Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:13][C:4]2([CH2:10][CH:9]3[C:11](=O)[CH:6]([CH2:7]C3)C2)[O:3][CH2:2]1.CC[N:16]([CH2:19][CH3:20])[CH2:17]C.CN.[BH4-].[Na+]>C1COCC1.CO.Cl[Ti](Cl)(Cl)Cl>[CH2:2]1[O:3][C:4]2([CH:10]3[CH2:9][CH2:11][CH:6]2[CH2:7][CH:19]([NH:16][CH3:17])[CH2:20]3)[O:13][CH2:1]1
Reactant: CCN(CC)CC
Reactant: O=C1C2CCC1CC1(C2)OCCO1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CN
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Product: CNC1CC2CCC(C1)C21OCCO1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of bicyclo[3,2,1]octane-3,8-dione8-ethylene ketal (53.1 mg, 0.27 mmol, 1.0 eq.) in THF (1.0 mL) at 0° C. was added Et3N (0.11 mL, 2.9 eq.) followed by MeNH2 (2.0 M in THF, 0.21 mL, 1.5 eq.). After stirring at room temperature for 5 minutes, TiCl4 (0.30 mL, 10.0 eq.) was introduced dropwise and the resulting mixture was stirred at 0° C. for 45 minutes. A solution of NaBH4 (53.1 mg, 5.1 eq.) in MeOH (2.0 mL) was then introduced and the resulting mixture was stirred at 0° C. for 1 h. The reaction was quenched with saturated NaHCO3 and the separated aqueous layer was extracted with 3×EtOAc. The combined organic phase was dried over MgSO4, filtered and concentrated to give the crude product, 3-methylamino-bicyclo[3,2,1]octan-8-one ethylene ketal (24.1 mg).
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=O)[CH2:18]Br)=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Br:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]2[C:9]3=[C:10]4[C:5]([C:6](=[O:11])[CH2:7][CH2:8]3)=[CH:4][CH:3]=[CH:2][N:1]4[CH:18]=2)=[CH:15][CH:14]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: O=C1CCCc2ncccc21
Solvent: Cc1ccccc1
Product: O=C1CCc2c(-c3ccc(Br)cc3)cn3cccc1c23
Temperature: 25 °C

Procedure:
5,6,7,8-Tetrahydroquinolin-5-one (20 g) was dissolved in 500 ml of toluene. To this solution was added 4-bromophenacyl bromide (37.8 g) gradually and refluxed for 18 hours. The reaction mixture was cooled to room temperature, and depositing solids were collected by filtration (33 g). These crystals were dissolved in 300 ml of N,N-dimethylformamide. To this solution was added, molecular sieves 3A (15 g) and triethylamine (13 ml), and the reaction mixture was heated at 100 ° C. for 1 hour. The reaction mixture became dark brown. The dark brown solution that obtained after removing insoluble matter by filtration was concentrated under reduced pressure. To the residue was added 300 ml of water and extracted with 200 ml of methylene chloride three times. The methylene chloride solution was washed with 100 ml of brine and dried over anhydrous sodium sulfate. The dark brown solution that obtained after removing drying agent by filtration was concentrated under reduced pressure, the resultant dark brown residue was purified by alumina column chromatography. The title compound was obtained as dark brown crystals (12 g).
Reaction SMILES: [OH-].[Li+].O.C([O:6][P:7]([CH2:16][C@@H:17]([OH:29])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[O:8])C>C(O)C>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[Cl:27])[CH2:20][NH:19][CH2:18][C@H:17]([OH:29])[CH2:16][P:7]([CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])(=[O:6])[OH:8]
Reactant: CCOC(OCC)P(=O)(C[C@@H](O)CNCc1ccc(Cl)c(Cl)c1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(OCC)P(=O)(O)C[C@@H](O)CNCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.254 g of lithium hydroxide and 6 ml of water are added to a solution of 2.26 g of 3-[N-(3,4-dichlorobenzyl)amino]-2(S)-hydroxy-propyl(diethoxymethyl)-phosphinic acid ethyl ester in 3 ml of ethanol and the mixture is stirred at 60° for 24 hours. The mixture is allowed to cool to room temperature, adjusted to pH 7 with aqueous phsophoric acid and concentrated to dryness by evaporation. The evaporation residue is made into a slurry in hot methanol and filtered. The filtrate is concentrated to dryness by evaporation and the glassy evaporation residue is taken up in a small amount of ethanol. The pH value is adjusted to pH 1 with ethanolic hydrochloric acid and the solvent is removed. Crystallisation from acetonitrile yields 3-[N-(3,4-dichlorobenzyl)amino]-2(S)-hydroxy-propyl(diethoxymethyl)phosphinic acid; [α]20D =-10.8°±1.7° (c=0.595 in methanol); 1H-NMR (CD3OD): δ=7.76 (1H,m), 7.61 (1H,m), 7.45 (1H,m), 4.46 (1H,d), 4.29 (1H,m), 4.20 (2H,m) 3.80 (2H,m), 3.69 (2H,m), 3.25 (1H,dd), 3.02 (1H,d,d), 2.04 (1H,dd), 1.87 (1H,d,d); 1.20 (6H,t).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:10].[C:18](N1C=CN=C1)([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:19].CCOCC.O>C(Cl)Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[O:19])=[C:3]([C:9](=[O:10])[C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccc(Br)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(c1ccc(Br)cc1)c1cc(Cl)ccc1NC(=O)n1ccnc1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl [2-(4-bromobenzoyl)-4-chlorophenyl]carbamate (10 g, 25 mmol) in MeOH (50 mL) at 25° C. was added 2 M HCl-MeOH (100 ml), and the reaction mixture stirred for 4 h. The organic layer was evaporated, then the residue was partitioned between CH2Cl2 (300 ml) and water (200 ml). The organic layer was washed with 10% Na2CO3 (to pH=9) and brine, dried over Na2SO4 and evaporated to give 7.5 g (98% yield) (2-amino-5-chlorophenyl)(4-bromophenyl)methanone. To a solution of (2-amino-5-chlorophenyl)(4-bromophenyl)methanone (13 g, 42 mmol) in 500 ml CH2Cl2 was added solid carbonyldiimidazole (15.7 g, 96 mmol) portionwise. The resulting yellow solution was allowed to stir at 40° C. for 16 hrs, concentrated to give a yellow foam. The foam was treated with 30 ml of ether and 20 ml of water with vigorous stirring resulting in a solid precipitate. After filtration, the cake was recrystallized from CH2Cl2/Ether (1:5) to give N-[4-chloro-2-(4-bromobenzoyl)phenyl]-1H-imidazole-1-carboxamide as a yellow solid. 1HNMR: (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.55 (dd, J=8.4, 1.6 Hz, 1H), 7.33 (s, 1H), 6.98˜7.10 (m, 5H), 6.71 (d, J=2.0 Hz, 1H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]=1[C:13]1[CH:27]=[C:26]([Br:28])[CH:25]=[CH:24][C:14]=1[C:15]([N:17](C(C)C)C(C)C)=[O:16].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Br:28][C:26]1[CH:25]=[CH:24][C:14]2[C:15]([OH:16])=[N:17][C:2]3[C:3]([C:13]=2[CH:27]=1)=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:5]=[CH:6][CH:7]=3
Reactant: CCCCOc1nccc(N)c1-c1cc(Br)ccc1C(=O)N(C(C)C)C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOc1nccc2nc(O)c3ccc(Br)cc3c12
Reaction time: 2 h

Procedure:
To a solution of 2-(4-amino-2-butoxypyridin-3-yl)-4-bromo-N,N-diisopropylbenzamide (8.5 g, 19.0 mmol) in THF (135 mL) was added sodium bis(trimethylsilyl)amide (38 mL, 38 mmol, 1.0 M in THF) dropwise at 0° C. under nitrogen. The solution was allowed to stir for 2 hr then quenched with water. The solid precipitate was filtered, collected, and dried under vacuum to afford 9-bromo-1-butoxybenzo[c]-1,6-naphthyridin-6-ol as a white solid. 1H NMR (600 MHz, CD6SO) δ 9.22 (s, 1H), 8.2 (d, 1H), 8.05 (d, 1H), 7.78 (d, 1H), 6.92, (d, 1H), 4.45 (t, 2H), 1.86 (m, 2H), 1.59 (m, 21-1), 1.0 (t, 3H). LRMS (ESI) calc'd for (C16H15BrN2O2) [M+H]+, 347.0; found 347.0.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:16][C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(COC)OC>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]2[CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:1]=[C:2]2[CH:11]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: COc1ccc2c(Cl)cc(N)nc2c1
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(cc(Cl)c3ccc(OC)cc32)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.3 g of 2-amino-4-chloro-7-methoxyquinoline were dissolved in 20 ml of dimethoxyethane and 1.3 g of ethyl bromopyruvate were added thereto. The mixture was stirred at room temperature for 2 hours and the crystalline intermediate thus formed was filtered off, washed with ether and then was dissolved in 20 ml of ethanol. The resultant solution was refluxed for 3 hours and ethyl 5-chloro-8-methoxyimidazo-[1,2-a]-quinoline-2-carboxylate melting at 215°-216° C. was isolated by the procedure of Example 9.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:35])[C:18]([OH:34])([C:23]3[CH:33]=[CH:32][C:26]4[N:27]([CH3:31])[C:28](=[O:30])[O:29][C:25]=4[CH:24]=3)[C:19]([F:22])([F:21])[F:20])=[C:13]([Cl:36])[CH:12]=2)=[CH:7][C:6]=1[F:37])=[O:4].[Li+].[OH-].O>C1COCC1>[Cl:36][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[C:6]([F:37])[CH:7]=2)[CH:16]=[CH:15][C:14]=1[CH:17]([CH3:35])[C:18]([OH:34])([C:23]1[CH:33]=[CH:32][C:26]2[N:27]([CH3:31])[C:28](=[O:30])[O:29][C:25]=2[CH:24]=1)[C:19]([F:22])([F:20])[F:21]
Reactant: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4c(c3)oc(=O)n4C)C(F)(F)F)c(Cl)c2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccc(-c2ccc(C(=O)O)c(F)c2)cc1Cl)C(O)(c1ccc2c(c1)oc(=O)n2C)C(F)(F)F
Temperature: 25 °C
Yield: 22.2 %

Procedure:
3′-Chloro-3-fluoro-4′-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-6-yl)-propyl]-biphenyl-4-carboxylic acid methyl ester (60 mg, obtained in Example 134, step 1) was dissolved in THF (4 mL) followed by the addition of aqueous LiOH solution (1.0M, 0.145 mL). The mixture was stirred over night at r.t. The reaction mixture was poured into water and extracted with ethyl acetate. The aqueous phase was acidified with 2 M aqueous HCl to pH 1 and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, CH2Cl2:MeOH=7:3 to 1:1) to give the title compound as a brown solid (13 mg, 22%). MS (neg. ion, m/e)=522.2 [(M−H)−].
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][CH2:8][CH2:9][CH2:10][S:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[Cl-].[Na+]>CO>[Cl:7][CH2:8][CH2:9][CH2:10][S:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOC(=O)CSCCCCl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CS(=O)CCCCl
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 95.6 %

Procedure:
To 4 ml of an aqueous solution of 0.39 g of sodium metaperiodate was added 3 ml of a methanol solution of 0.30 g of ethyl [(3-chloropropyl)thio]acetate obtained in Reference Example 1. The mixture was stirred at room temperature for 100 minutes To the reaction mixture was added 30 ml of a saturated aqueous sodium chloride solution followed by extraction with ethyl acetate The extract was dried over anhydrous magnesium sulfate The solvent was then distilled off. The residue was applied to silica gel column chromatography. Elution with a solvent mixture of hexaneethyl acetate (1:3) gave 0.31 g of ethyl (3-chloropropylsulfinyl)acetate.
Reaction SMILES: [Na+].[S:2]([O-:16])(=[O:15])([C:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7]([NH2:8])=[CH:6][CH:5]=1)=[O:3]>O>[S:2]([OH:16])(=[O:15])([C:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7]([NH2:8])=[CH:6][CH:5]=1)=[O:3]
Reactant: Nc1ccc(S(=O)(=O)[O-])c2ccccc12
Agent: [Na+]
Solvent: O
Product: Nc1ccc(S(=O)(=O)O)c2ccccc12

Procedure:
In a large beaker, add naphthionic acid sodium salt and water and stir to complete solution, pH=9.2-9.4. Slowly add hydrochloric acid, and white precipitation occurs at pH=2.2-2.4. Stir the slurry for at least 4 hours, then filter the slurry. Use the wetcake in Stage 2.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[C:12]([OH:14])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[I:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[C:12]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([I:25])=[CH:27][CH:28]=2)=[O:14])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Nc1ccc(I)cc1
Reactant: CC(C)(C)c1ccc(C(Cc2ccc([N+](=O)[O-])cc2)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(Cc2ccc([N+](=O)[O-])cc2)C(=O)Nc2ccc(I)cc2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
To 2-(4-tert-Butyl-phenyl)-3-(4-nitro-phenyl)-propionic acid (4.58 g, 14 mmol) in 100 ml toluene was added 4-iodoaniline (3.37 g, 15.4 mmol), N,N′-dicyclohexyl-carbodiimide (3.2 g, 15.4 mmol), and 4-dimethylaminopyridine (171 mg, 1.4 mmol). The reaction mixture was stirred at 100° C. for 16 h, and was filtered. The filtrate was concentrated and chromatography of the residue (10% ethyl acetate in hexane) afforded 2-(4-tert-Butyl-phenyl)-N-(4-iodo-phenyl)-3-(4-nitro-phenyl)-propionamide as a grey powder (3 g, 41%). 1HNMR (CDCl3) δ 8.06-8.09 (2H, d, J=8.8 Hz), 7.56-7.59 (2H, d, J=8.5 Hz), 7.36-7.39 (2H, d, J=8.2 Hz), 7.27-7.30 (2H, m), 7.17-7.26 (4H, m), 6.95 (1H, s), 3.67-3.75 (2H, m), 3.08-3.17 (1H, m), 1.32 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][C:4](=[O:16])[C:3]=1[S:17][CH2:18][C:19]([O:21]CC)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:10]1([CH2:9][S:8][C:6]2[NH:7][C:2]3[NH:1][C:19](=[O:21])[CH2:18][S:17][C:3]=3[C:4](=[O:16])[N:5]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)CSc1c(N)[nH]c(SCc2ccccc2)nc1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1CSc2c([nH]c(SCc3ccccc3)nc2=O)N1

Procedure:
To a solution of the product from step b) (0.30 g) in dry toluene (60 ml) was added p-toluene sulphonic acid (50 mg) and the solution heated under reflux for 11 hours. The resultant solid was collected by filtration, washed with ether and dried to give the subtitle compound as a colourless solid (0.290 g)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.CCN(C(C)C)C(C)C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:25][N:26]=[C:27]=[O:28].[N-]=C=O>CN1C(=O)CCC1.CN(C1C=CN=CC=1)C>[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:25][NH:26][C:27](=[O:28])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1csc(N)n1
Agent: CN(C)c1ccncc1
Agent: [N-]=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Temperature: 160 °C

Procedure:
The commercial starting material ethyl 2-aminothiazole-4-carboxylate (2 mmol) was dissolved in NMP and DIEA (1 equivalent) was added followed by addition of the 3,4-dichloro-benzyl isocyanate (1 equivalent). Add 5% DMAP. Heat at 160° C. under microwave irradiation for 30 min Added additional isocyanate reagent (1.0 eq) and microwave for another 30 minutes at 160° C. to obtain ethyl 2-(3-(3,4-dichlorobenzyl)ureido)thiazole-4-carboxylate in >90% conversion.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.F[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccccn1
Reactant: CC(=O)NC(C)c1cc2ccc(CCc3ccc(O)cc3)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)NC(C)c1cc2ccc(CCc3ccc(Oc4ccccn4)cc3)cc2o1
Yield: 34.7 %

Procedure:
N-(1-{6-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (40.0 mg, 0.123 mmol) obtained in Example 165, 2-fluoropyridine (0.0369 mL, 0.371 mmol) and potassium carbonate (51.3 mg, 0.371 mmol) were stirred in DMSO (0.5 mL) at 100° C. for 2 days. The reaction mixture was purified by basic silica gel column chromatography (hexane:ethyl acetate=1:0 to 2:3), and the solvent was evaporated. The residue was triturated with a small amount of diisopropyl ether to give the title compound (17.1 mg, yield 35%) as a white solid.
Reaction SMILES: [OH-].[Na+].S[C:4]1[S:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.Br[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(Cl)(Cl)Cl>O.C(O)C.C(O)(C)C.CCCCCC>[CH3:20][C:14]([C:4]1[S:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)([CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Sc1nc2ccccc2s1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)(C)c1nc2ccccc2s1
Reaction time: 8 h

Procedure:
3.8 grams of sodium hydroxide was dissolved in 50 ml water. The solution was cooled and to this cooled solution was added 50 ml ethanol. 15 grams of 2-mercaptobenzothiazole was added and the solution diluted with 25 ml ethanol and 25 ml water. Following the addition of 17.5 grams of ethyl 2-bromoisobutyrate the mixture was stirred overnight. The reaction mixture was then concentrated in vacuo and the residue partitioned between ether and water. The ether fraction was washed, (H2O and aqueous Na2CO3) dried (MgSO4), filtered and concentrated in vacuo. This mixture was then partitioned between ether and 10% sodium hydroxide. The ether fraction was washed with 2×25 ml 10% sodium hydroxide and then brine. The ether layer was then dried (MgSO4), filtered, and concentrated to yield a solid which was shown by TLC (CHCl3 and 3% isopropanol/hexane) and 1H NMR to be the titled compound. (b) 2-methyl-2-(2-benzothiazolyl)propionic acid
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14]2([C:27]([O:29]CC)=[O:28])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+].C1COCC1>CO>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C:14]([CH2:13][S:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:7][CH:8]=2)([C:27]([OH:29])=[O:28])[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC#CCOc1ccc(SCC2(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(SCC2(C(=O)O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 893.4 %

Procedure:
A mixture of 0.288 g (0.0643 mmol) of 1-(tert-butyl) 4-ethyl 4-({[4-(2-butynyloxy) phenyl]sulfanyl}methyl)-1,4-piperidinedicarboxylate, 3.25 mL of 1N NaOH 3.25 mL of THF and 3.25 mL of MeOH was heated to reflux for 3 h. The organics were removed and the residue was diluted with H2O, acidified and extracted with EtOAC. The organics were washed with H2O, brine, dried over mgSO4, filtered and concentrated in vacuo to provide 0.241 g (89%) of the desired product as an off white gum. Electrospray Mass Spec: 464.3 (M+FA−H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=O)[CH:5]=[CH:4][N:3]=1.Cl[C:20]1[N:25]=[C:24](/[CH:26]=[C:27](\[C:29]2C=C(C=CC=2)C#N)/O)C=C[N:21]=1.C1C(=O)N(Br)C(=O)C1.NC1C=CC=CN=1>C(Cl)Cl.CCOC(C)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[N:25]3[CH:24]=[CH:26][CH:27]=[CH:29][C:20]3=[N:21][C:9]=2[C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1cccc(C(=O)Cc2ccnc(Cl)n2)c1
Reactant: N#Cc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1
Agent: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: N#Cc1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Temperature: 0 °C
Yield: 75 %

Procedure:
A mixture of tautomers, 3-[(2-chloro-4-pyrimidinyl)acetyl]benzonitrile and 3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]benzonitrile, (1.56 g, 6.05 mmol) was dissolved in 100 mL of DCM with stirring and cooled to 0° C. NBS (1.08 g, 6.07 mmol) was added and the reaction was allowed to warm to rt. The reaction was stirred for one hour and concentrated in vacuo. The residue was dissolved in dioxane with stirring. 2-Aminopyridine (1.71 g, 18.2 mmol) was added, and the reaction was heated to 60° C. The reaction was stirred overnight and cooled to rt. The reaction was poured into H2O and EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with DCM (2×) and EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography, and fractions containing product were concentrated in vacuo. The residue was triturated with diethyl ether and hexanes (˜1:1), filtered, and the solid was washed with diethyl ether and hexanes (˜1:1). The solid was collected to provide 1.50 g (75%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J=7.0 Hz, 1H), 8.60 (d, J=5.3 Hz, 1H), 8.14 (s, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.67 (t, J=7.9 Hz, 1H), 7.59 (dd, J=6.8, 1.1 Hz, 1H), 7.31-7.17 (m, 2H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][C:10]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S-:30][C:31]#[N:32].[K+]>C(O)(=O)C>[CH2:1]([N:8]1[C:9]2[C:10](=[CH:11][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:13][CH:14]=2)[C:19]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=2)=[N:32][C:31]1=[S:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCOc1ccc(NCc2ccccc2)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(=O)O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=S)n2Cc1ccccc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 16.1 %

Procedure:
To a solution of 140 mg (0.365 mmol) (2-benzylamino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone in 5 ml acetic acid is added 68 mg (0.695 mmol) potassium thiocyanate. The reaction is stirred for two days at 60° C. The solvent is removed and the residue is extracted with water/dichloromethane. After evaporation of the organic phase the crude product is purified by flash-chromatography (MeOH/CH2Cl2, 1:9) to give 25 mg (16%) of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(C(Cl)=O)=O.[NH2:24][C:25]1[C:26]([F:33])=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[CH3:31].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C1COCC1.O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([NH:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[C:27]([OH:32])[C:26]=1[F:33])=[O:6]
Reactant: O=C(O)c1cc(-c2cccc(F)c2)ccc1F
Reactant: Cc1ccc(O)c(F)c1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(O)c(F)c1NC(=O)c1cc(-c2cccc(F)c2)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
To a mixture of 2 fluoro-5-(3-fluorophenyl) benzoic acid (intermediate III(a)) (730 mg, 3.1 mmol, 1.1 eq) and (COCl)2 (1.1 g, 8.49 mmol, 3 eq) in DCM (20 mL) was added DMF (5 drops). The reaction mixture was stirred at 0° C. for 1h and then concentrated in vacuo. The residue obtained was dissolved in THF (5 mL) and added dropwise to a solution of 3-amino-2-fluoro-4-methyl-phenol (400 mg, 2.83 mmol, 1 eq) 25 and NaHCO3 (951 mg, 11.3 mmol, 4 eq) in THF (15 mL) at 0° C. After the addition, the reaction mixture was stirred at room temperature for 3h. The resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:4) to give the title compound as a yellow solid (600 mg, 60%).