Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl[C:10]1[N:15]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:13]=[CH:12][CH:11]=1>C1COCC1.CN1C(=O)CCC1.CCOCC>[CH2:1]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=S(=O)(Oc1cccc(Cl)n1)C(F)(F)F
Reactant: CCCCCC[Mg]Br
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CCCCCCc1cccc(CCCCCC)n1
Yield: 73 %

Procedure:
A solution of n-hexylmagnesium bromide (2M in Et2O, 3.3 mL) is added to a solution of 6-chloro-2-(trifluoromethanesulfonyloxy)pyridine (435 mg, 1.66 mmol) in THF (7 mL) and NMP (0.5 mL) at 0° C. The reaction mixture turns black and GC inspection indicates quantitative conversion of the substrate after 5 min reacion time. For work-up, the mixture is diluted with Et2O (20 mL) and quenched with brine (20 mL), the aqueous phase is repeatedly extracted with Et2O, the combined organic layers are dried over Na2SO4 and evaporated, and the residue is purified by flash chromatography (hexanes/ethyl acetate, 15/1) to afford 2,6-di(hexyl)pyridine as a colorless liquid (301 mg, 73%). 1H NMR (300 MHz, CDCl3): δ 7.47 (t, J=7.7 Hz, 1H), 6.93 (d, J=7.7 Hz, 2H), 2.70 (t, J=7.8 Hz, 4H), 1.68 (m, 4H), 1.32 (m, 12H), 0.88 (t, J=6.5 Hz, 6H). 13C NMR (75 MHz, CDCl3): δ 161.9, 136.2, 119.5, 38.5, 31.8, 30.0, 29.1, 22.7, 13.9. IR: 3060, 2955, 2926, 2871, 2856, 1590, 1577, 1456, 1378, 750 cm−1. MS m/z (rel. intensity) 247 (5, [M+]), 218 (7), 204 (22), 190 (23), 177 (100), 134 (12), 120 (44), 107 (15). HR-MS (C17H29N) calcd. 247.229999; found 247.229778.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:20][CH2:19][CH2:18][CH2:17][N:8]2[CH:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[O:32])=[CH:26][CH:25]=1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Reactant: O=C=Nc1ccc(Cl)cc1
Product: O=C(NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1)Nc1ccc(Cl)cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 4-chlorophenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([O:17][CH3:23])=[O:16])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1cnoc1-c1ccc(Br)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(Br)cc1
Yield: 96 %

Procedure:
A mixture of 3-[5-(4-bromophenyl)-4-isoxazolyl]propionic acid (5.00 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(4-bromophenyl)-4-isoxazolyl]propionate (5.03 g, yield 96%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 58–59° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)[CH3:19]>CC(N(C)C)=O>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:24][N:25]1[CH2:26][CH2:27][CH:28]([NH:31][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:3]=2)[CH2:29][CH2:30]1)[CH3:19]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3nc(-c4ccccc4)nc4ccccc34)CC2)ccc1OC
Yield: 3 %

Procedure:
A solution of 4-chloro-2-phenyl-quinazoline (36.1 mg, 0.15 mmol, 1.0 equiv; commercially available) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (1.5 mL) was heated by microwave irradiation to 180° C. for 10 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 1.6 mg (3%) of the title compound. MS (ISP): 469.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=O)[CH3:5].[NH2:8][C:9]1[N:13]=[C:12]([SH:14])[NH:11][N:10]=1.N1CCCCC1>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:5])[N:10]2[N:11]=[C:12]([SH:14])[N:13]=[C:9]2[N:8]=1
Reactant: Nc1n[nH]c(S)n1
Reactant: CC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: Cc1cc(C)n2nc(S)nc2n1
Temperature: 125 °C
Yield: 81.6 %

Procedure:
A mixture of 2,4-pentanedione (6.46 g, 64.6 mmol), 3-amino-5-mercapto-1,2,4-triazole (7.5 g, 64.6 mmol), glacial acetic acid (230 mL), and piperidine (0.58 mL, 5.9 mmol) was added to a 500 mL RBF with a magnetic stirring bar. The flask was fitted with a condenser, and warmed in an oil bath to a gentle reflux at 125° C. The mixture was heated for 45 hours, and solids remained visible in the flask throughout the heating period. Progress of the reaction was monitored by analytical HPLC with UV detection at 215 and 254 nm. The starting material 3-amino-5-mercapto-1,2,4-triazole elutes rapidly with retention time of 1.05 min, and the product elutes with retention time of 1.87 min. The mixture was cooled to room temperature. Solids were isolated by filtration, rinsed with 75 mL of acetic acid, and then dried under reduced pressure to afford the title compound as a pale yellow powder (9.5 g, 82% yield). A sample of 120 mg was recrystallized in warm acetic acid to afford 60 mg (50% recovery) of fine off-white needles, while the crude powder was used in the next step. 1H NMR (DMSO-d6+CDCl3, 400 MHz) δ ppm: 14.05 (br s, 1H), 7.25 (s, 1H), 2.67 (s, 3H), 2.56 (s, 3H). (NMR from crystalline material.)
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1>>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:3])=[O:11])=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(F)cc1[N+](=O)[O-]
Product: O=C(Cl)c1ccc(F)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
5 mL of thionyl chloride was added to 0.5 g of 4-fluoro-2-nitrobenzoic acid and stirred overnight. The thionyl chloride was removed to obtain the title compound.
Reaction SMILES: Cl.O1[CH2:7][CH2:6]OCC1.[C:8]1([CH3:49])[C:9]([C:14]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]([C:28]([C:30]34[CH2:39][CH:34]5[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]5)[CH2:31]3)[CH2:37]4)=[O:29])[CH2:20][CH:19]([NH:40][C:41](OC(C)(C)C)=[O:42])[C:18]2=[O:48])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1>C(O)C>[C:8]1([CH3:49])[C:9]([C:14]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]([C:28]([C:30]34[CH2:37][CH:36]5[CH2:35][CH:34]([CH2:33][CH:32]([CH2:38]5)[CH2:31]3)[CH2:39]4)=[O:29])[CH2:20][CH:19]([NH:40][C:41]([NH:17][C:23]3[CH:22]=[CH:27][CH:26]=[C:6]([CH3:7])[CH:24]=3)=[O:42])[C:18]2=[O:48])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C1COCCO1
Reactant: Cc1ccccc1C(=O)CN1C(=O)C(NC(=O)OC(C)(C)C)CN(C(=O)C23CC4CC(CC(C4)C2)C3)c2ccccc21
Agent: Cl
Solvent: CCO
Product: Cc1cccc(NC(=O)NC2CN(C(=O)C34CC5CC(CC(C5)C3)C4)c3ccccc3N(CC(=O)c3ccccc3C)C2=O)c1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 93.1 %

Procedure:
4N HCl-dioxane (5.0 ml) was added to 1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(adamantan-1-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (400 mg) in anhydrous ethanol (15 ml), and the mixture was stirred at 50° C. for 15 minutes. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate was added to the residue, followed by extraction with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, to thereby obtain 1-(2-toluoylmethyl)-2-oxo-3-amino-5-(adamantan-1-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine. Subsequently, this compound was dissolved in anhydrous tetrahydrofuran (10 ml), and m-tolyl isocyanate (0.10 ml) was added to thereto. The mixture was stirred at room temperature for 15 minutes. The solvent was evaporated under reduced pressure. A solvent mixture of isopropyl ether and ethanol was added thereto for solidification and collection by filtration, to thereby obtain 394 mg of the title compound (yield: 93.1%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.BrC1C=CC([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[CH:21][C:20]=2[O:28][CH3:29])=NC=1>>[CH3:29][O:28][C:20]1[CH:21]=[C:22]([CH2:25][CH2:26][CH3:27])[CH:23]=[CH:24][C:19]=1[O:18][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: CCCc1ccc(Oc2ccc(Br)cn2)c(OC)c1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: CCCc1ccc(Oc2ccc([N+](=O)[O-])nc2)c(OC)c1
Yield: 103.3 %

Procedure:
According to the procedure of example 20(a), except substituting 1-fluoro-4-nitro-2-(trifluoromethyl)benzene for 5-bromo-2-nitropyridine (406 mg, 2 mmol), the title compound (220 mg; 38%) was prepared as a white solid, after chromatography on silica gel (gradient cyclohexane/dichloromethane), along with 5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine (238 mg; 37%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:10]([NH:23]C=O)[CH:9]=2)=[O:5])[CH3:2].Cl>CC(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[C:10]([NH2:23])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)c(NC=O)cc2[nH]1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)c(N)cc2[nH]1

Procedure:
5-Benzyloxy-6-formylamino-1H-indole-2-carboxylic acid ethyl ester (0.2 g, 0.591 mmol) is suspended in a 9:1 mixture of acetone/water (10 mL). The suspension is treated with 1N HCl (1.8 mL) and brought to reflux for 1 h. The separated solid is filtered, washed with saturated aqueous sodium bicarbonate and water, and air dried for 2 h to afford 6-amino-5-benzyloxy-1H-indole-2-carboxylic acid ethyl ester as a grey solid: (M−H)−=311.
Reaction SMILES: N[CH:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH:12]([CH2:17][C:18]([O:20]C)=[O:19])[C:13]([O:15]C)=[O:14])[CH:5]=[N:4][C:3]1=2.C(O)(=[O:24])C.N([O-])=O.[Na+].C(OCC)C>O>[O:24]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH:12]([C:13]([OH:15])=[O:14])[CH2:17][C:18]([OH:20])=[O:19])[CH:5]=[N:4][C:3]1=2
Reactant: CC(=O)O
Reactant: COC(=O)CC(Cn1cnc2c1N=CNC2N)C(=O)OC
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(O)CC(Cn1cnc2c(=O)[nH]cnc21)C(=O)O
Yield: 31 %

Procedure:
2.00 g (6.82 mmol) of 2-[(1,6-dihydro-6-amino-9H-purin-9-yl)methyl]butanedioic acid, dimethyl ester (AIT-0073) was placed into a 50 ml round bottom flask equipped with a magnetic stirring bar. Then 10 ml glacial acetic acid was added and the solution was stirred until homogeneous. 2.35 g (34.10 mmol) of NaNO2 in 4 ml of H2O was added to the stirring solution dropwise. The stoppered solution was stirred for 24 hours at room temperature. An additional 0.775 g (11.23 mmol) of NaNO2 in 1 ml H2O was added and the solution was stirred for another 24 hours. The acetic acid was removed under reduced pressure on the rotary evaporator. Water was added and was removed in the same manner. This was repeated again until little or no more acetic acid was left. 10 ml of H2O was added to the semi-solid residue to completely dissolve the mixture. This solution was extracted with 30 ml-40 ml of acetonitrile and the aqueous layer was discarded. The organic layer was washed twice with 30 ml of saturated brine. Upon evaporation of the solvent, a light orange oil was obtained. This was treated with 35 ml of ethyl ether and triturated with methanol to yield 615 mg of 3-[(1,6-dihydro-6-oxo-9H-purin-9-yl)methyl]butanedioicacid, methyl diester (AIT-0075) as an off-white solid. Yield: 31% m.p. 130°-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:26])[C:9](=[O:25])[CH2:10][CH:11]([CH2:18][CH2:19]OS(C)(=O)=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:27]1([CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOC(C)=O.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:26])[C:9](=[O:25])[CH2:10][CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18][CH2:19][N:37]2[CH2:38][CH2:39][N:34]([CH2:33][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:35][CH2:36]2)=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CN(C(=O)CC(CCOS(C)(=O)=O)c1ccccc1)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)CC(CCN1CCN(Cc2ccccc2)CC1)c1ccccc1)c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 44.7 %

Procedure:
N-(4-Chlorophenyl)-beta-(2-methanesulfonyloxyethyl)-N-methyl-benzenepropanamide (0.93 g) in DMF (10 mL) was treated with N-phenylmethylpiperazine (1.03 g) and the mixture heated at 80° C. for 2 hours. The cooled reaction mixture was diluted the EtOAc (50 mL) and water (50 mL) and the aqueous phase removed. The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic extracts, washed with water (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give an oil. Silica gel chromatography eluting with 10% MeOH:CH2Cl2 gave the title compound (0.5 g). Mass spectrum (FAB): 476.3.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([CH:11]=O)[CH:7]=1.[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([N:19]=[CH:20][C:21]([S:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]3)=[N:22]2)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([N:19]=[CH:20][C:21]([S:25][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][CH:31]([NH:34][CH2:11][C:8]4[CH:7]=[C:6]([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)[O:10][N:9]=4)[CH2:32][CH2:33]3)=[N:22]2)=[CH:17][CH:16]=1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Reactant: O=Cc1cc(-c2cccs2)on1
Product: COc1ccc2ncc(SCCN3CCC(NCc4cc(-c5cccs5)on4)CC3)nc2c1

Procedure:
The title compound is prepared as a yellow oil (57 mg, 52% yield) following Scheme 3 and in analogy to Example 40 using 5-thiophen-2-yl-isoxazole-3-carbaldehyde (43 mg, 0.22 mmol 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70 mg, 0.22 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[CH:4]=[N:3][CH:2]=1.[Br:10]Br>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Br:10][C:9]1[C:5]2[CH:4]=[N:3][CH:2]=[N:1][C:6]=2[NH:7][CH:8]=1
Reactant: c1ncc2cc[nH]c2n1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c[nH]c2ncncc12
Reaction time: 1.5 h

Procedure:
5-Bromo-7H-pyrrolo[2,3-d]pyrimidine (7) is prepared by dissolving 7H-pyrrolo[2,3-d]pyrimidine (6) in chloroform and slowly adding Br2 in carbon tetrachloride at 0° C. After stirring for 1-2 hours, the reaction may be quenched in aqueous hydrochloric acid. Isolation by conventional means (e.g. extraction and silica gel chromatography) provides compound 7.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Br[C:27]1[CH:28]=[C:29]([C:33]2[CH:38]=[C:37]([C:39]([OH:42])([CH3:41])[CH3:40])[N:36]=[C:35]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)[CH:34]=2)[CH:30]=[N:31][CH:32]=1.C(Cl)Cl>COCCOC.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[C:37]([C:39]([OH:42])([CH3:41])[CH3:40])[N:36]=[C:35]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=5)[CH:34]=4)[CH:30]=[N:31][CH:32]=3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)(O)c1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Reactant: CC(C)N1CCN(Cc2ccc(B(O)O)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)N1CCN(Cc2ccc(-c3cncc(-c4cc(-c5ccccn5)nc(C(C)(C)O)c4)c3)cc2)CC1

Procedure:
To a solution of 4-((4-isopropyl-piperazin-1-yl)methyl)-phenyl boronic acid (Intermediate B3) (1.2 eq, 0.324 mmol, 0.085 g) and 2M Na2CO3 (2.4 eq, 0.648 mmol, 0.32 ml) in DME (3 ml) is added 2-(5″-bromo-[2,2′;4′,3″]terpyridin-6′-yl)-propan-2-ol (1 eq, 0.27 mmol, 0.1 g) followed by [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II), complex with DCM (0.1 eq, 0.027 mmol, 0.022 g). The reaction mixture is heated using microwave radiation at 95° C. for 90 minutes. The reaction mixture is dissolved in EtOAc and washed with water. The organic layer is washed with brine, dried over MgSO4, filtered and the organic solvent is reduced in vacuo. The crude residue is purified by reverse phase column chromatography (Isolute™ C18, 0-20% acetonitrile in water—0.1% TFA). The appropriate fractions are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 508.
Reaction SMILES: [C:1]([C:4]1[C:20]([OH:21])=[CH:19][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[C:15]#[N:16])=[C:6]([CH2:22][CH3:23])[CH:5]=1)(=[O:3])[CH3:2].[OH-:24].[Na+]>C(O)C>[C:1]([C:4]1[C:20]([OH:21])=[CH:19][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:17])([CH3:18])[C:15]([NH2:16])=[O:24])=[C:6]([CH2:22][CH3:23])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCc1cc(C(C)=O)c(O)cc1OCCCCCC(C)(C)C#N
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCc1cc(C(C)=O)c(O)cc1OCCCCCC(C)(C)C(N)=O

Procedure:
A mixture of 500 mg of 7-(4-acetyl-2-ethyl-5-hydroxyphenoxy)-2,2-dimethylheptanenitrile in 150 ml of 5N sodium hydroxide and 50 ml of ethanol was heated at reflux overnight. The ethanol was removed by evaporation, 100 ml of water were added, and the solution was extracted with diethyl ether. The organic layer was separated, dried, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography over silica gel eluting with 1:1 ethyl acetate/hexane to provide 34 mg of the desired title product, m.p.=73°-74° C.
Reaction SMILES: C([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=O)CCC.FC1C=CC=CC=1N>O1CCOCC1>[CH3:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][CH:6]=[CH:15]2
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Agent: Nc1ccccc1F
Solvent: C1COCCO1
Product: Cc1cccc2cccnc12
Yield: 154.3 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (2.48 g, 10 mmol), 2-fluoroaniline (1.45 ml, 15 mmol) and 1,4-dioxan (10 ml) were stirred at room temperature overnight then heated at reflux for 30 minutes. The hydrochloride salt was filtered off, converted to free base and recrystallised from aqueous ethanol to give 3-butyryl-4- 2-fluorophenylamino)-8-methylquinoline (2.21 g), m.p. 109°-111°.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[C:29]([C:33]3[N:34]=[CH:35][N:36]([CH2:38][CH2:39][C:40]([NH2:42])=[O:41])[CH:37]=3)[CH:30]=[C:31]([CH3:32])[C:5]=2[N:4]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[C:29]([C:33]3[N:34]=[CH:35][N:36]([CH2:38][CH2:39][C:40]([NH2:42])=[O:41])[CH:37]=3)[CH:30]=[C:31]([CH3:32])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(-c3cn(CCC(N)=O)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(C)cc(-c3cn(CCC(N)=O)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-ethyl-4-methyl-6-(1-(2-aminocarbonylethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Br:11].CN([C:15]([O:19][N:20]1N=NC2C=CC=N[C:21]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CONC>CN(C)C=O.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:20]([O:19][CH3:15])[CH3:21])=[O:7])=[CH:4][C:3]=1[Br:11]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1ccc(C(=O)O)cc1Br
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1-L round-bottom flask, was placed a solution of 4-amino-3-bromobenzoic acid (50 g, 231.45 mmol, 1.00 equip) in N,N-dimethylformamide (500 mL), TEA (128 mL, 4.00 equip), HATU (106 g, 278.78 mmol, 1.20 equip), and methoxy(methyl)amine hydrochloride (45 g, 461.33 mmol, 2.00 equip). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with water (1 L). The resulting solution was extracted with ethyl acetate (1 L) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2) to yield 4-amino-3-bromo-N-methoxy-N-methylbenzamide as a yellow solid. LCMS (ES, m/z) 259 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C@@H:19]([CH3:25])[CH2:20][C:21]([O:23]C)=[O:22])=[C:8]2[CH3:26])=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C@@H:19]([CH3:25])[CH2:20][C:21]([OH:23])=[O:22])=[C:8]2[CH3:26])=[CH:4][CH:3]=1
Reactant: COC(=O)C[C@H](C)Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(C[C@@H](C)CC(=O)O)c(C)n2Cc1ccc(Br)cc1
Yield: 84 %

Procedure:
To a solution of ester from Step 4 (75 mg) in THF (1.5 mL) and methanol (1.5 mL) there was added 1N aq. NaOH (1 mL) and the mixture was refluxed for 1 h. The mixture was concentrated until solids appeared, diluted with water and acidified with 1N aq. HCl (2 mL). The mixture was extracted twice with ether, the extracts washed twice with water, dried and evaporated to a solid residue which was triturated with hexane and filtered, affording the title compound as a cream colored solid (61 mg). [α]D =-4.4° (c=1, acetone)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14]([S:20][CH3:21])=[N:15][CH:16]=2)[NH:11][C:10]1=O.O=P(Cl)(Cl)[Cl:25].C(N(C(C)C)CC)(C)C>>[Cl:25][C:10]1[N:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:18](=[O:19])[C:17]2[C:12]([N:11]=1)=[N:13][C:14]([S:20][CH3:21])=[N:15][CH:16]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc2c(=O)n(-c3c(F)cccc3Cl)c(=O)[nH]c2n1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc2c(=O)n(-c3c(F)cccc3Cl)c(Cl)nc2n1

Procedure:
A mixture of Example 95A (0.960 g, 2.83 mmol) in POCl3 (3.5 ml, 37.5 mmol) and diisopropylethylamine (DIEA) (3.5 ml, 20.04 mmol) was heated at 90° C. for 1.5 hours. After concentrating the reaction mixture, the residue was treated with ice and aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, concentrated and purified on a 40 g silica column using the ISCO Companion flash system eluting with hexane/ethyl acetate (7:3 to 6:4) to provide the title compound.