Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:20]=[N:19][CH:18]=[CH:17][N:16]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=O.[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:2])=[N:14][C:13]=2[C:15]2[CH:20]=[N:19][CH:18]=[CH:17][N:16]=2)[CH:8]=[C:9]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cnccn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cnccn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 73.6 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyrazin-2-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.086 mmol), β-alanine (768 mg, 8.62 mmol) and NaOMe solution (13 mL, 6.47 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 4, and the resulting precipitate was isolated by filtration to give 33 mg of the title compound as a light yellow solid. MS: (+) m/z 522.29 (M+1).
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]4)=[CH:17][C:15]3=2)[CH:10]=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl.CCCCCC>[CH3:5][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]4)=[CH:17][C:15]3=2)[CH:10]=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)c1cc2ccc3cc4ccccc4cc3c2[nH]1
Reactant: COS(=O)(=O)OC
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(=O)c1cc2ccc3cc4ccccc4cc3c2n1C
Yield: 96.2 %

Procedure:
Using the procedure outlined in Example 34A except that dimethyl sulfate was used as the alkylating agent, ethyl 1H-naphth[2,3-g]indole-2-carboxylate (H.G. Pars Pharmaceutical Laboratories, Inc.) gave a 96.2% yield of ethyl 1-methyl-1H-naphth[2,3-g]indole-2-carboxylate, mp 165°-165.5°, (CH2Cl2 /hexane), (C,H,N).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[OH:11].[CH2:12]([O:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH3:13].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:12]([O:14][C:15](=[O:19])/[CH:16]=[C:17](/[O:11][C:3]1[C:4]([F:10])=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[F:1])\[CH3:18])[CH3:13]
Reactant: COc1ccc(F)c(O)c1F
Reactant: CC#CC(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1c(F)ccc(OC)c1F
Yield: 76.1 %

Procedure:
To a stirred mixture of 2,6-difluoro-3-methoxy-phenol (5.00 g, 0.031 mol) and ethyl-2-butynoate (7.00 g, 0.062 mol) in tetrahydrofuran (40 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.76 g, 0.031 mol) in tetrahydrofuran (10 mL) slowly. After addition was complete the mixture was stirred at reflux overnight. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated and the residue purified by ISCO column chromatography (Teledyne Isco RediSep Flash Column 120 g, 0% to 15%) ethyl acetate/hexanes which afforded (E)-3-(2,6-difluoro-3-methoxy-phenoxy)-but-2-enoic acid ethyl ester (6.42 g, 76%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]#[N:16])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=3[F:24])[N:12]=[C:11]3[NH:25][N:26]=[CH:27][C:10]=23)=[CH:5][CH:4]=1)#[N:2].[N-:28]=[N+:29]=[N-:30].[Na+].C([Sn](Cl)(CCCC)CCCC)CCC.Cl>CN(C=O)C>[N:2]1[NH:28][N:29]=[N:30][C:1]=1[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:14]([C:15]#[N:16])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=3[F:24])[N:12]=[C:11]3[NH:25][N:26]=[CH:27][C:10]=23)=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(-c2c(C#N)c(-c3ccc(O)cc3F)nc3[nH]ncc23)cc1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccc(O)cc2F)nc2[nH]ncc2c1-c1ccc(-c2nn[nH]n2)cc1
Temperature: 130 °C
Yield: 28.7 %

Procedure:
To a solution of 100 mg (0.28 mmol) of 4-(4-cyanophenyl)-6-(2-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile in 5 ml of anhydrous DMF are added 84 mg (1.12 mmol) of sodium azide and 305 μL (366 mg, 1.12 mmol) of tributyltin chloride. The mixture is heated to 130° C. under nitrogen for 8 h. Then 19 mg (0.28 mmol) of sodium azide and 77 μL (92 mg, 0.28 mmol) of tributyltin chloride are added, and the mixture is again heated to 130° C. for 48 h. After return to room temperature, the mixture is poured onto a water/ice mixture and acidified with a 6N HCl solution. The aqueous phase is extracted once with dichloromethane and twice with chloroform. The organic phase is washed with sodium chloride saturated solution, dried over sodium sulfate, filtered, and concentrated. The solid obtained is then purified by chromatography on silica (methanol gradient in dichloromethane: 15 to 25%) to give 0.032 g (29%) of 4-(4-(2H-tetrazole-5-yl)phenyl)-6-(2-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile in the form of beige crystals.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=2[C:10]#[N:11])=[CH:5][CH:4]=1.[OH:21]O.O>C(O)(=O)C>[CH3:1][S:2]([C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=2[C:10]#[N:11])=[CH:5][CH:4]=1)=[O:21]
Reactant: CSc1ccc(Oc2ccc([N+](=O)[O-])cc2C#N)cc1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To a slurry of 10.0 g (0.0350 moles) of 2-(4-(methylthio)phenoxy)-5-nitrobenzonitrile in 100 ml of glacial acetic acid was added a solution of 4.0 g of aqueous 30 percent (30%) hydrogen peroxide (0.0350 moles) dissolved in 20 ml of glacial acetic acid over 5 minutes. The reaction mixture was stirred at room temperature for 16 hrs and heated at 50° C. for 3 hrs. The reaction mixture was poured into water and the product collected by filtration, washed well with water and dried to obtain 9.8 g of product (92.8% yield). Recrystallization from ethanol afforded purified 2-(4-(methylsulfinyl)phenoxy)-5-nitrobenzonitrile, mp 159°-160° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][O:9][CH2:8][C:7]2=O.FC1C=CC=C2C=1OCCC2[NH2:24]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][O:9][CH2:8][CH:7]2[NH2:24]
Reactant: NC1CCOc2c(F)cccc21
Reactant: O=C1COCc2c(F)cccc21
Product: NC1COCc2c(F)cccc21

Procedure:
The title compound was prepared from 8-fluoro-1H-isochromen-4(3H)-one via the procedure described above for the synthesis of 8-fluorochroman-4-amine.
Reaction SMILES: [Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[S:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:29]=1)[NH:26][CH:25]=[CH:24]2.C([SiH](CC)CC)C>C(Cl)Cl>[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:29]=1)[NH:26][CH:25]=[C:24]2[CH:16]1[CH2:17][CH2:18][S:13][CH2:14][CH2:15]1
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Reactant: O=C1CCSCC1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(C3CCSCC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
TMSOTf (3.38 mL, 18.7 mmol) was added dropwise to a solution of tetrahydro-4H-thiopyran-4-one (2.17 g, 18.7 mmol) in DCM (100 mL) at 0° C. (bath temp) under nitrogen. A solution of ethyl 5-bromo-1H-indole-7-carboxylate (5 g, 18.7 mmol) in DCM (30 mL) was then added and the reaction was stirred for 30 min. Triethylsilane (4.47 mL, 28.1 mmol) was added and the reaction was allowed to warm to room temperature overnight. The reaction mixture was washed with saturated aqueous Na2CO3 (1×100 mL, and the organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was washed with MeOH, giving 4.92 g (72%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]3([CH3:26])[CH2:25][CH2:24]3)=[O:21])[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:27][C:28]([OH:30])=O.[NH:31]1[CH2:34][CH2:33][CH2:32]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:31]1([C:28](=[O:30])[CH2:27][C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][C@@H:11]3[CH2:13][C@@H:12]3[CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]4([CH3:26])[CH2:24][CH2:25]4)=[O:21])[CH2:18][CH2:19]3)=[CH:7][C:2]=2[F:1])[CH2:34][CH2:33][CH2:32]1
Reactant: CC1(OC(=O)N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)CC1
Reactant: C1CNC1
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: CN(C)C=O
Product: CC1(OC(=O)N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)c(F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2-fluoro-4-{2-[(1S,2R)-2-(1-{[(1-methylcyclopropyl)oxy]carbonyl}piperidin-4-yl)cyclopropyl]ethoxy}phenyl)acetic acid (100 mg, 0.238 mmol) in 1 ml anhydrous DMF at RT was added azetidine (16.3 mg, 0.286 mmol) and N,N-diisopropylethylamine (0.125 ml, 0.715 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (181 mg, 0.477 mmol) was added into the solution and stirred at RT for 4 hrs. The reaction mixture was filtered and purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 35-95% acetonitrile in 0.1% formic acid in water gradient) to give the title compound. LC/MS (m/z): 459.3 (M+H)+. GPR119 Human EC50: 3.3 nM
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:51]=[C:52]([Cl:54])[CH:53]=1)[O:31][C:32]1[C:33]([CH2:49][CH3:50])=[N:34][N:35]([CH2:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:36]=1[CH2:37]O>ClCCl>[Br:1][CH2:37][C:36]1[N:35]([CH2:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[N:34]=[C:33]([CH2:49][CH3:50])[C:32]=1[O:31][C:30]1[CH:29]=[C:28]([Cl:27])[CH:53]=[C:52]([Cl:54])[CH:51]=1
Reactant: BrBr
Reactant: CCc1nn(CCNC(=O)OC(C)(C)C)c(CO)c1Oc1cc(Cl)cc(Cl)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1nn(CCNC(=O)OC(C)(C)C)c(CBr)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
Bromine (16011,3.12 mmol) was added dropwise to a stirred solution of triphenylphosphine (820 mg, 3.12 mmol) and imidazole (213 mg, 3.12 mmol) in dichloromethane (15 ml) at room temperature under nitrogen. A solution of the alcohol of Example 135 (1.12 g, 2.60 mmol) in dichloromethane (5 ml) was then added to the reaction. The reaction was stirred at room temperature for 2 hours, diluted with dichloromethane (50 ml), washed with brine (20 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (98:2, by volume) to provide the title compound (969 mg) as a white foam.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15](=O)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1.[CH3:25][C:26]1[N:27]([C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH2:40])=[NH:39])=[CH:33][CH:32]=2)[CH:28]=[CH:29][N:30]=1>>[CH3:25][C:26]1[N:27]([C:31]2[CH:32]=[CH:33][C:34]([NH:37][C:38]3[N:39]=[C:15]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[C:3]4[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7][C:2]=4[N:40]=3)=[CH:35][CH:36]=2)[CH:28]=[CH:29][N:30]=1
Reactant: Cc1ccc(CC(=O)C2CN(C(=O)OC(C)(C)C)CCC2=O)cc1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Product: Cc1ccc(Cc2nc(Nc3ccc(-n4ccnc4C)cc3)nc3c2CN(C(=O)OC(C)(C)C)CC3)cc1
Yield: 44 %

Procedure:
tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenyl amino)-4-(4-methylbenzyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (236 mg, 44%) was synthesised from tert-butyl 4-oxo-3-(2-p-tolylacetyl)piperidine-1-carboxylate and 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (Example 41c) according to the general procedure for synthesis of pyrimidines. MS (ES+) m/z 511.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.C(Cl)Cl.[F:22][C:23]([F:35])([F:34])[C:24]1[CH:25]=[C:26]([CH2:30][C:31](Cl)=[O:32])[CH:27]=[CH:28][CH:29]=1.C(NCC)(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:31](=[O:32])[CH2:30][C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:34])([F:22])[F:35])[CH:25]=4)=[CH:13][CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: NCc1ccc(-c2cnc3cc(Cl)ccn23)cc1
Reactant: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Agent: CCNC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Cc1cccc(C(F)(F)F)c1)NCc1ccc(-c2cnc3cc(Cl)ccn23)cc1
Temperature: 40 °C

Procedure:
In a 40 mL septum capped vial purged with N2, add 4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-benzylamine (125 mg, 0.48 mmol), magnetic stir bar, CH2Cl2 (6 mL), cool the vial in an ice bath and slowly add 1 mL (CH2Cl2 solution of m-trifluoromethyl-phenylacetyl chloride, 0.48 mmol). Add isopropyl ethyl amine (0.8 mL) with THF (2 mL). Remove the vial from the ice bath and heat to 40° C. for 6 hours. Add a trace of MeOH and evaporate the solvents under vacuum and take up the oil into a minimal amount of CH2Cl2 and chromatograph using SiO2 eluting with a gradient of 0.5% to 5% of 2 M NH3 in MeOH with the balance CH2Cl2. Isolate the product, dry in a vacuum oven at 40° C. for 24 hours to give 144 mg (67%) MS (ES), m/z 444 (M+1).
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:19])[C:9]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:5][C:6]1[CH:7]=[C:8]([O:19][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)[C:9]([C:13]2[N:14]=[CH:15][CH:16]=[CH:17][N:18]=2)=[N:10][C:11]=1[CH3:12]
Reactant: Cc1cc(O)c(-c2ncccn2)nc1C
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3cc(C)c(C)nc3-c3ncccn3)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
Dimethyl sulfoxide (2.5 ml) was added to 5,6-dimethyl-2-pyrimidin-2-yl-pyridin-3-ol (50 mg), 4-chloro-6,7-dimethoxyquinoline (167 mg), and cesium carbonate (243 mg), and the mixture was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (54 mg, yield 55%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23]CC)=[O:22])=[C:15]([C:26]([F:29])([F:28])[F:27])[CH:14]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CCO.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[C:3]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[C:15]([C:26]([F:29])([F:28])[F:27])[CH:14]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(C)cc3ccccc23)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc2ccccc2c(Oc2ccc(/C=C/C(=O)O)c(C(F)(F)F)c2)c1-c1ccccc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
The saponification procedure described in Example 1 (Step 10) was followed. Ethyl (2E)-3-[4-[(3-methyl-2-phenyl-1-naphthalenyl)oxy]-2-(trifluoromethyl)phenyl]-2-propenoate (241) (0.070 g, 0.147 mmol) was dissolved in 1:1 THF:EtOH (6 mL). To the above mixture was added 1 N NaOH (1 mL, excess) at room temperature followed by heating at 70° C., with stirring, for 30 min. The reaction mixture was cooled at RT, subjected to standard work up and purification to afford 0.065 g (99%) of the title compound (242) as a white foam. IR (film) 3058, 1693, 1606, 1491, 1313, 1165, 1128 cm−1. 19F NMR (282.2 MHz, CD3OD): δ −60.98. 1H NMR (400 MHz, CD3OD): δ 7.91 (br d, J=8.0 Hz, 1H), 7.84 (d, J=16.0 Hz, 1H), 7.79 (s, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.52 (dd, J1=7.2 Hz, J2=7.2 Hz, 1H), 7.43 (dd, J1=7.6 Hz, J2=7.6 Hz, 1H), 7.28 (m, 3H), 7.15 (br s, 1H), 7.14 (s, 1H), 6.90 (s, 1H), 6.76 (d, J=8.4 Hz, 1H), 6.33 (d, J=16.0 Hz, 1H), 2.26 (s, 3H).
Reaction SMILES: [C:1]([C:9]([OH:11])=[O:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]([CH3:15])=[O:14].S(=O)(=O)(O)O>C(O)(=O)C>[C:2]1([C:1]2[C:9](=[O:10])[O:11][C:13]3([CH:15]=[C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:9](=[O:10])[O:14]3)[CH:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C1OC2(C=C1c1ccccc1)C=C(c1ccccc1)C(=O)O2
Temperature: 25 °C

Procedure:
Benzoylformic acid, 25 g, and 11.25 g of acetone in 30 g of acetic acid and 45 g of concentrated sulfuric acid were heated at 105° C.-110° C. for 1 hour. After the resulting mixture was cooled to ambient temperature, it was poured onto ice and the mixture was allowed to warm to room temperature. The suspended particles were recovered by filtration and recrystallized from ethanol to give 3,8-diphenyl-2,7-dioxo-1,6-dioxaspiro[4.4]nona-3,8-diene, m.pt. 235°-237° C., as white powder. Infrared and nuclear magnetic resonance spectra of the powder were consistent with this structure.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:19]2[CH2:31][C:22]3[NH:23][C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=4[C:21]=3[CH2:20]2)([F:18])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH2:17])[N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:32]([C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:41][O:40][C:38](=[O:39])[C:37]1[CH:42]=[CH:43][C:34]([CH2:32][NH:17][CH2:16][C:13]2[N:12]=[C:11]([C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])([CH:19]3[CH2:31][C:22]4[NH:23][C:24]5[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=5[C:21]=4[CH2:20]3)[F:18])[O:15][N:14]=2)=[CH:35][CH:36]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNCc2noc(C(F)(C3Cc4[nH]c5ccc(Cl)cc5c4C3)S(=O)(=O)c3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
To a stirred solution of 50 mg (0.1 mmol) of (RS,SR)-C-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-yl}-methylamine in 5 mL MeOH at 0° C. was added 19 mg (0.1 mmol, 1 eq) of methyl 4-formylbenzoate, 7 mg (0.1 mmol, leg) sodium cyanoborohydride and one drop of acetic acid. The reaction mixture was stirred at 0° C. for 20 minutes and then the temperature was raised to RT and the reaction quenched with saturated aqueous solution of NaHCO3. The reaction mixture was poured on water and extracted with EtOAc. The organic phase were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel (heptane/EtOAc 1:1) yielded 30 mg (45%) of (RS,SR)-4-[({5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-ylmethyl}-amino)-methyl]-benzoic acid methyl ester as a light yellow powder, MS: 609 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)#[N:27]>>[C:26]([C:28]1[CH:29]=[CH:30][C:31]([NH:34][C:35](=[O:36])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[CH:32][CH:33]=1)#[N:27]
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(C#N)cc4)cc3)cc2C1=O

Procedure:
The compound of example 39 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 4-cyanophenyl isocyanate. The compound of example 39 was used directly without isolation for the preparation of compound of example 40.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1(O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C)C=O.C(OCC)C>[C:1]1([NH:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:11]([O:13][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(C(=O)O)cc1Nc1ccccc1
Reactant: Oc1ccccc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(C(=O)Oc2ccccc2)cc1Nc1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
N,N′-Carbonyldiimidazole (0.41 g, 2.5 mmol) was added to a stirred solution of 3-(phenylamino)-4-methoxybenzoic acid (0.6 g, 2.5 mmol) in dimethylformamide (15 mL) under an inert atmosphere. After 30 minutes, the solution was heated to 50° C. for 1 hour, then phenol (0.24 g, 2.6 mmol) was added followed by diazabicycloundecene (0.40 g, 2.6 mmol) and heating at 50° C. was continued for 20 more hours. The mixture was allowed to cool and was then diluted with diethyl ether (100 mL) and washed successively with 2N HCl, water, 0.5N K2CO3, and saturated brine then dried over MgSO4. The solvent was removed under reduced pressure, and the residue was chromatographed on a column of silica gel in ethyl acetate to afford the product (0.27 g); m.p. 130-131° C. after recrystallization from acetonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]=[N:10][N:11]([CH2:13][Si](C)(C)C)[CH:12]=2)[N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[N:3]=1
Reactant: C[Si](C)(C)Cn1cc(-c2cccc(Br)n2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-6-{1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}pyridine (550 mg, 1.77 mmol) in THF (10 mL) was added TBAF (1.0 M in THF, 5.30 mL, 5.30 mmol). The reaction was stirred at room temperature for 2 h. It was subsequently diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (20-100% EtOAc/hexanes) afforded the title compound as a colorless solid.