2cccc[n+]2[O-])cc1[N+](=O)[O-]
Reactant: CC(=O)OO
Solvent: CC(=O)O
Product: Cc1ccc(CS(=O)(=O)c2cccc[n+]2[O-])cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a mixture of 12.1 g (0.042 mole) 2-[[(4-methyl-3-nitrophenyl)methyl]sulfinyl]-pyridine-1-oxide in 35 ml of acetic acid was added, dropwise at room temperature over one-half hour, a solution of 9.2 g (1. 16 mole) of 40% peracetic acid in acetic acid. The reaction mixture was heated to 70° C. for two hours, and then allowed to cool and stir at room temperature overnight. An additional period of heating at 70° C. for five hours was instituted after which time work-up of a small portion of the mixture indicated some starting material to still be present. Heating and stirring at 70° C. for two more hours, and then standing at room temperature over the weekend completed the reaction. Excess peracetic acid was then destroyed with sodium bisulfite followed by the addition of 100 ml of water and neutralization with potassium carbonate. The aqueous mixture was chilled in an ice bath to precipitate yellow/white crystals. These were filtered off, washed with water and dried. Recrystallization from ethanol gave 2.9 g of white fluffy needles, having a melting point of 154-156° C. Infrared and NMR spectra were in agreement with the proposed structure.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH2:17][N:18]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[C:19]1[N:20]=[N:21][N:22]([CH3:24])[N:23]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4].[CH2:40](I)[CH3:41]>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:40][CH3:41])[C:10]2[C:15]([C:16]=1[CH2:17][N:18]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[C:19]1[N:20]=[N:21][N:22]([CH3:24])[N:23]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: CCI
Reactant: CCOC(=O)c1[nH]c2ccccc2c1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2ccccc2n1CC
Reaction time: 0.25 h
Yield: 75.9 %

Procedure:
To a suspension of NaH (0.01 g, 0.38 mmol) in DMF (5 mL) was added 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1H-indole-2-carboxylic acid ethyl ester (0.1 g, 0.19 mmol), obtained in step (vi) of Example 124, at 0° C., and stirred for 15 min. Ethyl iodide (0.09 g, 1.08 mmol) was added to this at the same temperature and this reaction was stirred for 1 h. The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford the crude residue which was purified by column chromatography over 100-200 mesh silica gel using 15% ethyl acetate and pet ether to afford 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1-ethyl-1H-indole-2-carboxylic acid ethyl ester (0.08 g, 80%).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4](S(OCCCCCC#C)(=O)=O)=[CH:3][CH:2]=1.[F:19][C:20]([F:30])([F:29])[CH2:21][CH2:22][S:23]([CH2:26][C:27]#[N:28])(=[O:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:30][C:20]([F:19])([F:29])[CH2:21][CH2:22][S:23]([CH:26]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]#[CH:18])[C:27]#[N:28])(=[O:24])=[O:25]
Reactant: C#CCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: N#CCS(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C#CCCCCCC(C#N)S(=O)(=O)CCC(F)(F)F
Temperature: 60 °C
Reaction time: 48 h
Yield: 20.7 %

Procedure:
To a solution of 1.0 g of 6-heptynyl p-toluenesulfonate and 0.8 g of (3,3,3-trifluoropropylsulfonyl)acetonitrile in 20 ml of dimethyl sulfoxide was added 0.5 g of potassium carbonate at room temperature. The reaction mixture was stirred at room temperature for 1 hour and at 60° C. for 2 days. The reaction mixture was allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.23 g of 2-(3,3,3-trifluoropropylsulfonyl)-8-nonynenitrile (hereinafter referred to as the present compound (24)).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([CH:10]1[CH2:15][CH2:14][CH:13]([CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([C@H:24]3[CH2:29][CH2:28][C@H:27]([CH:30]=O)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)[CH2:8][CH3:9]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:7]([CH:10]1[CH2:15][CH2:14][CH:13]([CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][CH:27]([CH:30]=[CH2:1])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)[CH2:8][CH3:9]
Reactant: CCCC1CCC(C=Cc2ccc([C@H]3CC[C@H](C=O)CC3)cc2)CC1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1CCC(c2ccc(C=CC3CCC(CCC)CC3)cc2)CC1

Procedure:
Potassium tert-butoxide (1.0 eq, 0.44 g, 3.62 mmol) was added slowly with stirring for 3 minutes to 32 ml of solution including methyltriphenylphosphonium bromide (1.2 eq, 1.55 g, 4.33 mmol) dissolved in THF. Then, the solution was stirred for 30 minutes at a room temperature and THF solution (35 ml) of trans-4-{4-[2-(4-propyl-cyclohexyl)ethenyl]phenyl}cyclohexane carbaldehyde (1.23 g, 3.62 mmol) obtained in Example 2-2 was added slowly dropwise for 10 minutes to reaction mixture, and then was stirred at a room temperature for 24 hours.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH:2]=1.C([OH:24])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:24])[NH:11]3)[CH:2]=1
Reactant: CCO
Reactant: c1ccc(-c2cccc(-c3cccc4[nH]ccc34)c2)cc1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: O=C1Cc2c(cccc2-c2cccc(-c3ccccc3)c2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To the suspension of 4-biphenyl-3-yl-1H-indole (3.5 g, 13 mmol) in t-BuOH: ethanol: acetic acid (82 mL: 49 mL: 269 mL) was added pyridinium tribromide (12.7 g, 40 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (63 mL). Zinc dust (4.39 g, 67 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (3×), sat. NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 2.67 g (72%) of 4-biphenyl-3-yl-1,3-dihydro-indol-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[OH:8].N.OO.Cl.[Cl:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[OH:22]>O>[NH2:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:21][C:19]2[CH:18]=[CH:17][C:16]([OH:22])=[C:15]([Cl:14])[CH:20]=2)[C:4](=[O:9])[CH:3]=1
Reactant: Nc1cc(O)ccc1O
Reactant: Nc1ccc(O)c(Cl)c1
Agent: Cl
Agent: N
Agent: OO
Solvent: O
Product: NC1=CC(=O)C(Nc2ccc(O)c(Cl)c2)=CC1=O
Reaction time: 5 h

Procedure:
0.02 mole (2.78 g) of 3-amino-4-hydroxy phenol is dissolved in 200 cc of water to which have been added 20 cc of ammonia (22° Be). To this solution there are initially added 100 cc of H2O2 (20 volumes) and the immediately thereafter, with good agitation, 0.02 mole (3.60 g) of 2-chloro-4-amino phenol hydrochloride in 200 cc of water. The reaction mixture is left to stand for 5 hours at ambient temperature at which time it is filtered to recover the 2-amino-5-(3'-chloro-4'-hydroxyanilino)-1,4-benzoquinone which is then washed with water, recrystallized in a mixture of dimethylformamide and water and dried for 5 hours under a vacuum with a boiling water bath. The product is chromatographically pure.