Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2]/[C:3](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)\[CH2:5]Br.[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.O>C(Cl)Cl>[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([N:24]2[CH2:5][C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:2]2)=[CH:22][CH:21]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: BrC/C(=C(\CBr)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(N2CC(c3ccccc3)=C(c3ccccc3)C2)cc1
Reaction time: 4 h

Procedure:
After dissolving compound 20 (300 mg, 0.819 mmol) and 4-chloroaniline (105 mg, 0.819 mmol) in DCM (10 ml), TEA (457 l, 3.28 mmol) was added thereto and the reflux was conducted for 4 hours. After the termination of the reaction, the temperature was reduced to room temperature and water was added thereto. The organic layer was washed with water and water was removed by using anhydrous Na2SO4. After the distillation under the reduced pressure was carried out for the removal of the solvent, column chromatography was conducted to obtain compound 21.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:19]I.Cl>O1CCCC1>[CH3:19][O:9][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[CH3:8]
Reactant: Cc1ccccc1C(C)(O)c1ccccc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(c1ccccc1)c1ccccc1C
Reaction time: 6 h

Procedure:
2 g of 1-Phenyl-1-tolylethanol are stirred overnight with 0.56 g of 80% NaH in 50 ml of tetrahydrofuran, 3.7 g of methyliodide added and stirring continued for 6 hours. The mixture is worked up with aq. HCl, extracted with dichloromethane and the oily product purified over a silica gel column with cyclohexane as eluant.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C:3](=[O:14])[C:4]([N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)=[CH:5]N(C)C.[CH:17]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.O.Cl>CCOCC>[CH:17]1([CH:5]=[C:4]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)[C:3](=[O:14])[C:2]([CH3:1])([CH3:15])[CH3:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CN(C)C=C(C(=O)C(C)(C)C)n1cncn1
Reactant: Br[Mg]C1CCCCC1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)C(=O)C(=CC1CCCCC1)n1cncn1
Reaction time: 1 h
Yield: 82.6 %

Procedure:
11.1 g (0.05 mol) of 4,4-dimethyl-1-dimethylamino-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one were dissolved in 250 ml of ether. An ethereal solution of 13.1 g (0.07 mol) of cyclohexyl-magnesium bromide was added dropwise to this solution in the course of 30 minutes. The reaction mixture was subsequently stirred for one hour, 250 ml of water were added and the mixture was adjusted to a pH value of 6-7 with hydrochloric acid. The organic phase was separated off, dried and filtered and the filrate was concentrated. 10.8 g (83% of theory) of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one of refractive index nD20 1.5003 were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1cccc(Br)c1
Yield: 39 %

Procedure:
The title compound was synthesized from methyl 4-(3-bromobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.099 g, 0.30 mmol, 1 equiv) and lithium hydroxide (0.124 g, 2.96 mmol), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to the title compound: 37 mg, 39% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.03-2.11 (m, 1H), 2.48-2.57 (m, 1H), 2.60-2.64 (m, 2H), 2.75 (dd, J1=7.32 Hz, J2=3.71 Hz, 2H), 3.21-3.28 (m, 1H), 6.31 (s, 1H), 7.14-7.20 (m, 2H), 7.32-7.35 (m, 2H); LCMS-MS (ESI−) 318.0 (M−H); HPLC (UV=98.99%), (ELSD=100%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[C:13]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]([O:37]CC2C=CC(OC)=CC=2)[CH:22]([CH2:30][CH2:31]OS(C)(=O)=O)[C:23]([O:25]C(C)(C)C)=[O:24])=[CH:15][CH:14]=1>CN(C)C=O>[C:13]1([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH:21]([OH:37])[CH:22]([CH2:30][CH2:31][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[C:23]([OH:25])=[O:24])=[CH:17][CH:18]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(COC(CCc2ccc(-c3ccccc3)cc2)C(CCOS(C)(=O)=O)C(=O)OC(C)(C)C)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(O)C(CCN1C(=O)c2ccccc2C1=O)C(O)CCc1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
Potassium phthalimide (8.8 mg, 60 μmol) was added in one portion to a stirred solution of 1,1-dimethylethyl 5-(4-biphenylyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)-2-{2-[(methylsulfonyl) oxy]ethyl}pentanoate (28.4 mg, 50 μmol) in dimethylformamide (0.5 mL) under nitrogen at room temperature. The resulting solution was heated at 80° C. for 1 h 45 min then cooled to room temperature. The volatiles were evaporated and the residue taken up in dichloromethane (0.5 mL). Trifloroacetic acid (0.5 mL) was added in one portion and the resulting solution stirred for 1 h at room temperature. The volatiles were evaporated and the residue purified by mass directed auto-preparative HPLC to give the title compound as a white solid (6.0 mg, 27%). LC/MS: 3.43 min; z/e 444, calcd (M+1) 444. 1H NMR (400 MHz: CDCl3): 7.85 (2H), 7.70 (2H), 7.55 (1H), 7.50 (1H), 7.45 (2H), 7.30 (1H), 7.25 (4H), 3.85 (3H), 2.95 (1H), 2.75 (1H), 2.60 (1H), 2.20 (1H), 2.05 (1H), 1.90 (2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:17](=[O:18])[CH2:16][C:15]2[N:11]([C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:13][N:14]=2)[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]1=2)([CH3:4])([CH3:3])[CH3:2].[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[CH:31]1.N1CCCCC1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:17](=[O:18])[C:16](=[CH:39][C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:30][CH:31]=2)[C:15]2[N:11]([C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:13][N:14]=2)[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]1=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)CN1C(=O)C(=Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Temperature: 110 °C
Reaction time: 24 h
Yield: 133.4 %

Procedure:
To a solution of (5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetic acid tert-butyl ester (Preparation 13(B)) (3.66 g, 9.37 mmol) in toluene (94 mL) was added 1H-indole-3-carbaldehyde (1.63 g, 11.2 mmol) and piperidine (2.78 mL, 28.1 mmol). The reaction was heated to 110° C. in a Soxhlet for 10 hours and was stirred at room temperature for 24 hours. The precipitate was filtered and was washed with toluene to provide 6.47 g of [4-(1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-acetic acid tert-butyl ester. MS 518.5 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13].S([C:34]#[N:35])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[N:14]1([C:12](=[O:13])[CH2:11][S:10][C:2]2[N:3]([C:34]#[N:35])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: O=C(CSc1nc2ccccc2[nH]1)N1CCCc2ccccc21
Solvent: C1CCOC1
Product: N#Cn1c(SCC(=O)N2CCCc3ccccc32)nc2ccccc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 59.2 %

Procedure:
To a solution of compound 16 (0.52 g, 1.6 mmol, 1.0 eq) in 6 mL of dry THF stirred at −78° C. under N2 LiHMDS (1.7 mL, 1.05 eq) was added. The mixture was stirred for 15 min. at −78° C. and then TosCN (306 mg, 1.05 eq. in 1 mL of THF) was added dropwise. The reaction mixture was quickly allowed to warmed up to RT. The reaction mixture was quenched with 10 mL of NH4Cl (sat.), extracted into ethyl acetate, washed with brine and concentrated to give creamy solid. The crude was purified by column chromatography (ethyl acetate/hexanes) to give 79 (330 mg, 59%). MP=153.3-154.2° C. Anal/Calcd. for C19H16H4OS: C, 65.50; H, 4.63; N, 16.08; S, 9.20. Found C, 65.59; H, 4.66; N, 16.06; S, 9.16.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.[CH2:21]([N:25]=[C:26]=[O:27])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([NH:25][C:26]([NH:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH:20][C:26]([NH:25][CH2:21][CH2:22][CH2:23][CH3:24])=[O:27])=[N:8][C:6]=2[N:7]=1)=[O:27])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN=C=O
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Product: CCCCNC(=O)Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)NCCCC)nc2n1
Temperature: 25 °C

Procedure:
A mixture of 0.5 g 2,7-Diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine from Example 1 and 15 mL of n-butyl isocyanate is refluxed for 2 hours. The reaction mixture is allowed to cool to room temperature and the insoluble material filtered. The solid is recrystallized several times from ethanol to give the title compound; mp 200-202° C.
Reaction SMILES: [I-].[Na+].Cl[CH2:4][CH2:5][CH2:6][N:7]1[C:20]2[CH:19]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2.C(N(CC)CC)C.[CH3:32][CH:33]([OH:43])[CH:34]([CH3:42])[O:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>C(C(C)=O)C>[F:22][C:21]([F:24])([F:23])[C:18]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:6][CH2:5][CH2:4][N:39]3[CH2:40][CH2:41][CH:36]([O:35][CH:34]([CH3:42])[CH:33]([CH3:32])[OH:43])[CH2:37][CH2:38]3)[C:20]=2[CH:19]=1
Reactant: CC(O)C(C)OC1CCNCC1
Reactant: FC(F)(F)c1ccc2c(c1)N(CCCCl)c1ccccc1S2
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: CC(O)C(C)OC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Yield: 47.9 %

Procedure:
22.5 g (0.15 mole) of sodium iodide were added to a solution of 51.5 g (0.15 mole) of 10-(3-chloropropyl)-2-trifluoromethyl-phenothiazine in 400 ml of methyl ethyl ketone followed by the addition of 15.2 g (0.15 mole) of triethylamine and then 26 g (0.15 mole) of 1,2-dimethyl-2-(4-piperidyloxy)-ethanol. The mixture was then refluxed for 20 hours and after cooling, the precipitate formed was removed by vacuum filtration. The filtrate was evaporated to dryness and the oil residue was chromatographed over 1 kg of neutral alumina. Elution with ethyl acetate gave 34.5 g (48% yield) of 2-trifluoromethyl-10-[3-(4-[1,2-dimethyl-2-hydroxyethoxy]-piperidino)-propyl]-phenothiazine in the form of a clear amber oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].I[C:20]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH3:30]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:22]1[CH:23]=[C:24]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:25]=[CH:20][C:21]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(C)(=O)=O)cc1I
Product: Cc1ccc(S(C)(=O)=O)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 2-iodo-1-methyl-4-(methylsulfonyl)benzene (Intermediate 17), the title compound was obtained as a colorless oil after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].Br[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25])#[N:2]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(C#N)cc23)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
A mixture of 5-cyanoindole (10 g) and freshly prepared silver carbonate on diatomaceous earth (40.66 g) was stirred and heated under reflux in toluene (100 ml) for 18 hr, under an atmosphere of nitrogen. The mixture was cooled to room temperature, methyl 4-bromomethyl-3-methoxybenzoate (22.7 g) added, and stirring continued for 4 hr. Ethyl acetate (200 ml) was added, the mixture filtered through diatomaceous earth, the filter pad washed with ethyl acetate and the filtrate evaporated. The dark oil obtained was purified by flash chromatography, eluting with 45:45:10 hexane:methylene chloride:ethyl acetate, to give a foam which was crystallized from toluene to give methyl 4-(5-cyanoindol-3-ylmethyl)-3-methoxybenzoate (11.8 g, 53%) as white crystals; mp 148°-149°; partial NMR (250 MHz, DMSO-d6): 3.83(s, 3H, OCH3), 3.91(s, 3H, OCH3), 4.08(s, 2H, ArCH2Ar'), 8.00(s, 1H, H4 -indole), 11.49(br s, 1H, H1 -indole).
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:17]=1[O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21]([O-:23])=[O:22].[F:38][C:39]([F:55])([F:54])[C:40]1[CH:41]=[C:42]([S:50](Cl)(=[O:52])=[O:51])[CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1>N1C=CC=CC=1>[F:49][C:46]([F:47])([F:48])[C:44]1[CH:43]=[C:42]([S:50]([NH:15][C:16]2[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[CH:30][C:17]=2[O:18][C:19]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=2[C:21]([OH:23])=[O:22])(=[O:51])=[O:52])[CH:41]=[C:40]([C:39]([F:55])([F:54])[F:38])[CH:45]=1.[CH:1]([OH:14])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)[O-])c(Oc2ccc(C(F)(F)F)cc2N)c1
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: OC(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)O)c(Oc2ccc(C(F)(F)F)cc2NS(=O)(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1

Procedure:
Benzhydrol-2-(2-amino-4-trifluoromethylphenoxy)-4-methoxybenzoate (950 mg, 0.0019 mol) and 3,5-bis(trifluoromethyl)benzenesulfonyl chloride (2.4 g, 0.008 mol) were mixed in pyridine, under argon, at room temperature for 16 h. The solvent was evaporated and the residue flash chromatographed (silica gel, ethyl acetate/hexane) to yield the title compound. 1H NMR (250 MHz, CDCl3) δ8.11 (s, 1H), 7.86-7.98 (m, 2H), 7.08-7.32 (s, 10 H), 6.94 (s, 1H), 6.87 (d, 1H), 6.70 (q, 3H), 6.48 (d, 1H), 6.11 (d, 1H), 3.73 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>O>[CH:24]([C:23]([C:11]1[C:2]([OH:1])=[CH:3][C:4]2[C:5]([CH3:15])([CH3:14])[CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9]=2[CH:10]=1)=[O:27])([CH3:26])[CH3:25]
Reactant: CC(C)C(=O)Cl
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(C)C(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
The synthesis process is as set forth in the chemical reaction formula below. To 5,6,7,8-tetrahydro-2-hydroxy-5,5,8,8-tetramethylnaphthalene (204 mg, 1.00 mol) were added anhydrous dichloromethane (1 mL), aluminum chloride (148 mg, 1.12 mmol), and isobutyryl chloride (117 mg, 1.10 mmol) followed by stirring at 60° C. for 2 hours. The reaction solution was poured into cold water, and extracted by ethyl acetate. The organic layer was washed by water, a saturated sodium hydrogen carbonate aq. solution, and a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using hexane/ethyl acetate (20/1) as an elution solvent. The yield was 128 mg (47%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](O)=[O:15])=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].O[N:22]=[C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=1)[NH2:24].N1C=CC=CC=1>CC#N>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=3)[N:22]=2)=[CH:10][C:9]=1[C:17]([F:19])([F:20])[F:18]
Reactant: NC(=NO)c1ccc(CO)cc1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C(F)(F)F
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Intermediate 5 (4.32 g, 15.4 mmol) in MeCN (15 mL) was added 1-ethyl-3-dimethyl aminopropylcarbodiimide (4.14 g, 21.6 mmol) followed by Intermediate 72 (2.81 g, 17.0 mmol). The mixture was stirred at RT for 18 hours and then pyridine (5 mL) added. The mixture was heated under microwave irradiation at 150° C. for 30 minutes. The solvent was removed in vacuo and the residue partitioned between DCM and H2O. The layers were separated, the organic layer washed with H2O and the mixture passed through a hydrophobic frit. The solvent was removed in vacuo and the residue was recrystallised from EtOAc and petrol to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.63 (1H, s), 8.40 (1H, d, J=8.0 Hz), 8.20 (2H, d, J=8.0 Hz), 7.54 (2H, d, J=7.9 Hz), 7.47 (1H, d, J=7.9 Hz), 7.38-7.21 (3H, m), 7.16 (1H, d, J=7.5 Hz), 4.81 (2H, d, J=5.7 Hz), 2.14-1.94 (3H, m). LC/MS (Method A): 411 (M+H)+. HPLC (Method G) Rt 4.50 min (Purity: 97.9%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:16](=[O:17])[C:6]2[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[S:9][C:5]=2[CH2:4][CH2:3]1.C1COCC1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1.CCOCC>[NH4+].[Cl-]>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:16]2([OH:17])[C:6]3[CH:7]=[C:8]([C:10]4[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=4)[S:9][C:5]=3[CH2:4][CH2:3][C:2]2([CH3:18])[CH3:1])=[CH:27][CH:26]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC1(C)CCc2sc(-c3ccncc3)cc2C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)CCc2sc(-c3ccncc3)cc2C1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 100 mL round bottomed flask were placed 5,5-dimethyl-2-pyridin-4-yl-6,7-dihydro-1-benzothiophen-4(5H)-one (380 mg, 1.5 mmol) and THF (30 mL). To the mixture was added a solution of 4-chlorophenylmagnesium bromide in ether (1.0 M, 3.5 mL, 3.5 mmol) then the reaction was stirred for 3 hr at rt. LCMS indicated that starting material still remained, so additional 4-chlorophenylmagnesium bromide in ether (1.0M, 2.5 mL, 2.5 mmol) was added and the reaction was stirred for 16 hr at rt then for 10 hr at 70° C. The mixture was allowed to cool to rt then additional 4-chlorophenylmagnesium bromide in ether (1.0M, 5 mL, 5 mmol) was added and the mixture was stirred for 16 hr at rt. The mixture was then diluted with a saturated aqueous solution of NH4Cl (50 mL) and was extracted with EtOAc (50 mL×2). The combined organic phases were dried over anhydrous MgSO4. The insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (24 g RediSep column, gradient 30% EA in hexane to 100% EA in hexane) to give the product (530 mg; 97%) as a colorless foam: 1H NMR (400 MHz, DMSO-d6) δ: 8.48 (dd, 2H), 7.45 (dd, 2H), 7.32-7.35 (m, 2H), 7.23-7.25 (m, 3H), 5.55 (s, 1H), 2.87-2.91 (m, 2H), 1.84-1.90 (m, 1H), 1.57-1.63 (m, 1H), 0.91 (s, 3H), 0.63 (s, 3H).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=O)=[CH:5]1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:26]=[CH:27][C:28]=1[NH2:29].C(N(CC)CC)C>C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:26]=[CH:27][C:28]=1[NH:29][C:13]([C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:15]
Reactant: CC(C)n1cc(C(=O)O)c2ccccc21
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(NC(=O)c2cn(C(C)C)c3ccccc23)c(Cl)c1
Temperature: -15 °C
Yield: 91.1 %

Procedure:
To a solution of 1-isopropylindole-3-carboxylic acid (159.6 mg, 0.785 mmol) in methylene chloride (3.5 ml) was added oxalyl chloride (101.0 μl, 1.178 mmol) under stirring at −15° C. The reaction mixture was stirred for 2.5 hours at room temperature and then distilled under reduced pressure to remove the solvent. The residue was dissolved in methylene chloride (3.5 ml), followed by the addition of a solution of methyl 3-chloro-4-aminophenylacetate (164.6 mg, 0.824 mmol) in methylene chloride (3.5 ml) and triethylamine (0.35 ml, 2.474 mmol) under stirring at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then distilled under reduced pressure to remove the solvent. The residue was dissolved in chloroform. The resulting solution was washed successively with 1N HCl and saturated saline, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby methyl 3-chloro-4-((1-isopropyl-3-indolylcarbonyl)amino)phenylacetate (275.3 mg, 91%) was obtained as a brown solid. The resulting compound was provided for the subsequent reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:10])(S(F)(=O)=O)C(O)=O.[OH:11][C:12]1[N:17]=[C:16]([CH:18]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[C:26]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][C:32]4=[O:37])=[N:27][CH:28]=[CH:29][CH:30]=3)[CH2:19]2)[CH:15]=[CH:14][CH:13]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].O>C(#N)C>[F:1][CH:2]([F:10])[O:11][C:12]1[N:17]=[C:16]([CH:18]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[C:26]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][C:32]4=[O:37])=[N:27][CH:28]=[CH:29][CH:30]=3)[CH2:19]2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: O=C1CCCCN1c1ncccc1CCN1CCC(c2cccc(O)n2)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1CCCCN1c1ncccc1CCN1CCC(c2cccc(OC(F)F)n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
2,2-Difluoro-2-(fluorosulfonyl)acetic acid (9.72 mg, 0.054 mmol, 1 eq) is added slowly, under stirring, to a mixture of 1-(3-{2-[3-(6-hydroxypyridin-2-yl)pyrrolidin-1-yl]ethyl}pyridin-2-yl)piperidin-2-one a16-1 (20 mg, 0.054 mmol, 1 eq) and dry sodium sulfate (0.78 mg, 0.005 mmol, 0.1 eq) in dry acetonitrile (400 μl). The reaction is stirred for 2 h at room temperature, then water (100 μl) is added. The resulting solution is concentrated in vacuo. The residue is purified by basic reverse phase chromatography (gradient: H2O/acetonitrile/NH4OH from 50/50/0.1 to 20/80/0.1) to afford 9.4 mg of 1-[3-(2-{3-[6-(difluoromethoxy)pyridin-2-yl]pyrrolidin-1-yl}ethyl)pyridin-2-yl]piperidin-2-one 109.