Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26](=O)[NH:27][CH:28]=1>COCCOC>[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[N:27][CH:28]=1
Reactant: O=c1ccc(F)c[nH]1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Solvent: COCCOC
Product: N#Cc1ccc(N(CCOc2ccc(F)cn2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 27B from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 15B) and 5-fluoro-2(1H)-pyridinone, using dry DME as the reaction solvent: MS (APCI) m/z 408 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][O:10][C:11]2[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=2[CH3:20])=[C:4]([O:21][CH:22]([CH3:24])[CH3:23])[CH:3]=1.[CH:25]([C:28]1[C:36]2[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][C:31]=2[NH:30][N:29]=1)([CH3:27])[CH3:26].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:22]([O:21][C:4]1[C:5]([CH2:9][O:10][C:11]2[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=2[CH3:20])=[C:6]([CH3:8])[N:7]=[C:2]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:36]=2[C:28]([CH:25]([CH3:27])[CH3:26])=[N:29][NH:30]3)[CH:3]=1)([CH3:24])[CH3:23]
Reactant: Cc1ccc(C(C)C)cc1OCc1c(OC(C)C)cc(Cl)nc1C
Reactant: CC(C)c1n[nH]c2cccc(B(O)O)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(C)C)cc1OCc1c(OC(C)C)cc(-c2cccc3[nH]nc(C(C)C)c23)nc1C
Temperature: 100 °C

Procedure:
A mixture of 6-chloro-4-isopropoxy-3-(5-isopropyl-2-methyl-phenoxymethyl)-2-methyl-pyridine (185 mg, 0.53 mmol), 3-isopropyl-1H-indazole-4-boronic acid (109 mg, 0.53 mmol), Pd(PPh3)4 (31 mg, 0.027 mmol), and Na2CO3 (169 mg, 1.6 mmol) in dioxane (8 mL) and water (2 mL) is heated for 24 hours at 100° C. The mixture is poured into water and extracted with EtOAc. The combined extract are dried (Na2SO4) and concentrated in vacuo. The residue is purified by flash chromatography (elution with MeOH/CH2Cl2 1:10) to yield 4-[4-isopropoxy-5-(5-isopropyl-2-methyl-phenoxymethyl)-6-methyl-pyridin-2-yl]-3-isopropyl-1H-indazole. 1H NMR (CDCl3) 9.95 (br s, 1H), 7.45 (d, 1H), 7.39 (t, 1H), 7.13 (d, 1H), 7.09 (d, 1H), 6.92 (m, 2H), 6.78 (d, 1H), 5.20 (s, 2H), 4.68 (m, 1H), 3.19 (m, 1H), 2.88 (m, 1H), 2.64 (s, 3H), 2.20 (s, 3H), 1.99 (d, 6H), 1.24 (d, 6H), 1.11 (d, 6H). LCMS (m/z): 472.63 (MH)+
Reaction SMILES: O[CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)(=O)C.CCCCCC>[NH:23]([CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:18])([CH3:17])[CH3:19])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccccc1
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2Nc1ccccc1
Yield: 79 %

Procedure:
Using N-(3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 235 and aniline, the title compound was synthesized in the same manner as in Example 297. Yield: 79%. Melting point: 151-152° C. (ethyl acetate-hexane).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[C:19]([C:21]#[N:22])[C:18]3[N:23]=[N:24][N:25]([CH3:26])[C:17]=3[CH:16]=2)=[CH:11][C:10]=1[C:27]([F:30])([F:29])[F:28])(=O)=O.[CH3:31][C:32]1[N:37]=[C:36]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:35]=[CH:34][CH:33]=1>CN1CCCC1>[CH3:26][N:25]1[C:17]2[CH:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:41]4[CH2:42][CH2:43][N:38]([C:36]5[CH:35]=[CH:34][CH:33]=[C:32]([CH3:31])[N:37]=5)[CH2:39][CH2:40]4)=[C:10]([C:27]([F:28])([F:29])[F:30])[CH:11]=3)[N:20]=[C:19]([C:21]#[N:22])[C:18]=2[N:23]=[N:24]1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCOS(C)(=O)=O)c(C(F)(F)F)c3)cc21
Reactant: Cc1cccc(N2CCNCC2)n1
Agent: CN1CCCC1
Product: Cc1cccc(N2CCN(CCOc3ccc(-c4cc5c(nnn5C)c(C#N)n4)cc3C(F)(F)F)CC2)n1
Temperature: 150 °C
Yield: 7.4 %

Procedure:
A mixture of 2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl methanesulfonate (0.15 g) and 1-(6-methylpyridin-2-yl)piperazine (0.361 g) in N-methylpyrollidine (2 ml) was heated at 150° C. under microwave condition for 30 minutes. Solvent removed under vacuum and residue dissolved in methanol (1 ml) and purified by basic prep HPLC to give methyl-6-(4-(2-(4-(6-methylpyridin-2-yl)piperazin-1-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (0.0132 g). 1H NMR (MeOD) δ: 8.45 (m, 3H), 7.43 (m, 2H), 6.57 (m, 2H), 4.46 (s, 3H), 4.41 (m, 2H), 3.35 (m, 3.35), 2.97 (m, 2H), 2.78 (m, 4H), 2.35 (s, 3H). MS m/z 523.2 (M+H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:25])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1)[CH3:3].C(N(C(C)C)C(C)C)C.[Br:35][CH2:36][C:37](Br)=[O:38]>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:25])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][N:16]1[C:37](=[O:38])[CH2:36][Br:35])[CH3:3]
Reactant: CCOC(=O)COc1ccc(F)cc1C1NCCc2ccccc21
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(F)cc1C1c2ccccc2CCN1C(=O)CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution under N2 of (±)-[4-fluoro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (2.0 g, 5.2 mmol, 1.0 eq.) in DCM (13 mL), N-ethyldiisopropylamine (2.7 mL, 15.6 mmol, 3.0 eq.) was added. A solution of bromoacetyl bromide (0.5 mL, 5.7 mmol, 1.1 eq.) in DCM (5 mL) was added dropwise. The cooling bath was removed and the brown solution stirred at r.t. for 2 hours. The solution was diluted with AcOEt (170 mL), washed with sat. aq. NaHCO3 soln. (1×90 mL), with sat. aq. NaCl soln. (1×90 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash master (column: 100 g, flow: 35 mL/min, heptane to heptane+AcOEt) to yield the title compound as a brown oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][C@@H:19]3[CH2:23][CH2:22][N:21]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:20]3=[O:30])=[C:13]([Cl:31])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>C1COCC1>[Cl:31][C:13]1[CH:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)[CH:16]=[C:15]([Cl:17])[C:14]=1[CH2:18][C@@H:19]1[CH2:23][CH2:22][N:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:20]1=[O:30]
Reactant: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCCCC4)C3=O)c(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCCCC4)C3=O)c(Cl)c2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 93.3 %

Procedure:
Treat a solution of (R)-3′,5′-dichloro-4′-(2-oxo-1-piperidin-1-yl-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid methyl ester (0.21 g) in THF (10 mL) with 5N NaOH (1 mL) and stir at 60° C. for 12 hours. Partition the mixture between ethyl acetate and water. Dry the organic layer (Na2SO4) and remove the solvent in vacuo to afford 0.19 g (93%) of the title compound. MS (m/z): 447 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:35])[N:27]3[C:30]([O:32][CH2:33]Cl)=[O:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.[C:36]([OH:41])(=[O:40])[CH2:37][CH2:38][CH3:39].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:35])[N:27]3[C:30]([O:32][CH2:33][O:41][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])=[O:31])=[CH:22][CH:21]=2)[CH2:13][CH2:14]1
Reactant: CCCC(=O)O
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(=O)OCOC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of chloromethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (1.20 g, 2.22 mmol) in dimethyl formamide (20 mL) was added butyric acid (0.30 mL, 3.33 mmol) followed by cesium carbonate (542 mg, 1.67 mmol). The reaction was then stirred at ambient temperature overnight. The reaction was diluted with ethyl acetate (50 mL) and quenched with water/brine (1:1, 50 mL). The reaction was extracted with ethyl acetate (3×50 mL). The combined organics were washed with water (50 mL) then brine (50 mL) and dried (MgSO4) and concentrated. The crude product was purified by column chromatography on silica eluting with 010% tetrahydrofuran/dichloromethane with 1% Et3N to give the product which required further purification. The product was purified by column chromatography on silica eluting with 0.51.5% Et3N/ethyl acetate to give butyryloxymethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate, Compound-88 (348 mg, 26% over 2 steps).
Reaction SMILES: C([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17](O)=O)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][C:28]([NH2:30])=[N:27][C:26]=2[CH:31]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][C:28]([NH:30][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:20])[S:12][CH:13]=3)=[N:27][C:26]=2[CH:31]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Reactant: Nc1nc2cc(Cl)ccc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCNc2nc3cc(Cl)ccc3o2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound obtained using {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid synthesized in Example 3 and 5-chloro-1,3-benzoxazol-2-amine as starting materials and by operations similar to those of Example 242-1 and Example 242-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=20:1). Ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (the objective compound was extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:8]1[S:9][C:10]2[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: Cc1nc2cccc(Cl)c2s1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc2nc(CBr)sc12
Temperature: 25 °C
Yield: 6.2 %

Procedure:
A mixture of 900 mg (4.9 mmol) of 7-chloro-2-methyl-1,3-benzothiazole (16-4), 1.13 g (6.37 mmol) of N-bromosuccinimide and 47 mg (0.196 mmol) of benzoyl peroxide in CCl4 (25mL) was refluxed under irradiation by a UV lamp for 4 hours. After this time the reaction was cooled to room temperature and the insolubles were filtered off. The reaction was purified on a silica column eluted with EtOAc:hexanes (3:97 to 1:1) and 80 mg of the desired product 16-5 was isolated. HRMS: measured 261.9080; theoretical 261.9087. 1H NMR (CDCl3): 4.80 (s, 2H), 7.43 (m, 2H), 7.92 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.N1C=CC=CC=1.C(O)(=O)C(O)=O.[F:53][C:54]1[CH:59]=[CH:58][C:57]([CH:60]2[CH2:64][CH2:63][NH:62][CH2:61]2)=[CH:56][CH:55]=1>C(#N)C>[F:53][C:54]1[CH:55]=[CH:56][C:57]([CH:60]2[CH2:64][CH2:63][N:62]([C:14]([C:10]3[CH:11]=[N:12][O:13][C:9]=3[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=3)=[O:16])[CH2:61]2)=[CH:58][CH:59]=1
Reactant: Fc1ccc(C2CCNC2)cc1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)C(=O)O
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCC(c2ccc(F)cc2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 16.5 %

Procedure:
5-[4-(Trifluoromethyl)phenyl]isoxazole-4-carboxylic acid (30 mg, 0.12 mmol) was dissolved in acetonitrile (1.5 mL) followed by the addition of o-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (52 mg, 0.16 mmol), pyridine (60 μL, 0.72 mmol) and 3-(4-fluorophenyl)pyrrolidine oxalate (36 mg, 0.14 mmol), and stirred at 60° C. for 2 h. The residue was purified on reversed phase HPLC to yield the title compound (8 mg). HRMS (ESI, pos. ion) m/z calcd for C21H16F4N2O2: 404.1148, found 404.1152.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([OH:14])[CH:8]=2)([O-:3])=[O:2].[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[CH2:17]([O:14][C:9]1[CH:8]=[C:7]2[C:12]([CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[N:6]2)=[CH:11][CH:10]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cnc2cc(O)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.3 %

Procedure:
In DMF (75 mL) was dissolved 3-nitro-7-hydroxyquinoline (5.0 g, 26.2 mmol.). Under chilling with ice, to the solution was added sodium hydride (1.15 g, 29 mmol.). After 20 minutes, benzyl bromide (3.4 mL, 29 mmol.) was further added for 10 minutes. The mixture was then stirred overnight at room temperature. After the completion of reaction was confirmed, the mixture was poured into a mixture of ice and water. The precipitated crystalline product was collected by filtration, washed with water, and dried, to give the desired compound (7 g) as a white crystalline product (yield 95%).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[C:37]1([S:43]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:37]1([S:43]([N:46]2[CH2:51][CH2:50][N:49]([CH2:6][C:7]3[N:12]=[CH:11][C:10]4[N:13]=[CH:14][N:15]([C:16]5[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=6[C:30]([F:31])([F:32])[F:33])[CH3:23])[CH:20]=5)[C:9]=4[CH:8]=3)[CH2:48][CH2:47]2)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Reactant: O=S(=O)(c1ccccc1)N1CCNCC1
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CN4CCN(S(=O)(=O)c5ccccc5)CC4)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
100 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate are dissolved in 2.5 ml dichloromethane. Under N2 atmosphere benzenesulfonyl piperazine (209 mg) is added. The reaction mixture is stirred at 40° C. for 1 hour and then concentrated to dryness under vacuum. The residue is purified by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 97/3 to 0/100 (v/v)) to obtain the title product.
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([NH2:22])[CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:23])[CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1.CCOCC>[CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([NH:22][S:25]([CH3:24])(=[O:27])=[O:26])[CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:23])[CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2cn(C)c3c(N)cccc23)CCc2cc(F)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCC1(c2cn(C)c3c(NS(C)(=O)=O)cccc23)CCc2cc(F)ccc21
Yield: 84.8 %

Procedure:
Dissolve 3-(1-ethyl-5-fluoro-indan-1-yl)-1-methyl-1H-indol-7-ylamine (0.18 g, 0.58 mmol) in pyridine (3 ml). Add methanesulfonyl chloride (0.05 ml, 0.70 mmol, 1.20 equivalents) and stir at room temperature under nitrogen overnight. Dilute with ether, wash with 1N aqueous hydrochloric acid (2×), dry over anhydrous sodium sulfate, filter, and concentrate solution in vacuo. Purify the residue on silica eluting with 0 to 100% ethyl acetate/hexanes over 25 minutes to provide the title compound as a white solid (0.19 g, 86%). LC-MS m/z 387.1 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:48](=[O:52])[CH:49]([CH3:51])[CH3:50].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=1[F:20])[C:49]([CH3:51])([CH3:50])[CH:48]2[OH:52])=[O:21])[CH3:2]
Reactant: CCOC(=O)c1ccc(N=Cc2cc(Br)ccc2F)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(Br)ccc1F)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.8 %

Procedure:
To a mixture of 4-{[1-(5-bromo-2-fluoro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (2.76 g, 7.9 mmol) and ytterbium(III) triflate hydrate (0.49 g, 0.79 mmol) in dry tetrahydrofuran (10 mL) at 25° C. was added isobutyraldehyde (0.72 mL, 7.9 mmol) and water (0.14 mL, 7.9 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(5-bromo-2-fluoro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.33 g, 100%) as a light yellow oil: LC/MS m/e calcd for C20H21BrFNO3 M+: 422.3, observed: 404.2, 406.2.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[NH:24]1[CH2:29][CH2:28][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][O:30]2)[CH2:26][CH2:25]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:24]1[CH2:29][CH2:28][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][O:30]2)[CH2:26][CH2:25]1)=[O:5]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: c1ccc2c(c1)COC21CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC2(CC1)OCc1ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.4 %

Procedure:
A solution of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (144 mg, 0.48 mmol) and 3H-spiro[isobenzofuran-1,4′-piperidine]hydrochloride (109 mg, 0.48 mmol) in N,N-dimethylacetamide (2 mL) was treated with triethylamine (0.168 mL, 1.21 mmol) and O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (256 mg, 0.68 mmol). The resulting mixture was stirred at ambient temperature for 5 hours, before being filtered and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness and lyophilised to afford the desired compound as a white solid (118 mg, 52.1% yield); 1H NMR (400.132 MHz, DMSO) δ 1.53-1.62 (2H, m), 1.73-1.83 (3H, m), 1.91-1.99 (1H, m), 3.10-3.18 (1H, m), 4.40 (2H, s), 4.54-4.60 (1H, m), 5.03-5.11 (2H, m), 7.26-7.37 (5H, m), 7.45-7.50 (2H, m), 7.83-7.93 (2H, m), 8.02 (1H, d), 8.30 (1H, d), 12.13-12.59 (1H, br s); m/z (LC-MS, ESI+), RT=2.14 (M+H 470.9).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]1([C:21]([OH:23])=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.C([O:31][C:32](=[O:42])[C@H:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH2:34])C1C=CC=CC=1.C(N1CCOCC1)C>ClCCl.CN(C=O)C>[CH:16]1([C:21]([NH:34][C@H:33]([C:32]([OH:42])=[O:31])[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(O)C1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)C1CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A cool solution of 2.06 gm of dicyclohexylcarbodiimide in 10 ml of dichloromethane was added to a solution of 1.4114 gm of cyclopentanecarboxylic acid in 5 ml of dichloromethane at -5° C. It was followed by the addition of 4.28 gm of phenylalanine benzyl ester touluenesulfonate salt in 10 ml of DMF which was neutralized with 1.36 ml of N-ethyl morpholine. The reaction mixture was stirred at 0° C. for one hour and then at room temperature for three hours. Dicyclohexylurea was removed by filtration and 50 ml of ethyl acetate was added to the filtrate. The organic phase was washed until neutral, dried over anhydrous MgSO4 and filtered. The solvent was removed with a rotary evaporator. The residue was crystallized from isopropanol and hexane yielding 2.35 gm of white crystals having a melting point of 88°-89° C. Elemental analysis of these crystals yielded the following.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9])#[N:2].[OH-:15].[Na+].Cl>CS(C)=O.O>[CH3:14][O:13][C:6]1[C:7]([C:8]([OH:10])=[O:9])=[CH:12][C:3]([C:1]([NH2:2])=[O:15])=[CH:4][CH:5]=1
Reactant: COC(=O)c1cc(C#N)ccc1OC
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C(N)=O)cc1C(=O)O
Temperature: 80 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
Methyl 5-cyano-2-methoxybenzoate (2 g) prepared in step A was dissolved in 24 mL of dimethyl sulfoxide, and 12 mL of a 1 M aqueous solution of sodium hydroxide was added. After stirring for 4 hours and a half at 80° C., the mixture was cooled in an ice bath, and adjusted to pH of about 4 with the use of 10 mL of 1 M hydrochloric acid. The resulting solution was diluted with 200 mL of water, and cooled for several hours in a refrigerator. The precipitate formed was separated by filtration, washed with cold water, and then dried over diphosphorus pentoxide under reduced pressure to obtain 1.3 g (63%) of 6-methoxyisophthalamic acid.