Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[CH:15]=[N:14][CH:13]=[CH:12][C:11]=3[C:10](=O)[C:9]=2[C:8](F)=[CH:7][CH:6]=1>N1C=CC=CC=1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:2]([CH3:1])[N:3]=[C:10]3[C:11]4[CH:12]=[CH:13][N:14]=[CH:15][C:16]=4[C:17](=[O:19])[C:18]=1[C:9]=23
Reactant: CNN
Reactant: O=C1c2ccncc2C(=O)c2c(Cl)ccc(F)c21
Solvent: c1ccncc1
Product: Cn1nc2c3c(c(Cl)ccc31)C(=O)c1cnccc1-2
Reaction time: 0.1 h
Yield: 71 %

Procedure:
A solution of methyl hydrazine (0.76M; 0.021 g) in pyridine (0.6 mL) is added dropwise over two min to a stirred solution of 9-chloro-6-fluorobenzo[g]isoquinoline-5,10-dione of Preparative Example 13 in pyridine (0.5 mL) cooled with an ice-bath. A yellow precipitate appears in the dark solution after 6 min. After 1.3 h the reaction mixture is reduced to half its volume by a gentle stream of nitrogen and quenched with ice (5 g). The pale yellow precipitate is collected by suction filtration and washed with ice-water (2×1 mL) and dried under vacuum. The yellow solid is purified by silica gel column chromatography (eluant: chloroform/methanol 96/4 v/v) to yield 5-chloro-2-methylisoquino[5,6,7-cd]indazole-6(2H)-one (0.033 g; 71% yield) as a yellow solid.
Reaction SMILES: COC([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([NH:17][CH:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([CH3:28])[CH:26]=4)[O:21][CH2:20][CH2:19]3)=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=O.COC(N1C2C(=C(NC(NC3C4C(=CC(C(C)(C)C)=CC=4)OCC3)=O)C=CC=2)C=N1)=O>O>[NH:5]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([NH:17][CH:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([CH3:28])[CH:26]=4)[O:21][CH2:20][CH2:19]3)=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CCOc4ccc(C)cc43)cccc21
Agent: COC(=O)n1ncc2c(NC(=O)NC3CCOc4cc(C(C)(C)C)ccc43)cccc21
Solvent: O
Product: Cc1ccc2c(c1)C(NC(=O)Nc1cccc3[nH]ncc13)CCO2

Procedure:
The title compound was prepared using the procedure as described in Example 1E, substituting the product of Example 7C for the product of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ 13.00 (broad s, 1H), 8.56 (s, 1H), 8.02 (s, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.20 (m, 1H), 7.12-6.94 (m, 3H), 6.86 (d, J=7.5 Hz, 1H), 6.70 (d, J=7.5 Hz, 1H), 4.92 (m, 1H), 4.33-4.00 (m, 2H), 2.22 (s, 3H), 2.20-1.93 (m, 2H). MS (ESI) m/e 323 (M+H)+. Calcd. For C18H18N4O2.0.9; H2O 0.25 NaCl: C, 61.21; H, 5.65; N, 15.86. Found: C, 61.02; H, 5.74; N, 15.84.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:15][CH2:16]1)[C:10]([O:12][CH3:17])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CC1)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](CC1CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a mixture of (S)-2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoic acid (CAN 89483-06-7, 6.792 g, 30 mmol) and K2CO3 (8.173 g, 59 mmol) in DMF (100 mL) was added MeI (10.37 g, 73 mmol). The reaction mixture was stirred overnight at room temperature. After filtration, the filtrate was concentrated to give the title compound as yellow oil (6.44 g, 89%); MS (EI): m/e=266.2 [M+Na]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:10]([CH2:25][CH2:26][CH3:27])[CH:11]1[CH2:20][C:19]2[C:14](=[C:15]([C:21]([NH2:23])=O)[CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=O)[CH2:8][CH3:9]>C1COCC1>[NH2:23][CH2:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[NH:13][CH2:12][CH:11]([N:10]([CH2:25][CH2:26][CH3:27])[CH2:7][CH2:8][CH3:9])[CH2:20]2
Reactant: CCCN(CCC)C1Cc2cccc(C(N)=O)c2NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCN(CCC)C1CNc2c(CN)cccc2C1
Yield: 59 %

Procedure:
Lithium aluminum hydride (1.5 g) was added to a stiffed solution of 3-(dipropylamino)-1,2, 3,4-tetrahydro-2-oxo-8-quinolinecarboxamide (0.75 g) in THF (125 mL) and the solution was refluxed for 2 days. The solution was cooled and excess hydride was destroyed by addition of methanol (20 mL) and the solvents were removed under reduced pressure. The residue was partitioned between ethyl acetate (400 mL) and water (15 mL). The ethyl acetate was decanted from the inorganic solids and the solvent removed under reduced pressure. The residual oil was dissolved in chloroform and chromatographed on silica gel. Elution of the column with 5% methanol:chloroform gave 0.40 g of 1,2,3,4-tetrahydro-8-(aminomethyl)-N,N-dipropyl-3-quinolinamine.
Reaction SMILES: [CH2:1]([C:8]1[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O.[NH2:28][NH2:29]>CCO>[CH2:1]([C:8]1[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:28][NH2:29])=[O:20])=[CH:17][CH:16]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NN
Reactant: CCCCCCCc1ccc(C(=O)Nc2ccc(C(=O)OC)cc2)cc1
Solvent: O
Solvent: CCO
Product: CCCCCCCc1ccc(C(=O)Nc2ccc(C(=O)NN)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
To a suspension of methyl 4-[(4-heptylbenzoyl)amino]benzoate (823 mg, 2.33 mmol) in EtOH (10 mL) was added hydrazine hydrate (1.8 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (1×2 mL) and water (2×2 mL), and drying under vacuo at rt for 72 hrs gave 619 mg of the title compound (75%) as a white solid in 99.4% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:23])=[O:5])[CH3:2].[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([Br:24])[C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2nc(-c3cccc(OC)c3)sc2c1O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2nc(-c3cccc(OC)c3)sc2c1O
Temperature: 25 °C
Yield: 42.4 %

Procedure:
A mixture of 7-hydroxy-2-(3-methoxy-phenyl)-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (643 mg, 1.95 mmole), N-bromosuccinimide (364 mg, 2.04 mmole) and benzoyl peroxide (23 mg, 9.74 mmole) in carbon tetrachloride (9.5 ml) was refluxed for 5 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (338 mg). MS: (+) m/z 409.11, 411.11 (M+1, 79Br/81Br).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5]Cl.[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])([CH3:10])([CH3:9])[CH3:8]>CN(C)C=O>[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:3][O:4][CH3:5])([CH3:10])([CH3:8])[CH3:9]
Reactant: COCCl
Reactant: CC(C)(C)c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccccc1C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 111.7 %

Procedure:
Sodium hydride (214 g, 4.90 mol) and chloromethyl methyl ether (394 g, 4.90) were gradually added to a solution of 2-tert-butylphenol (700 g, 4.67 mol) in dimethylformamide (3000 ml) while cooling on ice and the mixture was stirred at 0° C. for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate, and then the organic layer was washed with water and brine in that order and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1013 g) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][CH3:8])=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([NH:16][C@@H:17]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:40])([F:39])[F:38])[CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)=[O:15])[S:12][CH:13]=2)[N:4]([CH3:41])[N:3]=1.NN>O1CCCC1.CO>[NH2:19][CH2:18][C@@H:17]([NH:16][C:14]([C:11]1[S:12][CH:13]=[C:9]([C:5]2[N:4]([CH3:41])[N:3]=[C:2]([Cl:1])[C:6]=2[CH2:7][CH3:8])[CH:10]=1)=[O:15])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38]
Reactant: CCc1c(Cl)nn(C)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: CCc1c(Cl)nn(C)c1-c1csc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)c1
Yield: 81.2 %

Procedure:
To a solution of 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (190 mg, 0.32 mmol) in tetrahydrofuran (1.58 ml) and methanol (1.58 ml) at 25° C. was added hydrazine (0.08 ml, 2.53 mmol) dropwise. After 12 h the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH4OH)). The free base was transferred to the HCl salt by addition of excess 4M HCl in Ether (2 ml) to the residue in DCM (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (145 mg, 0.26 mmol, 83% yield) as a yellow solid: LCMS (ES) m/z=471, 473 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.80 (br. s., 1H) 7.87-7.99 (m, 6H) 7.69 (d, J=7.71 Hz, 1H)) 7.57 (d, J=7.83 Hz, 1H) 7.40-7.44 (m, 1H) 4.43-4.48 (m, 1H) 3.74 (s, 3H) 2.99-3.06 (m, 4H) 2.40 (d, J=7.58 Hz, 2H) 1.04 (t, J=7.58 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=3)[C:11]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:8]2[S:9][CH:10]=1)=[O:5])[CH3:2].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:36]([NH:35][C:32]4[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:38])[F:39])=[CH:34][CH:33]=4)=[O:37])[CH:15]=3)[C:11]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)=[C:8]2[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1csc2c(-c3ccncc3)c(-c3cccc(N)c3)nn12
Solvent: ClCCl
Product: CCOC(=O)c1csc2c(-c3ccncc3)c(-c3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
6-(3-Amino-phenyl)-7-pyridin-4-yl-pyrazolo[5,1-b]thiazole-3-carboxylic acid ethyl ester (33 mg, 0.091 mmol) was dissolved in dry DCM (0.5 mL) under nitrogen atmosphere. p-Trifluoromethylphenylisocyanate (0.014 mL, 0.100 mmol, 1.1 eq) was added and the mixture was stirred at room temperature for 1 hour. The solution was evaporated to dryness and the crude product was purified by chromatography on silica gel (DCM/MeOH 97:3) to give 31 mg (61%) of 7-pyridin-4-yl-6-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-pyrazolo[5,1-b]thiazole-3-carboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1.CO.Cl.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34]Cl>[OH-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10]([CH2:34][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)([CH2:17][C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1
Reactant: O=C1C(Cc2ccncc2)c2cccnc2N1c1ccc(Cl)cc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1N(c2ccc(Cl)cc2)c2ncccc2C1(Cc1ccncc1)Cc1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 1,3-dihydro-1-(4-chlorophenyl)-3-(4-pyridinylmethyl)-2H-pyrrolo[2,3-b]pyridin-2-one (3.0 g, 8.93 mmol) in 20 ml 1N NaOH was treated with enough MeOH to effect solution. The solution was treated dropwise with a solution of 2-picolylchloride hydrochloride (1.6 g, 9.82 mmol) in 10 ml water over 10 min. The mixture was stirred at room temperature for 16 h, and the resulting solid was colledted by filtration, washed with water, and dried. The solid was recrystallized from CHCl3 --C6H12 to give the desired product in 79% (3.0 g) yield : m.p. 193°-195° ; 1H NMR (300 MHz, CDCl3TMS) δ [3.34 (d, J=12, 1H), 3.56 (d, J=12, 1H) CH2 -(2-Pyr)], [3.48 (d, J=14, 1H), 3.78 (d, J=14, 1H) CH 2 -(4-Pyr)], [6.95 (m, 1H), 8.0 (m, 1H), 8.27 (d, J=7, 1H) Pyr], [7.0 (m, 6H), 7.5 (m, 2H) 2-Pyr & 4-Cl-Phe]), [7.42 (d, J=7, 2H), 8.32 (d, J=7, 2H) 4-Pyr]; IR (Nujol) 1732 (C=O) cm-1 ; MS (NH3 -CI) m/e 427(M+1)/100; Analysis calc'd for C25H19N4OCl H2O: C, 67.49; H, 4.76; N, 12.59; found: C, 67.38; H, 5.01; N, 12.34.
Reaction SMILES: CS(O[CH:6]([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)(=O)=O.[Li+].[Br-:18]>CC(C)=O>[Br:18][CH:6]([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1
Reactant: [Br-]
Reactant: COc1cccc(CC(C)OS(C)(=O)=O)c1
Agent: [Li+]
Solvent: CC(C)=O
Product: COc1cccc(CC(C)Br)c1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
A round-bottomed flask was charged with 1-methyl-2-[3-(methyloxy)phenyl]ethyl methanesulfonate (2) (90 g, 0.368 mol), LiBr (80 g, 0.92 mol), and acetone (650 mL). The reaction mixture was refluxed for 24 h under N2 and then cooled to room temperature. The reaction mixture was filtered and concentrated under reduced pressure to afford the crude product. The product was passed through a pad of silica gel to remove inorganic impurities. The product was distilled under reduced pressure (2-3 mm Hg) at 130-135° C. to afford ˜85 g (100%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 7.25 (dd, J1=8.00 Hz, J2=8.00 Hz, 1H), 6.84-6.78 (m, 3H), 4.32 (sextet, J=4.00 Hz, 1H), 3.82 (s, 3H), 3.25 and 3.21 (dd, J1=16.00 Hz, J2=8.00 Hz, 1H), 3.07 and 3.04 (dd, J1=16.00 Hz, J2=8.00 Hz, 1H), 1.71 (d, J=8.00 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17](Br)[CH:16]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2].[C:29]([C:31]1[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1)#[CH:30].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:16]=[C:17]([C:30]#[C:29][C:31]3[CH:32]=[CH:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][CH:36]=3)[CH:18]=[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:20]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2]
Reactant: CCOC(=O)COc1ccc(SCc2cc(Br)cc(OCC(C)C)c2)cc1C
Reactant: C#Cc1ccc(S(C)(=O)=O)cc1
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(SCc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(OCC(C)C)c2)cc1C

Procedure:
The title product was prepared from [4-(3-Bromo-5-isobutoxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (300 mg; 0.64 mmol) and 1-Ethynyl-4-methanesulfonyl-benzene (347.0 mg; 1.93 mmol) applying the procedure described for {4-[3-[2-(4-Chlorophenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method A). Yield: 260 mg (72%). HPLC-MS: m/z: 567.6 (M+H)+; Rt: 2.77 min
Reaction SMILES: [N:1]1([CH2:10][C:11]([OH:13])=O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.S(Cl)(Cl)=O.[C:18]1([C:24]2[N:29]=[C:28]([NH2:30])[CH:27]=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CC=CC=1>CN(C)C=O>[N:1]1([CH2:10][C:11]([NH:30][C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:29]=2)=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)Cn1cnc2ccccc21
Reactant: Nc1cccc(-c2ccccc2)n1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(Cn1cnc2ccccc21)Nc1cccc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1H-benzimidazol-1-yl)acetic acid (1 g, 5.68 mmol) (Example 1B) in N,N-dimethylformamide (25 mL) was added thionyl chloride (0.4 mL, 5.56 mmol) drop-wise and the reaction mixture stirred at room temperature for 1 h. 6-Phenyl-pyridin-2-ylamine (5.46 mmol) and pyridine (4 mL) were then added to the reaction mixture and stirred at room temperature for 17 h. The reaction mixture was then concentrated in vacuo and dichloromethane was added and transferred to a separating funnel where the organics were washed with 0.1M hydrochloric acid and 10% ammonium hydroxide solution. The organic layers were combined and washed with saturated aqueous sodium chloride, dried (Mg2SO4), filtered and concentrated in vacuo. The residue was then purified by column chromatography using silica and eluting with 0-10% methanol in dichloromethane, affording the title compound. 1H NMR (400 MHz, CD3OD) δ ppm 5.29 (2H, s), 7.28-7.35 (2H, m), 7.39-7.48 (3H, m), 7.54 (1H, d, J=7.2 Hz), 7.62 (1H, d, J=7.7 Hz), 7.71 (1H, d, J=7.3 Hz), 7.81 (1H, t, J=7.9 Hz), 7.98 (1H, br d), 8.05 (2H, d, J=7.3 Hz), 8.23 (1H, s). MS (ES) m/z: 329.1 [M+H].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]([OH:21])=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15]([CH2:22][NH:23][C:24]([C:26]2[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][C:27]=2[CH2:35][CH2:36][CH2:37][CH3:38])=[O:25])=[CH:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:40][C:41]#[N:42].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]([O:21][CH2:40][C:41]#[N:42])=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15]([CH2:22][NH:23][C:24]([C:26]2[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][C:27]=2[CH2:35][CH2:36][CH2:37][CH3:38])=[O:25])=[CH:16]3)=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCBr
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(C(C)(C)C)cc3)c(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(C(C)(C)C)cc3)c(OCC#N)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid [5-(4-tert-butyl-phenyl)-6-hydroxy-naphthalen-2-ylmethyl]-amide (400 mg, 0.79 mmol), prepared in the previous step, bromoacetonitrile (66 μL, 0.95 mmol) and potassium carbonate (547 mg, 3.96 mmol) in 20 mL of DMF was stirred under nitrogen at room temperature for 19 h (overnight). The reaction was diluted with ethyl acetate, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give a light brown solid. Purification of the solid on a 40 g KP-SIL 60 Δ Biotage column gave 2-butyl-benzofuran-3-carboxylic acid [5-(4-tert-butyl-phenyl)-6-cyanomethoxy-naphthalen-2-ylmethyl]-amide (262 mg, 63%) as a white solid, mp 162-164° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8]N)[CH:5]=[CH:6][CH:7]=1.[N:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][C:11]=1[OH:17].C1(C)C=CC=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:12]3[C:11](=[O:17])[NH:10][CH:15]=[CH:14][C:13]=3[NH:8][C:4]=2[CH:3]=1
Reactant: Oc1ccnc(O)c1
Reactant: NNc1cccc(Br)c1
Solvent: Cc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1[nH]ccc2[nH]c3cc(Br)ccc3c12
Temperature: 232 °C
Reaction time: 0.75 h

Procedure:
(3-Bromophenyl)hydrazine HCl (20.5730 g, 92.4 mmol) was dissolved in 6.25 N aqueous NaOH (16 mL, 100 mmol), ethanol (80 mL) and water (60 mL), and extracted with EtOAc (200 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. CH2Cl2 (150 mL) was added, dried over MgSO4, filtered and concentrated in vacuo to give (3-bromophenyl)hydrazine as a light orange oil. To a heterogeneous solution of (3-bromophenyl)hydrazine (17.19 g, 92 mmol) in Phenyl ether (82 mL) was added pyridine-2,4-diol (5.11 g, 46.0 mmol). A Dean-Stark trap was set up, and the reaction was heated at 232° C. for 4 hours. A strong effervescence and gas evolution occurred often for 45 min. The solution turned homogeneous with decrease in frequency of strong effervescence and gas evolution. The reaction mixture was cooled to room temperature; precipitation ensued. HPLC and LCMS showed completion of reaction (86784-071-01). Toluene (100 mL) was added, and the mixture stirred overnight at room temperature. The mixture was filtered and the precipitate was collected. Methanol (40 mL) was added, and the solution was stirred for 20 min. The precipitate was filtered and washed with methanol, dried to give 7-bromo-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one as a tan solid. Methanol (60 mL) was added, and the mixture was stirred for 7 h. The precipitate was collected to give 7-bromo-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (4.4374 g, 16.87 mmol, 36.7% yield) a light tan solid. The precipitate was collected to give 7-bromo-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (4.4374 g, 16.87 mmol, 36.7% yield) a light tan solid. The product had an HPLC Retention Time=2.585 min[mixture of rotamers] [4 min grad, 10% MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50 mm, 220 nM; LC/MS+1 263.04; 265.04
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].C(=O)([O-])[O-].[K+].[K+].[C:39](Cl)(=[O:41])[CH3:40]>CN(C)C=O>[C:39]([N:11]1[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=2)[C@H:9]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:10]1)(=[O:41])[CH3:40]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reaction time: 3 h

Procedure:
To a stirred mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (0.15 g) and potassium carbonate (0.14 g) in dimethylformamide (10 ml) was added acetyl chloride (0.04 ml) at room temperature. After being stirred for 3 hours, the reaction mixture was quenched with water (50 ml) and extracted with dichloromethane (50 ml). The organic layer was washed with aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified on a silica gel column (10 g) eluting with a mixture of dichloromethane and methanol (20:1). The fractions containing object compound were collected and evaporated under reduced pressure. To the resulting oily product was added a mixed solvent of ethyl ether and diisopropyl ether, and the mixture was concentrated under reduced pressure. The obtained powder was collected by filtration and dried in vacuo to give (2R)-4-acetyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (0.09 g) as a powder.