Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[NH:13][CH:14]=[C:15]([CH2:19][C:20]3[CH:21]=[N:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=3)[C:16](=[O:18])[N:17]=2)=[CH:6][C:3]=1[C:4]#[N:5].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]=1[C:36]([F:39])([F:38])[F:37].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:2]2[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]3[NH:13][CH:14]=[C:15]([CH2:19][C:20]4[CH:21]=[N:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=4)[C:16](=[O:18])[N:17]=3)=[CH:6][C:3]=2[C:4]#[N:5])=[CH:31][C:30]=1[C:36]([F:37])([F:38])[F:39]
Reactant: COc1ncc(Cc2c[nH]c(CCc3ccc(F)c(C#N)c3)nc2=O)cn1
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(CCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(C#N)c3)nc2=O)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.3 %

Procedure:
To a solution of 2-fluoro-5-[2-(5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-4-oxo-1,4-dihydro-2-pyrimidinyl)ethyl]benzonitrile (80 mg, 0.219 mmol) and 4-chloro-3-(trifluoromethyl)phenol (64.6 mg, 0.328 mmol) in NMP (2 mL), K2CO3 (60.5 mg, 0.438 mmol) was added. The reaction vessel was sealed and stirred at room temp for 10 min, and heated by microwave to 150° C. for 2 h. Purification via MDAP then afforded the title compound as a white solid (30 mg, 25.3% yield). LCMS: rt=3.19 min, [M+H+]=542
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][C:8]2([CH:16]([CH3:18])[CH3:17])[O:13][C:12](=[O:14])[CH:11]=[C:10]([OH:15])[CH2:9]2)=[CH:2]1.[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32][C:11]1[C:12](=[O:14])[O:13][C:8]([CH2:7][CH2:6][C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)([CH:16]([CH3:18])[CH3:17])[CH2:9][C:10]=1[OH:15])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: CC(C)C1(CCc2ccoc2)CC(O)=CC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccoc3)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared as described in General Method 16a using 6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one (Example E-18; 1 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 1.1 mmol), potassium carbonate (4 mmol) in DMF (4 mL). The product was flash chromatographed over silica gel using 70:20:10 hexane:EtOAc:CH2Cl2, mp 62-70° C. MS (APCI): 457 (M−H)
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:9])([CH2:7][O:8][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 20 h
Yield: 108 %

Procedure:
A mixture of methyl 2,2-dimethyl-3-hydroxypropionate (100 g, 0.76 mol), 4-toluenesulfonyl chloride (151 g, 0.80 mol), 4-dimethylaminopyridine (4.6 g, 0.038 mol), and pyridine (200 mL) was stirred for 20 hrs and then was diluted with 200 mL toluene, stirred for 30 min, and filtered. The filtrate was concentrated to 250 mL under reduced pressure, diluted with 100 mL toluene, filtered, and concentrated. The residue was suspended in 200 mL hexanes, and the solvent was removed under reduced pressure to yield the title compound, desired product (235 g, 100%) contaminated by a trace of 4-toluenesulfonyl chloride.
Reaction SMILES: [O:1]=[C:2]1[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:5](=[O:12])[CH2:4][S:3]1.[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=3)[C:21]([CH3:30])=[N:20]2)=[C:16]([C:33]([F:36])([F:35])[F:34])[CH:15]=1>>[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:28]=[C:4]4/[C:5](=[O:12])[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:2](=[O:1])[S:3]/4)=[CH:25][CH:26]=3)[C:21]([CH3:30])=[N:20]2)=[C:16]([C:33]([F:34])([F:36])[F:35])[CH:15]=1
Reactant: CS(=O)(=O)NN1C(=O)CSC1=O
Reactant: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(C=O)cc12
Product: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(/C=C3\SC(=O)N(NS(C)(=O)=O)C3=O)cc12

Procedure:
N-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from N-(2,4-dioxothiazolidin-3-yl)methanesulfonamide (from Example 360) and 1-[4-chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-carbaldehyde (from Example 36) following General Procedure E.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([CH2:10][S:11][C:12]3[NH:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=4[N:16]=3)[C:4]=2[CH:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:29])C=1.C([O-])(O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.O.CO>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([CH2:10][S:11]([C:12]3[NH:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=4[N:16]=3)=[O:29])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc2[nH]c(SCc3nccc4sccc34)nc2c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=S(Cc1nccc2sccc12)c1nc2ccccc2[nH]1
Reaction time: 0.5 h

Procedure:
To a solution of 278.6 mg (0.900 mmol) of 2-[(thieno[3, 2-c]pyridin-4-yl)methylthio]benzimidazole.2/3 H2O (Ia') in 20 ml of CHCl3 and 1 ml of MeOH was added 194.1 mg (0.900 mmol) of 80% mCPBA at -10° to -15° C. and stirred for 30 minutes. To the mixture were added 2.5 ml of saturated aqueous NaHCO3 and 0.5 ml of 10 % aqueous sodium sulfite. After bringing back to room temperature, water was added thereto, and the solution was extracted with CHCl3. After drying CHCl3 layer over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and washed with ether, whereby 274.6 mg (Yield : 92.5%) of the objective compound (Ic'), 2-[(thieno[3, 2-c]pyridin-4-yl)methylsulfinyl]benzimidazole was obtained as crystals.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:51][C:52]1[CH:64]=[CH:63][CH:62]=[CH:61][C:53]=1[O:54][CH:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>CN(C=O)C.O>[Cl:51][C:52]1[CH:64]=[CH:63][CH:62]=[CH:61][C:53]=1[O:54][CH:55]1[CH2:60][CH2:59][N:58]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:57][CH2:56]1
Reactant: Clc1ccccc1OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.038 g, 0.00013 mol) in DMF (2 mL) was added DIPEA (0.0872 g, 0.00067 mol), HOBt (0.023 g, 0.00017 mol) and EDCI.HCl (0.0325 g, 0.00017 mol) at ambient temperature. After 2 minutes 4-(2-chlorophenoxy)-piperidine hydrochloride (0.03347 g, 0.00013 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.0517 g (87%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 439.15 (M+1)+, 98.84%, 1H NMR (DMSO-d6): δ 13.7 (s, 1H), 8.1 (s, 1H), 7.8 (d, 2H), 7.42 (m, 3H), 7.32 (m, 1H), 7.24 (m, 2H), 7.1 (s, 1H), 7.0 (t, 1H), 4.7 (m, 1H), 4.1 (d, 2H), 3.7 (m, 2H), 3.4 (m, 2H), 1.9 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:16]=2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:10][C:9]=1[CH3:29].[CH:30]1(B(O)O)[CH2:32][CH2:31]1>>[CH:30]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:16]=3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:10][C:9]=2[CH3:29])[CH2:32][CH2:31]1
Reactant: Cc1ccc(Nc2cnc(-c3ccccc3Cl)c(C)c2)c(C(=O)OC(C)(C)C)c1
Reactant: OB(O)C1CC1
Product: Cc1ccc(Nc2cnc(-c3ccccc3C3CC3)c(C)c2)c(C(=O)OC(C)(C)C)c1

Procedure:
Obtained (0.152 g, 63% of yield) following the procedure described in Example 14 (step C) starting with tert-butyl 2-(6-(2-chlorophenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoate (0.49 mmol, 0.200 g) and cyclopropylboronic acid (1.47 mmol, 0.126 g).
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9](=[O:18])[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=[C:5]([CH2:19][C:20]([OH:22])=[O:21])[CH:4]=1.Br.O>C(O)(=O)C>[OH:2][C:3]1[C:8]2[C:9](=[O:18])[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=[C:5]([CH2:19][C:20]([OH:22])=[O:21])[CH:4]=1
Reactant: COc1cc(CC(=O)O)cc2c1C(=O)c1ccccc1CC2
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1cc(O)c2c(c1)CCc1ccccc1C2=O

Procedure:
4-Methoxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl acetic acid (0.3 g) is refluxed in acetic acid (4.5 ml) and 48% aqueous hydrobromic acid (4.5 ml) for 30 minutes. The cooled solution is poured into water and extracted with ethyl acetate. The extract is washed, dried, evaporated and the residue recrystallized from ethyl acetate/hexane to afford 4-hydroxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl acetic acid, mp 149°-151°.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]([CH3:19])[C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.I[CH2:21][CH:22]1[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH2:23]1.[CH2:30](N(CC)CC)C>>[ClH:1].[C:22]1([CH2:21][N:2]2[CH2:3][CH2:4][CH:5]([N:8]([CH2:19][CH3:30])[C:9](=[O:18])[O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:6][CH2:7]2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=1
Reactant: CN(C(=O)OCc1ccccc1)C1CCNCC1
Reactant: ICC1Cc2ccccc21
Reactant: CCN(CC)CC
Agent: Cl
Product: CCN(C(=O)OCc1ccccc1)C1CCN(CC2=Cc3ccccc32)CC1
Yield: 22.5 %

Procedure:
Benzyl N-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-ethylcarbamate hydrochloride was prepared from benzyl N-piperid-4-yl-N-methylcarbamate hydrochloride and 1-iodomethylbenzocyclobutene, in accordance with the process described in Stage C of Example 8, in the presence of triethylamine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:19]4=3)[C:14]3[C:9]2=[CH:10][C:11]([O:27][CH3:28])=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C)C=O>[CH3:26][O:25][C:23]1[CH:22]=[CH:21][C:19]2=[C:20]3[C:15](=[CH:16][CH:17]=[C:18]2[CH:24]=1)[C:14]1[C:9](=[CH:10][C:11]([O:27][CH3:28])=[CH:12][CH:13]=1)[CH:8]3[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:7][CH:6]=1
Reactant: COc1ccc2c(c1)C(c1ccc(O)cc1)c1c-2ccc2cc(OC)ccc12
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(c1ccc(OCCN3CCCCC3)cc1)c1c-2ccc2cc(OC)ccc12

Procedure:
A 1.8 g portion of the compound of Example 3 was combined with 3.4 g of potassium carbonate, 0.95 g of 1-(2-chloroethyl)piperidine hydrochloride and 20 ml of dimethylformamide, and the reaction was carried out and the product was isolated as described above in Example 6. The chromatography gave 2.05 g of purified product, which was recrystallized from ethyl acetate/isooctane to obtain 1.93 g of highly purified product, m.p. 162°-164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([O:17][CH3:18])=[N:10][C:11]([CH3:16])=[C:12]([CH:15]=2)[C:13]#N)[CH:5]=[CH:6][CH:7]=1.BrC1C(OC)=NC(C)=C(C=1)C#N.[Cl:31]C1C=C(B(O)O)C=CC=1.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:31][CH2:13][C:12]1[C:11]([CH3:16])=[N:10][C:9]([O:17][CH3:18])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:15]=1
Reactant: COc1nc(C)c(C#N)cc1-c1cccc(Cl)c1
Reactant: OB(O)c1cccc(Cl)c1
Agent: COc1nc(C)c(C#N)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1nc(C)c(CCl)cc1-c1cccc(Cl)c1
Temperature: 100 °C

Procedure:
5-(3-Chlorophenyl)-6-methoxy-2-methylnicotinonitrile. A 20 mL microwave vial was charged with 5-bromo-6-methoxy-2-methylnicotinonitrile (1.2 g, 5.28 mmol), (3-chlorophenyl)boronic acid (990 mg, 6.3 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride DCM complex (191 mg, 0.26 mmol), ACN (10 mL) and saturated aq. sodium bicarbonate (3 mL). The vial was sealed, purged with nitrogen and heated at 100° C. under microwave irradiation for 10 min. The layers were separated and the aq. phase extracted with EtOAc. The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-50%, EtOAc/hexanes) afforded the title compound as an off white solid (995 mg, 74%). [M+H]=259.06.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[S:11][C:10]([NH:12][Si](C)(C)C)=[N:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.C(Cl)(Cl)=O.CC[N:23](C(C)C)[CH:24]([CH3:26])[CH3:25].[CH3:30][N:31]([CH:33]=[O:34])[CH3:32]>C1(C)C=CC=CC=1.C(Cl)Cl>[NH2:23][CH:24]1[CH2:26][CH2:32][N:31]([C:33]([NH:12][C:10]2[S:11][C:7]([C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:6])=[CH:8][N:9]=2)=[O:34])[CH2:30][CH2:25]1
Reactant: CCN(C(C)C)C(C)C
Reactant: C[Si](C)(C)Nc1ncc(C(=O)NC2CC2)s1
Reactant: CN(C)C=O
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: NC1CCN(C(=O)Nc2ncc(C(=O)NC3CC3)s2)CC1

Procedure:
N-Cyclopropyl-2-[(trimethylsilyl)amino]-1,3-thiazole-5-carboxamide 23-5 (0.26 g, 1.0 mmol) was treated with 2 mL of phosgene (as a 20% solution in toluene) and 1 mL of methylene chloride at room temperature for 4 hours. The suspension was concentrated to dryness and the residue was treated with a suspension of DIEA (0.16 g, 1.2 mmol) and 4-boc-amino-1-piperidine 23-6 (0.20 g, 1.0 mmol) in 1 mL of dry DMF and 1 mL of methylene chloride overnight at room temperature. The intermediate product was purified on C18 column and the residue treated with TFA. The crude product was purified on a C18 preparative HPLC column and isolated via lyophilization to afford the final product 23-7. Hi-Res MS: calc: 310.1332 found: 310.1334. 1H-NMR (DMSO): 8.33 ppm (s, 1H); 7.92 ppm (s, 1H); 7.84 ppm (m, 3H); 3.27 ppm (m, 1H); 2.91 ppm (t, 2H); 2.75 ppm (m, 1H); 1.90 ppm (d, 2H); 1.40 ppm (q, 2H); 0.67 ppm (m, 2H); 0.52 ppm (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].N1C2C(=CC=CC=2)C=C1.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C=O)C>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13]1)[CH3:35]
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Agent: c1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2cc(OCc3ccccc3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
5-benzyloxyindole (10.0 g, 44.79 mmol) is dissolved into anhydrous DMF (100 mL) and cooled to 0° C. in an ice water bath. Sodium hydride (2.6 g, 67.18 mmol) is dissolved into anhydrous DMF (100 mL), then slowly added to the indole solution using an addition funnel. The reaction is allowed to stir at 0° C. for 1 h., then the ice bath is removed and the solution is allowed to warm slowly to room temperature. The solution is then cooled back down to 0° C. and ethyl bromoacetate (11.2 g, 67.18 mmol) is then added in one portion. The reaction is allowed to stir at 0° C. for 1 h., then the ice bath is removed and the solution is allowed to warm slowly to room temperature. Upon completion, the reaction is quenched carefully using water, then diluted with EtOAc (300 mL). Brine (100 mL) is added and the two layers are separated in a separatory funnel. The organic layer is rinsed with water (2×75 mL) and then dried over anhydrous magnesium sulfate. The organic layer is then concentrated and purified using flash column chromatography (5% EtOAc/Hexanes) to yield 11.86 g (86%) of (5-Benzyloxy-indol-1-yl)-acetic acid ethyl ester.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=4[NH2:28])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30].C([O-])(O)=O.[Na+].O>ClCCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:20][C:19]=4[NH:28][C:29](=[O:31])[CH3:30])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CC(=O)Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylamine, (Example 163), (0.25 g, 0.65 mmol) in 1,2-dichloroethane (6.5 mL) was added acetic anhydride (0.15 mL, 1.6 mmol). The mixture was stirred at room temperature for 18 h and then treated with satd NaHCO3 and H2O. The mixture was extracted with EtOAc (2×75 mL) and the combined extracts were washed with H2O (75 mL) and brine (75 mL), dried over Na2SO4, filtered, and concentrated onto silica gel. Purification by silica gel chromatography (gradient, 10 to 40% EtOAc/hexanes) afforded the title compound as a yellow solid. Mp: 137-138° C. MS (ESI, pos. ion) m/z: 479.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:9]2[C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[C:18]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31]OS(C)(=O)=O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:18]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][N:10]1[C:9]2[C:8]([O:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=[C:2]1[CH3:1])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CS(=O)(=O)OCCOCCOC(=O)c1ccccc1
Reactant: Cc1cc2ncnc(Oc3ccccc3)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2ncnc(Oc3ccccc3)c2n1CCOCCOC(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 21 h
Yield: 93.2 %

Procedure:
6-Methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine (299.9 mg) and 2-{2-[(methylsulfonyl)oxy]ethoxy}ethyl benzoate (464.1 mg) were dissolved in N,N-dimethylformamide (7 mL), potassium carbonate (431 mg) was added, and the mixture was stirred at 60° C. for 21 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→20:80) to give the title compound (517.8 mg) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1C=CC=CC=1.N1CCCCC1>O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)/[CH:5]=[CH:11]/[C:12]([OH:14])=[O:13]
Reactant: O=Cc1cccc(F)c1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)/C=C/c1cccc(F)c1
Reaction time: 8 h
Yield: 84 %

Procedure:
A mixture of 3-fluorobenzaldehyde (40 g), malonic acid (47 g), and an ethanolic solution (150 ml) containing pyridine (10 g) and piperidine (5 g) was heated at reflux with stirring for 8 hours. The reaction mixture was chilled and water (300 ml) was added, giving crystalline trans 3-fluorocinnamic acid which was removed by filtration, washed with water and dried. The trans 3-fluorocinnamic acid, m.p. 162°-163° C., was obtained in 84% yield (44.6 g).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[CH2:13]([O:15][C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])[CH3:14].CI>C1COCC1>[CH2:13]([O:15][C:16]([C:18]1([CH3:1])[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])[CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)C1CCCCN1C(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCCCN1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.3 %

Procedure:
To a solution of diisopropyl amine (2.11 g, 25.86 mmol) in THF (50 mL) at 0° C. was added nBuLi (9.4 mL, 23.51 mmol, 2.5M in hexanes). This solution was stirred for 15 min at 0° C. and then cooled to -78° C. Ethyl-1-benzoyl-piperidine-2-carboxylate (6.16 g, 23.5 mmol) was added and the reaction was allowed to stir for 45 min at which time methyl iodide (3.34 g, 23.51 mmol) was added. The reaction was warmed to room temperature and gently warmed (~40° C.) for 2 h. The reaction was quenched with NaHCO3, extracted with ether, dried over Na2SO4 and concentrated to give ethyl-1-benzoyl-2-methyl-piperidine-2-carboxylate (6.49 g, 100% yield). 1H NMR (300 MHz, CDCl3) δ1.10 (m, 3H), 1.45 (s, 3H), 1.4-1.7 (comp m, 4H), 2.90 (m, 2H), 3.5 (m, 2H), 4.14 (m, 2H), 7.24 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10].C(N(C1C=CC(C(O)=O)=CN=1)CC1C=CC=CC=1CCC1C=CC=CC=1)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10]
Reactant: CCN(Cc1cc(Br)ccc1CCc1ccccc1)c1ccc(C(=O)OC)cn1
Agent: CCN(Cc1ccccc1CCc1ccccc1)c1ccc(C(=O)O)cn1
Product: CCN(Cc1cc(Br)ccc1CCc1ccccc1)c1ccc(C(=O)O)cn1

Procedure:
2-[N-(5-bromo-2-(phenethyl)benzyl)-N-ethylamino]-5-pyridine carboxylic acid was prepared from methyl 2-[N-(5-bromo-2-(phenethyl) benzyl)-N-ethylamino]-5-pyridinecarboxylate using a similar method to that described in Example 4 paragraph (A).
Reaction SMILES: Br[C:2]1[C:3]([F:12])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8].C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC.O1CCOCC1.C1C(=O)N([Br:44])C(=O)C1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C1COCC1.O>[Br:44][CH2:20][C:18]([C:2]1[C:3]([F:12])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8])=[O:19]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc(F)c(Br)cc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(F)c(C(=O)CBr)cc1C#N
Temperature: 95 °C
Reaction time: 3 h

Procedure:
To a 500 mL flask was added 5-bromo-4-fluoro-2-methoxybenzonitrile (4.00 g, 17.4 mmol), Bis(Triphenylphosphine)Palladium(II)Chloride (0.61 g, 0.87 mmol), tributyl(1-ethoxy-vinyl)tin (9.42 mL, 26.1 mmol) followed by addition of 1,4 dioxane (40 mL). The resulting mixture was stirred at 95° C. for 3 h; the flask was taken out of the oil bath and cooled to rt followed by treatment with a mixture of THF/H2O (50/25 mL) and placed in an ice bath. To the flask was added NBS (6.19 g, 34.8 mmol) in small portions; after stirred for 0.5 h at 0° C., LC indicated formation of the desired product. The reaction mixture was taken out of the ice bath and slowly warmed up to rt. The reaction mixture was extracted with EtOAc (3×100 mL), washed with brine and water, it was then dried (Na2SO4), filtered and concentrated to dryness followed by separation over silica gel with the solvent systems of hexanes/EtOAc (1/0.5) to give the desired product. LC/MS: [(M+2)]+=274.