Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](C)([CH3:19])[CH2:15]C(O)=O)=[CH:10][CH:9]=1>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:19])([CH3:15])[CH2:1][C:2]([Cl:4])=[O:3])=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(CC(=O)O)c1ccc(F)cc1
Product: CC(C)(CC(=O)Cl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.6 %

Procedure:
Oxalyl chloride (46.5 g, 0.367 mol, Aldrich) was added to a solution of 3-(4-fluorophenyl)-3-methylbutyric acid (24 g, 0.122 mol) at -10° C. while protected from moisture by a nitrogen atmosphere. The stirring mixture was allowed to warm to 25° C. and was stirred for 2 h. Fractional distillation gave 26.6 g (76%) of 3-(4-fluorophenyl)-3-methylbutyryl chloride as a clear oil, b.p., 132-138° C.:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]([CH:21]=O)=[CH:17][CH:18]=[CH:19][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][N:12]1[CH2:11][CH2:10][N:9]([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:14][CH2:13]1
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1ccc(C)c(N2CCN(Cc3ccccc3-c3ccccc3)CC2)c1

Procedure:
35.8 mg of the target compound (0.10 mmol, 12.2%) was obtained using 1-(2,5-dimethylphenyl)piperazine (312 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH3:12])([CH3:3])[CH3:2].[Br-:13].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Br:13][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH3:12])=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9]=1[CH3:10]
Reactant: [Br-]
Reactant: COc1cccc(C)c1C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: COc1ccc(Br)c(C)c1C(C)C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of 2-iso-propyl-3-methylanisole (0.44 g, 2.7 mmol) in CH2Cl2 at room temperature was added a solution of tetrabutylammonium tribromide (1.42 g, 2.94 mmol) in CH2Cl2. The reaction mixture was stirred for 2 h and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with 5% ethyl acetate in hexanes to afford 4-bromo-2-iso-propyl-3-methylanisole as yellowish oil (0.60 g, 92%): 1H NMR (300 MHz, DMSO-d6): δ 7.37 (d, J=13.2 Hz, 1H), 6.78 (d, J=13.2 Hz, 1H), 3.74 (s, 3H), 3.38 (m, 1H), 2.38 (s, 3H), 1.25 (d, J=10.8 Hz, 6H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (5:95); Rf=0.80.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][CH:8]1[C:14](=[O:15])[N:13](CC2C=CC(OC)=CC=2)[C:12]2[CH:25]=[CH:26][CH:27]=[CH:28][C:11]=2[CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O>[O:15]=[C:14]1[NH:13][C:12]2[CH:25]=[CH:26][CH:27]=[CH:28][C:11]=2[CH2:10][CH2:9][CH:8]1[CH2:7][C:6]([OH:29])=[O:5]
Reactant: COc1ccc(CN2C(=O)C(CC(=O)OC(C)(C)C)CCc3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1CCc2ccccc2NC1=O
Temperature: 100 °C
Yield: 72 %

Procedure:
[1-(4-Methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl]-acetic acid tert-butyl ester (0.19 mmol) is dissolved in 1.5 mL of TFA and heated to 100° C. for 3 hours. The mixture is cooled down to room temperature and concentrated. The residue is treated with NaOH (1N) (1 mL) and extracted with EtOAc (3×1 mL). The aqueous layer is then neutralized to pH=2 with HCl (1M) and extracted with EtOAc (3×2 mL). The organic layers resulted from this extraction is concentrated to provide the crude (2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-acetic acid. Yield: 72%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([C:13](O)=[O:14])=[C:6]2[S:16][CH3:17].[CH3:18][NH2:19].[OH-].[NH4+]>>[CH3:18][NH:19][C:13]([C:7]1[N:8]([CH3:12])[C:9]2[C:5]([C:6]=1[S:16][CH3:17])=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)=[O:14]
Reactant: COc1ccc2c(c1)c(SC)c(C(=O)O)n2C
Reactant: CN
Agent: [NH4+]
Agent: [OH-]
Product: CNC(=O)c1c(SC)c2cc(OC)ccc2n1C
Yield: 45 %

Procedure:
Prepared from 5-methoxy-1-methyl-3-(methylthio)-1H-indole-2-carboxylic acid by the procedure of Example 1 with 40% aqueous methylamine solution substituted for ammonium hydroxide. Yield 45% after recrystallization from ethyl acetate-hexane; mp 137°-139° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[S:11][CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C.C(N(CC)CC)C>[Cl:41][C:42]1[CH:48]=[CH:47][C:45]([NH:46][C:15]([C:13]2[N:14]=[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]3)[S:11][CH:12]=2)=[O:17])=[CH:44][CH:43]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)N1CCC(c2nc(C(=O)O)cs2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(c2nc(C(=O)Nc3ccc(Cl)cc3)cs2)CC1
Yield: 29.1 %

Procedure:
A mixture of 29.1 mg (0.1 mmol) 2-(1-isopropyl-piperidin-4-yl)-thiazole-4-carboxylic acid; hydrochloride, 35.3 mg (0.11 mmol) 2-(1H-benzotriazol-1-yl-1,1,3,3-tetramethyl uronium tetrafluoroborate, 14.03 mg (0.11 mol) 4-chloroaniline and 140 ul (0.5 mmol) N-ethyldiisopropylamine in 1 ml DMF was reacted at room temperature for a prolonged period of time. The mixture was treated with 50 μl triethylamine and subjected to preparative HPLC purification on reversed phase material eluting with a gradient of acetonitrile/water/triethyamine (0.05%). The product fractions were evaporated to dryness to yield 10.6 mg (29%) of the title compound. MS (m/e): 364.1 (MH+, 100%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(=O)=O.[Li]CCCC.[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1.CCOCC>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(=O)OCC
Reactant: c1ccc2occc2c1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
To a solution of benzofuran (0.250 mL, 2.32 mmol) in tetrahydrofuran (12.5 mL) stiffing at −100° C. (CO2, ether bath) was added n-BuLi (1.377 mL, 2.203 mmol, 1.6 M in hexanes). The reaction was stirred for 30 min (yellow color) and added dropwise via a canulated into a solution of diethyl oxalate (0.314 mL, 2.32 mmol) in tetrahydrofuran (7 mL) stiffing at −100° C. The reaction mixture was stirred for 1 h and then quenched with saturated aqueous ammonium chloride solution. The mixture was warmed to rt, diluted with dichloromethane, and washed with 0.1 N HCl. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluted with dichloromethane). The fractions containing the title compound were collected and repurified by flash chromatography on silica gel (25% acetone/hexane) to provide the title compound (ethyl 2-(benzofuran-2-yl)-2-oxoacetate, 237 mg, 47% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[N:12]([O-])=[O:13].[Na+]>Cl.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([N:12]=[O:13])[CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: O=N[O-]
Reactant: Cc1ccc2c(c1)OCCN2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(c1)OCCN2N=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
3,4-Dihydro-7-methyl-2H-benzo[b][1,4]oxazine (280 mg, 1.87 mmol) was dissolved in 3N HCl (20 mL). Sodium nitrite (129 mg, 1.87 mmol) in water (1 mL) was added dropwise into the reaction mixture at 0° C. The reaction mixture was stirred for 2 h at RT. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under vacuum to obtain 270 mg of 7-Methyl-4-nitroso-3,4-dihydro-2H-benzo[1,4]oxazine (free base).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=2[OH:11])[CH2:3][CH2:2]1.ClC1C=CC=CC=1Cl.[OH-].[K+].[OH:22][C:23]1[CH:28]=[C:27]([Cl:29])[N:26]=[N:25][C:24]=1Cl>C(O)(C)(C)C>[Cl:29][C:27]1[N:26]=[N:25][C:24]([O:11][C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:23]([OH:22])[CH:28]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: Clc1ccccc1Cl
Solvent: CC(C)(C)O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.1 %

Procedure:
To a mixture of 12.8 g (86.4 mmol) of 2-cyclopropyl-6-methylphenol and 1,2-dichlorobenzene (78.3 mL) was added 5.09 g (86.4 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. and subjected to azeotropic dehydration under reflux while stirring for 30 minutes. To the resultant solution was added dropwise the preliminarily prepared solution of 5.00 g (purity: 95.0%; 28.8 mmol) of 4-hydroxy-3,6-dichloropyridazine in t-butanol (95.0 g) at 180° C. over 2 hours. (The t-butanol was distilled off simultaneously with the dropwise addition of the solution.) After stirring at 180° C. for another 2 hours, the reaction mixture was cooled to room temperature, and 78.7 g of pure water was added to the cooled mixture and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. 50.0 g of toluene was added to the resultant aqueous phase and stirred at room temperature for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol was separated. This operation was repeated twice. Then, the resultant aqueous phase containing a potassium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was added dropwise to a 4% aqueous hydrochloric acid solution at 0° C. to deposit solids, followed by filtration. The resultant solids were washed with pure water and dried under a reduced pressure, and dissolved in an organic solvent and quantitatively determined by an HPLC internal standard analysis method, which showed that 8.30 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (purity: 90.4%; yield: 90%) and 69 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.9%) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]3[S:18][C:19]4[CH2:20][NH:21][CH2:22][CH2:23][C:24]=4[C:11]=23)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:26][N:27]([CH3:34])[CH2:28]/[CH:29]=[CH:30]/[C:31](O)=[O:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]3[S:18][C:19]4[CH2:20][N:21]([C:31](=[O:32])/[CH:30]=[CH:29]/[CH2:28][N:27]([CH3:34])[CH3:26])[CH2:22][CH2:23][C:24]=4[C:11]=23)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1cnc2sc3c(c2c1Nc1ccc(F)c(Cl)c1)CCNC3
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc(F)c(Cl)c4)c23)C1

Procedure:
In analogy to Example 89, the title compound was prepared from 4-[(3-chloro-4-fluorophenyl)amino]-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c′]dipyridine-3-carbonitrile from Example 55A (100 mg, 0.28 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (65 mg, 0.39 mmol) to yield 53 mg (40%).
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[C:13](=[O:16])([O-:15])[O-:14].[Cs+].[Cs+].C(=O)=O.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C1C=CC(CCl)=CC=1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:13](=[O:14])([OH:16])[OH:15].[C:1]([O:11][CH3:12])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: O=C([O-])[O-]
Agent: C=Cc1ccc(C=C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COC(=O)C(O)c1ccccc1
Solvent: C=Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCc1ccccc1
Product: O=C(O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl mandelate(1 g, 6 mmol, 3 eq) is dissolved in anhydrous N,N-dimethylforamide (20 mL) to make a clear solution. Into the solution, are consecutively added cesium carbonate (1.95 g, 6 mmol) and tetrabutylammonium iodide (2.22 g, 6 mmol, 3 eq). The suspension is stirred at room temperature while passing carbon dioxide gas through for 1 hour before Merrifield's peptide resin (1 g, 2 mmol) is added to the solution. Carbon dioxide gas continuously bubbled through the solution and the reaction is allowed to proceed overnight at 60° C. The mixture is then cooled to room temperature, and diluted with water. The resin is washed successively with MeOH/H2O,H2O, 0.2 N HCl, H2O, THF, CH2Cl2, and MeOH. After drying under vacuum, 1.26 g of resin is obtained (76% yield): IR 3020, 2918, 2843, 1964, 1740, 1605, 1498, 1445, 1375, 1351, 1031, 771, 701, 551 cm−1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COc1cccc(I)c1
Product: COc1cccc(-n2ccc3ccccc32)c1

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-iodo-3-methoxybenzene: ESMS m/e: 224.0 (M+H)+.
Reaction SMILES: C(OC(=O)[N:7]([CH:25]([CH3:27])[CH3:26])[C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)(C)(C)C.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH:25]([NH:7][C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)([CH3:26])[CH3:27]
Reactant: CSc1nccc(-c2cnc3c(N(C(=O)OC(C)(C)C)C(C)C)nccn23)n1
Reactant: C1COCCN1
Product: CC(C)Nc1nccn2c(-c3ccnc(N4CCOCC4)n3)cnc12

Procedure:
Isopropyl-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine was prepared by a process analogous to that described in Example 12 starting from isopropyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (from Example 11 supra), and morpholine. LC-MS: [M+H]+ 340.3.
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>[OH-].[Na+]>[CH2:15]([O:14][C:12]([NH:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1(C(=O)O)CCCCC1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NC1(C(=O)O)CCCCC1)OCc1ccccc1
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a solution of l-aminocyclohexane-1-carboxylic acid (10.0 g, 70.0 mmol) in a 1M NaOH solution (100 mL) was added benzyl chloroformate (12.0 ml, 84.0 mmol). The reaction mixture was stirred for 2 h while maintaining pH 9 by addition of a 1M NaOH solution as necessary. The resulting solution was washed with Et2O (2×100 mL), then the aqueous layer was adjusted to pH 0 with a conc. HCl solution and the solution was extracted with EtOAc (3×150 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to yield 1-(benzyloxycarbonylamino)cyclohexane-1-carboxylic acid (17.3 g, 89%): TLC (25% EtOAc/hex) Rf0.07.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]([C:9](=[O:30])[C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH:26]([CH3:28])[CH3:27])[CH:19]=2)=[C:12]([Cl:29])[CH:11]=1)[CH2:5][C:6]([OH:8])=[O:7].C([O-])(=O)C.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O.C(O)(=O)C>[CH3:3][N:4]([C:9](=[O:30])[C:10]1[CH:11]=[C:12]([Cl:29])[C:13]([O:17][C:18]2[CH:19]=[C:20]([CH:26]([CH3:28])[CH3:27])[C:21]([O:24][CH3:25])=[CH:22][C:23]=2[Br:1])=[C:14]([Cl:16])[CH:15]=1)[CH2:5][C:6]([OH:8])=[O:7]
Reactant: BrBr
Reactant: COc1ccc(Oc2c(Cl)cc(C(=O)N(C)CC(=O)O)cc2Cl)cc1C(C)C
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Br)c(Oc2c(Cl)cc(C(=O)N(C)CC(=O)O)cc2Cl)cc1C(C)C
Temperature: 40 °C
Reaction time: 16 h
Yield: 1.6 %

Procedure:
Bromine (13 μL, 0.26 mmol) was added dropwise to a well stirred mixture of methyl-N-[3,5-dichloro-4-(4-methoxy-3-isopropylphenoxy)benzoyl]glycine (50 mg, 0.12 mmol), acetic acid (1.0 mL), sodium acetate (35 mg, 0.26 mmol) and a few drops of water. The reaction mixture was stirred at room temperature for three hours, heated at 40° C. for 90 minutes and finally left at room temperature for 16 hours. Sodium acetate (17 mg) and bromine (6 μL) was added and the reaction mixture heated to 40° C. for two hours. The reaction mixture was left at 4° C. for three days. Sodium thiosulfate (saturated) was added and the yellow mixture concentrated. The residue was diluted with ethyl acetate and washed with water. The aqueous phase was extracted with dichloromethane, the combined organic phases washed with brine and dried over sodium sulfate. After concentration, the residue was purified on column (hplc, C8, acetonitrile/water/formic acid, gradient elution from 20/80/0.5 to 100/0/0) to give 1.0 mg (2%) of methyl-N-[3,5-dichloro-4-(2-bromo-4-methoxy-5-isopropylphenoxy)benzoyl]glycine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1F)[O:9][CH2:8][CH2:7][CH:6]2[C:14]([OH:16])=[O:15])#[N:2].C([O-])([O-])=O.[K+].[K+].[Cl:23][C:24]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:25]=1[CH2:26][CH2:27][NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>CN1CCCC1=O>[Cl:23][C:24]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:25]=1[CH2:26][CH2:27][NH:28][C:29]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:12]2[CH:11]=[C:10]3[C:5]([CH:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][O:9]3)=[CH:4][C:3]=2[C:1]#[N:2])=[CH:32][CH:31]=1)=[O:37]
Reactant: N#Cc1cc2c(cc1F)OCCC2C(=O)O
Reactant: O=C(NCCc1ccc(Cl)cc1Cl)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)NCCc3ccc(Cl)cc3Cl)cc1)OCCC2C(=O)O
Temperature: 140 °C
Reaction time: 5 h
Yield: 5.2 %

Procedure:
6-cyano-7-fluorochroman-4-carboxylic acid (40 mg, 0.18 mmol) was diluted with N-methylpyrrolidone (2 mL) followed by the addition of K2CO3 (100 mg, 0.72 mmol) and N-(2,4-dichlorophenethyl)-4-hydroxybenzamide (56 mg, 0.18 mmol). The reaction was bubbled with argon for 10 minutes and then heated at 140° C. After stirring for 5 hours, the reaction was loaded directly onto a Biotage 25 cartridge eluting with 0.5% acetic acid/0.5% methanol/CH2Cl2 to 0.5% acetic acid/10% methanol/CH2Cl2 to yield the title compound (4.8 mg, 5.2% yield). 1H NMR (400 MHz, CD3OD) δ 8.57-8.59 (m, NH), 7.84 (d, J=8.7 Hz, 2H), 7.69 (s, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.26 (dd, J=1.7, 8.0 Hz, 1H), 7.13 (d, J=8.7 Hz, 2H), 6.40 (s, 1H), 4.29-4.34 (m, 1H), 4.20-4.26 (m, 1H), 3.85 (t, J=5.1 Hz, 1H), 3.64 (q, J=6.1 Hz, 2H), 3.06 (t, J=7.0 Hz, 2H), 2.32-2.37 (m, 1H), 2.08-2.16 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[C:17]1([C:23]2[N:24]=[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:31]2[CH2:32][CH2:33][N:28]([C:25]3[S:26][CH:27]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:24]=3)[CH2:29][CH2:30]2)=[O:16])[O:4][N:3]=1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4ccccc4)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 3 h
Yield: 13.8 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (258 mg, 0.897 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (200 mg, 0.815 mmol) and diisopropylethylamine (0.156 ml, 0.897 mmol) in dimethylsulfoxide (2.7 ml) was stirred at 70° C. for 3 hours. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to obtain the desired product (43.1 mg, 13.8%) as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>C(O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)ncn2)CC1
Yield: 87.7 %

Procedure:
A solution of 4,6-dichloropyrimidine (10.05 g), tert-butoxycarbonylpiperazine (11.94 g) and triethylamine (28.20 ml) in ethanol (150 ml) was heated at reflux for 18 hours. Solvent was evaporated and the residue dissolved in ethyl acetate and washed with water, saturated aqueous ammonium chloride solution, dried (Na2SO4) and evaporated. Recrystallisation from ethyl acetate/hexane gave, as a solid 1-(tert-butoxycarbonyl)-4-(6-chloro-pyrimidin-4-yl)piperazine (16.80 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH3:16])[N:10]([CH2:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]2=[N:6][C:7]=1[CH2:8][OH:9].[C:26]1(OB(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:13]([C:11]1[N:10]([CH2:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]2=[N:6][C:7]([CH2:8][OH:9])=[C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:3]=[C:4]2[N:12]=1)[CH2:14][CH2:15][CH3:16]
Reactant: OB(O)Oc1ccccc1
Reactant: CCCCc1nc2cc(Br)c(CO)nc2n1CC(=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCc1nc2cc(-c3ccccc3)c(CO)nc2n1CC(=O)c1ccccc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
4.8 g(0.01197 mole) of the compound obtained in step 7, 3.75 g(0.03591 mole) of phenylboric acid, 0.2 g(0.0012 mole) of palladium acetate, 0.46 g(0.0024 mole) of triphenylphosphine and 8.9 ml(0.0838 mole) of triethylamine were dissolved in 20 ml of dimethyl formamide. The reaction solution was stirred for 3 hours at 120° C., diluted with 100 ml of ethyl acetate and washed with water(50 ml×3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified with column chromatography(5% MeOH in CH2 Cl2) to obtain 4.57 g of the title compound(yield 96%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].CN(C=O)C.IC>O>[CH3:10][O:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(O)c(C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
2,4-dimethylphenol (7.5 g, 0.062 mol) and anhydrous potassium carbonate (25.4 g, 0.18 mol) were dissolved into DMF (75 mL) and then iodomethane (8.83 g, 0.062 mol) was dropped under an ice bath. The system was stirred overnight at room temperature. At the end of reaction, the reaction system was added with water and then extracted with ethyl acetate, and the organic phase was washed with saturated brine, then dried and evaporated in vacuum to obtain 7.11 g of the product (85%) by column chromatography.