Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:41])[C:5]([CH3:40])([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]([CH2:30][CH2:31][CH3:32])[C:18](=[O:29])[N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[CH:20]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>CCO>[CH3:40][C:5]([O:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]([CH2:30][CH2:31][CH3:32])[C:18](=[O:29])[N:19]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[CH:20]=2)=[CH:11][CH:12]=1)[C:4]([OH:41])=[O:3]
Reactant: CCCn1c(CCOc2ccc(CC(C)(Oc3ccccc3)C(=O)OCC)cc2)cn(Cc2ccc(C)cc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCn1c(CCOc2ccc(CC(C)(Oc3ccccc3)C(=O)O)cc2)cn(Cc2ccc(C)cc2)c1=O
Yield: 66.2 %

Procedure:
The 2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid ethyl ester (0.011 g, 0.020 mmol) was combined with aqueous 5 N NaOH (0.2 mL) in EtOH (3 mL) and heated to reflux under N2 for 1 h. The reaction was cooled and the solvent removed in vacuo to give a residue that was acidified with aqueous 1 N HCl (2 mL). The mixture was extracted with Et2O and water, the organic layer dried (MgSO4), and the solvent removed in vacuo to afford 0.007 g (67%) 2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid. HRMS (ES+) m/z exact mass calcd for C32H37N2O5 [M+1] 529.2702, found 529.2715. 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Br)=[CH:32][C:31]=1[F:38])[CH:27]=[CH2:28]>CN(C=O)C.CCOC(C)=O>[CH2:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][N:11]([C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])[S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])=[CH:32][C:31]=1[F:38])[CH:27]=[CH2:28]
Reactant: C=CCOc1ccc(CBr)cc1F
Reactant: CC(C)C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(CN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.5 %

Procedure:
To a solution of (2R)-2-(4-chlorobenzenesulfonylamino)-4-methyl-pentanoic acid amide (1.00 g, 3.29 mmol), and Cs2CO3 (1.29 g, 3.95 mmol) in DMF (25 mL) was added 1-allyloxy-4-bromomethyl-2-fluorobenzene (ref.: Graham, S. L. et al., EP Patent Application No. EP 487270 (1992): 0.88 g, 3.67 mmol). The resulting solution was stirred at rt for 18 h. The reaction was then diluted with 9:1 EtOAc:hexanes (350 mL) and washed with H2O (4×200 mL), brine, and dried over Na2SO4, to afford the titled compound (393 mg) as a white solid in 26% yield. MS (ESI), (M+H)+469.1; 1H NMR (CDCl3) δ 7.66 (d, 2H, J=8.1), 7.45 (d, 2H, J=8.1), 7.11 (d, 1H, J=12.0), 6.98 (m, 1H), 6.84 (t, 1H, J=8.0), 6.22 (br s, 1H), 6.04 (m, 2H), 5.42 (m, 1H), 5.16 (br s, 1H), 4.59 (m, 2H), 4.40 (m, 3H), 1.83 (m, 1H), 1.32 (m, 1H), 1.14 (m, 1H), 0.76 (d, 3H, J=7.0), 0.68 (d, 3H, J=7.0).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].Br[CH2:11][CH:12]([Cl:16])[CH2:13][CH2:14][CH3:15]>C(O)C>[Cl:16][CH:12]([CH2:13][CH2:14][CH3:15])[CH2:11][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[Br:2]
Reactant: CCCC(Cl)CBr
Reactant: Sc1ccccc1Br
Agent: [Na]
Solvent: CCO
Product: CCCC(Cl)CSc1ccccc1Br
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a solution of 23.0 g of sodium metal in 500 ml of absolute ethanol is added, in about 0.5 hour, a solution of 173.0 g of o-bromothiophenol in 250 ml of absolute ethanol. The mixture is stirred and heated under reflux for about 0.5 hour, cooled to 0°, and treated, dropwise, with 185.5 g of 1-bromo-2-chloropentane. The addition requires about 1 hour. The mixture is stirred for about 2 hours at 0°, warmed slowly to reflux, and then heated under reflux for two hours. The mixture is filtered and the filtrate concentrated in vacuo at 40° to give about 255.7 g of o-bromophenyl 2-chloro-1-pentyl sulfide as a pale yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[C:7]([O:12]C)[C:8]=1[CH2:9][CH2:10][CH3:11].B(Br)(Br)Br.O.[OH-].[Na+]>C(Cl)Cl>[C:16]1([CH:15]=[CH:14][C:5]2[CH:4]=[C:3]([OH:2])[C:8]([CH2:9][CH2:10][CH3:11])=[C:7]([OH:12])[CH:6]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCc1c(OC)cc(C=Cc2ccccc2)cc1OC
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCCc1c(O)cc(C=Cc2ccccc2)cc1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
To the crude 1-(3,5-dimethoxy-4-1-propylphenyl)-2-phenylethene (18.07 g) in dry CH2Cl2 (100 mL) at −78° C. under N2 was added BBr3 (5.2 mL, 55 mmol) dropwise. After the reaction was stirred at −78° C. for 1 h, the temperature was allowed to rise to room temperature and the reaction mixture was stirred at room temperature for 2 days. Water was added to quench the reaction, followed by 20% NaOH to adjust pH>12. The organic layer was removed and the aqueous layer was washed with hexane (2×100 mL). The aqueous layer was acidified with 6N HCl to pH 1 and extracted with ether (3×200 mL). The organic layer was separated and washed with water (50 mL) and brine (50 mL) and dried over anhydrous Na2SO4. Evaporation of ether gave a red syrup. Recrystallization with chloroform yielded pure stilbene product 20B (6.92 g) as a white crystal. The mother liquid was concentrated and the residue was recrystallized once more to afford an additional 2.5 g of 20B (total 9.42 g, 67.7% over two steps). 1HNMR (CDCl3, ppm): δ 1.38 (d, J=7.3 Hz, 6H), 3.46 (hept., J=7.3 Hz, 1H), 4.80 (s, 2H), 6.50 (s, 2H), 6.92 (d, J=17.2 Hz, 1H), 6.97 (d, J=17.2 Hz, 1H), 7.25 (m, 1H), 7.34 (m, 2H), 7.52 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Br:12])=[CH:7][CH:8]=2)[CH:3]=1.[Li][CH2:14]CCC.CI.O>CCOCC>[Br:12][C:6]1[CH:7]=[CH:8][C:9]2[C:4](=[CH:3][C:2]([CH3:14])=[CH:11][CH:10]=2)[CH:5]=1
Reactant: [Li]CCCC
Reactant: Brc1ccc2ccc(Br)cc2c1
Solvent: CCOCC
Solvent: O
Solvent: CI
Product: Cc1ccc2ccc(Br)cc2c1
Temperature: -30 °C
Reaction time: 2.5 h

Procedure:
Suspension of 2,7-dibromonaphthalene (61.4 g, 0.21 mole) in ether (400 ml) was cooled to −30° C., and n-BuLi (1.6M in hexane, 135 ml, 0.21 mole) was added. Reaction mixture was allowed to warm to room temperature, stirred for additional 2.5 h, cooled to −30° C., and CH3I (13.5 ml, 0.21 mole) was added. Reaction mixture was allowed to warm to room temperature, stirred for additional 16 h, treated by water (100 ml). Organic layer was separated, water layer was extracted by ether (6×100 ml). Combined organic fraction was evaporated, giving practically pure solid product. The yield 38.1 g (82%).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1.[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:31]4[CH:30]=[CH:29][C:28]([Cl:27])=[CH:33][C:32]=4[Cl:34])=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(I)cc3)cc2s1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(-c4ccc(Cl)cc4Cl)cc3)cc2s1
Yield: 41.9 %

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-4-iodo-benzamide (0.15 g, 0.31 mmol) and 2,4-dichloro-phenyl boronic acid (0.072 g, 0.38 mmol) to give the title compound (0.067 g, 0.13 mmol, 43%). LC/MS, Retention time=5.15 min; (m/z): calcd for C25H24Cl2N4OS: 499.5; found: 499.0.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:6]([C:22]([O:24][CH3:25])=[O:23])[C:5]([N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:4][CH:3]=1.OC[C@H]1CCCN1C(OC(C)(C)C)=O.BrC1C(O)=C(C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=CC=1)C(OC)=O>>[Br:1][C:2]1[C:7]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[C:6]([C:22]([O:24][CH3:25])=[O:23])[C:5]([N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(Br)c1OC[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(Br)c1O
Product: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(Br)c1OC[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 8, starting from tert-butyl (R)-2-hydroxymethylpyrrolidine-1-carboxylate and methyl 3-bromo-6-bis-(tert-butoxycarbonyl)amino-2-hydroxybenzoate (Intermediate 9).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[CH3:8][S:9]([N:12]1[CH2:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[CH2:34][C:25]4([CH2:33][C:27]5([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH2:26]4)[O:24][C:21]3=[CH:22][N:23]=2)[CH2:14][CH2:13]1)(=[O:11])=[O:10].C(N(CC)CC)C>ClCCl>[CH:5]([O:4][C:2]([N:30]1[CH2:31][CH2:32][C:27]2([CH2:26][C:25]3([O:24][C:21]4=[CH:22][N:23]=[C:18]([C:15]5[CH2:16][CH2:17][N:12]([S:9]([CH3:8])(=[O:11])=[O:10])[CH2:13][CH:14]=5)[CH:19]=[C:20]4[CH2:34]3)[CH2:33]2)[CH2:28][CH2:29]1)=[O:3])([CH3:7])[CH3:6]
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O1)C2
Reaction time: 3 h

Procedure:
Isopropyl chloroformate (1 mol/L in toluene; 0.15 mL) is added to a mixture of 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt; 60 mg), triethylamine (40 μL), and dichloromethane (5 mL) at room temperature. The solution is stirred for 3 h and then concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 4:1→1:4) to give the title compound. LC (method 1): tR=1.02 min; Mass spectrum (ESI+): m/z=476 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][NH:6][C:7]([O:9][C@@H:10]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1)[C@@H:11]1[N:16]2[CH2:17][CH2:18][C@H:13]([C@@H:14]([CH:19]=[CH2:20])[CH2:15]2)[CH2:12]1)=[O:8])C.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25]([N:24]=[CH:23][CH:22]=[C:21]2[C@H:10]([O:9][C:7]([NH:6][CH2:5][C:4]([OH:33])=[O:3])=[O:8])[C@@H:11]2[N:16]3[CH2:17][CH2:18][C@H:13]([C@@H:14]([CH:19]=[CH2:20])[CH2:15]3)[CH2:12]2)=[CH:26][CH:27]=1
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](OC(=O)NCC(=O)OCC)c1ccnc2ccc(OC)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](OC(=O)NCC(=O)O)c1ccnc2ccc(OC)cc12
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A solution of 120 mg (0.26 mmol) of (8) in 2 ml of methanol was added 200 mg of potassium carbonate and 0.5 ml of water. The mixture was heated to reflux for 2 h and cooled to room temperature. The reaction mixture was filtered and the filtrate was concentrated to remove methanol. The residue was redissolved in 2 ml of water and 1N HCl was added dropwise to the solution until the pH reached 7. The aqueous solution was concentrated, 100 ml of methanol was added and filtered. The filtrate was concentrated and yielded 95 mg (0.22 mmol, 85%) of (9).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:25]([O:32][CH2:33][CH:34]1[C:38](CO)=[CH:37][CH2:36][CH2:35]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>ClCCl>[Si:25]([O:32][CH2:33][CH:34]1[C:35]([CH2:1][Br:5])=[CH:36][CH2:37][CH2:38]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC=C1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1CCC=C1CBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
The carbon tetrabromide (8.5 g, 25.7 mmol) and triphenylphosphine (8.4 g, 3.22 mmol) were added in dichloromethane solution of (5-t-Butyldimethylsilyloxymethylcyclopent-1-en-1-yl)methyl alcohol (5.2 g, 21.4 mmol) under ice bath and then stirred for 30 min at 0° C. The reaction mixture was stirred for overnight at room temperature, extracted with dichloromethane, dried with MgSO4, filtered, concentrated and separated by column chromatography to give a desirable product (3.08 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[F:9].C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:20]=[O:21]>O1CCCC1>[Br:1][C:2]1[C:3]([F:9])=[CH:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: Fc1ccc(Cl)cc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1c(Cl)ccc(F)c1Br
Reaction time: 1 h
Yield: 13.3 %

Procedure:
To a −78° C. solution of 2-Bromo-4-chloro-1-fluoro-benzene (2.90 g, 13.9 mmol) in 30 mL tetrahydrofuran under an atmosphere of nitrogen was added lithium diisopropylamide solution (1.8M in tetrahydrofuran/heptane/ethylbenzene, 10.0 mL, 18.0 mmol) at such a rate that the internal reaction temperature did not exceed −69° C. After 1 hour at −78° C., dimethylformamide (1.39 mL, 18.0 mmol) was added at such a rate that the internal temperature did not exceed −69° C. After 30 minutes at −78° C., the reaction was quenched with saturated aqueous ammonium hydroxide solution. The resulting mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution with 0 to 5% ethylacetate/hexanes) to yield 2-Bromo-6-chloro-3-fluoro-benzaldehyde (440 mg, 1.85 mmol). MS (ESI) 236.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:55][C:56]([F:61])([CH3:60])[C:57](O)=O>CN(C=O)C>[F:16][C:13]1([F:17])[CH2:14][CH2:15][CH:10]([CH2:9][N:8]2[C:7]3[CH:6]=[CH:5][C:4]([NH:18][C:19](=[O:21])[CH3:20])=[CH:3][C:2]=3[N:1]=[C:57]2[C:56]([F:61])([F:55])[CH3:60])[CH2:11][CH2:12]1
Reactant: CC(F)(F)C(=O)O
Reactant: CC(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c(N)c1
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: CC(=O)Nc1ccc2c(c1)nc(C(C)(F)F)n2CC1CCC(F)(F)CC1
Temperature: 80 °C

Procedure:
N-(3-Amino-4-{[(4,4-difluorocyclohexyl)methyl]amino}phenyl)acetamide (99 mg, 0.333 mmol), DIPEA (0.087 mL, 0.500 mmol), HATU (140 mg, 0.366 mmol) and 2,2-difluoropropionic acid (40 mg, 0.366 mmol) were stirred in 5 mL of DMF at rt for 1 h. The solvent was evaporated. The residue was dissolved in 3 mL of glacial AcOH and heated at 80° C. for 2 h. The solvent was evaporated. The product was dissolved in EtOAc and washed with aqueous NaHCO3 solution, saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The product was purified by silica gel flash chromatography using EtOAc as eluent. Yield: 100 mg (81%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.39-1.52 (m, 2 H), 1.57-1.63 (m, 1 H), 1.64-1.71 (m, 3 H), 2.06-2.16 (m, 3 H), 2.22 (s, 3 H), 2.29 (m, 3 H), 4.25 (d, J=7.42 Hz, 2 H), 7.31 (s, 1 H), 7.35 (d, J=8.79 Hz, 1 H), 7.60 (dd, J=8.89, 1.86 Hz, 1 H), 7.86 (d, J=1.76 Hz, 1 H).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:17](=[O:27])[NH:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[F:26])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[NH:18][C:17]([C@@H:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][NH:8]1)=[O:27]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1c(F)cccc1F)[C@H]1NCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-1-(2,6-difluoro-phenylcarbamoyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester in CH2Cl2 (3 mL) was added TFA (1 mL) dropwise. The reaction was stirred at RT for 1 h and the mixture evaporated to afford (S)-2,3-dihydro-1H-isoindole-1-carboxylic acid (2,6-difluoro-phenyl)-amide which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:15]=3[N:14]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:15]=3[N:14]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH2:6][CH2:5]2
Reactant: Cc1cc(C)c2[nH]ccc2c1Cc1nc2cc(C#N)ccc2[nH]1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c2c(c1Cc1nc3cc(C#N)ccc3[nH]1)CCN2
Temperature: 25 °C

Procedure:
2-((5,7-Dimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (35 mg, 0.117 mmol) was suspended in DCM (1 mL), triethylsilane (0.37 mL, 2.33 mmol) and then TFA (0.5 mL) were added and the reaction was stirred at room temperature. After 1 hour the reaction was concentrated and then the resulting residue was dissolved in EtOAc and treated with 1 mL of aq. ammonium hydroxide. The residue was purified via FCC (0-100% EtOAc in heptanes) to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.47 (d, J=15.66 Hz, 1H) 8.02 (m) 7.88 (m) 7.56 (m) 7.50-7.54 (m) 6.60 (s, 1H) 5.08 (br. s., 1H) 4.08 (d, J=3.54 Hz, 2H) 3.40 (t, J=8.46 Hz, 2H) 2.91 (t, J=8.46 Hz, 2H) 2.09 (s, 3H) 1.94-2.03 (m, 3H). HRMS calcd. for C19H18N4 (M+H)+, 303.1604. found 303.1615.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([N+:15]([O-])=O)[CH:3]=1>CCOC(C)=O.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([NH2:15])[C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(Nc2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(Nc2ccccc2)c(N)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.3 %

Procedure:
A mixture of (4-methyl-2-nitrophenyl)phenylamine (1.41 g, 6.18 mmol) and 10% Pd/C (140 mg) in EtOAc (30 mL) was degassed with a stream of nitrogen and stirred at RT under a hydrogen atmosphere for 5 h. The suspension was then filtered through a PTFE frit and the filtrate was concentrated in vacuo affording 4-Methyl-N1-phenylbenzene-1,2-diamine as an off-white solid (1.18 g, 96%). LCMS: RT 3.08 min [M+H]+ 199.1.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.P(Cl)(Cl)([Cl:12])=O.P(Cl)(Cl)Cl>>[Cl:12][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][N:2]=1
Reactant: c1ccc2sncc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClP(Cl)Cl
Product: Clc1nsc2ccccc12

Procedure:
a method including reacting 1,2-benzisothiazole and phosphorus oxychloride or phosphorus trichloride in the absence of a solvent, to give 3-chloro-1,2-benzisothiazole (see, Patent Publication 1):
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:5][CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[C:19]([O-:22])(=[O:21])[CH3:20].[Na+].O>CC(N(C)C)=O>[C:19]([O:22][CH2:2][C:3]1[C:4]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:5][CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:21])[CH3:20]
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(CBr)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cnc(OCC(F)(F)F)c(COC(C)=O)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A mixture of methyl 5-(bromomethyl)-6-(2,2,2-trifluoroethoxy)nicotinate (0.68 g, 2.07 mmol, Step-2) and sodium acetate (0.51 g, 6.20 mmol) in DMA (10 mL) is stirred at 130° C. for 2 hours. After cooling to room temperature, the reaction mixture is poured into water, extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-Hexane/ethyl acetate (6:1) to give 0.35 g (56% yield) of the title compound as colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=1.NC(N)=[S:27].[OH-].[Na+].Cl>C(O)C>[SH:27][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCCBr)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(NCCCCCCCCCCCS)cc1

Procedure:
A solution of 10 g. of ethyl 4-[(11-bromoundecyl)amino]benzoate and 2.0 g. of thiourea in 80% of 95% ethanol is stirred under reflux for 3 hours, allowed to cool, treated with 12 ml. of 10 N aqueous sodium hydroxide solution and again stirred under reflux for 2 hours. The mixture is acidified with dilute hydrochloric acid and filtered. The solid is recrystallized from ethanol-water to yield the product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([O:16]CC)=[O:15])[CH:10]=[CH:11][CH:12]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)Cc1cccc(OCc2cc(C)cc(C)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C)cc(COc2cccc(CC(=O)O)c2)c1
Reaction time: 3 h

Procedure:
To a stirred solution Ethyl 2-(3-(3,5-dimethylbenzyloxy)phenyl)acetate (Step A, 2.38 g, 8.0 mmol) in absolute ethanol (40 ml) was added 1N NaOH (16 ml) at room temperature. The reaction mixture was stirred for 3 hours, or until all the starting material is gone, concentrated and diluted with chloroform and acidified by 1M HCl to bring the pH to 3.5-4. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to give the title compound as white solid.
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)(C)(C)C.[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([OH:20])=[O:19]>>[C:6]([CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:24]1[CH:25]=[CH:26][C:21]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=1)([OH:5])=[O:17]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: O=C(O)COc1ccc(Cl)cc1-c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared by the method of example 1 step (ii) and step (iii) using the product from example 1 step (i) and 4-carboxyphenylboronic acid. Yield 0.035 g
Reaction SMILES: N1C=CN=C1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([CH3:26])[N:16](O)[C:17]=2[C:18]2[CH:23]=[CH:22][NH:21][C:20](=[O:24])[CH:19]=2)=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:12]=[CH:11][C:10]2=[C:13]3[N:14]=[C:15]([CH3:26])[NH:16][C:17]3=[C:18]3[C:19]([C:20](=[O:24])[NH:21][CH:22]=[CH:23]3)=[C:9]2[CH:8]=1
Reactant: Cc1nc(-c2ccc(F)cc2)c(-c2cc[nH]c(=O)c2)n1O
Agent: c1c[nH]cn1
Product: Cc1nc2c3ccc(F)cc3c3c(=O)[nH]ccc3c2[nH]1

Procedure:
The title compound was prepared as a mixture of imidazole tautomers from 4-[4-(4-fluorophenyl)-1-hydroxy-2-methyl-1H-imidazol-5-yl]pyridin-2(1H)-one (EXAMPLE 8, Step A) following the procedure described in EXAMPLE 1, Step E.