Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=O.S(Cl)([Cl:12])=O>>[CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([Cl:12])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: Cc1occc1C(=O)O
Product: Cc1occc1C(=O)Cl

Procedure:
A first reaction mixture of chloroacetaldehyde dimethylacetal (300 g), water (400 mL) and 36% hydrochloric acid (40 mL) was stirred and brought to reflux. When the first reaction mixture became homogenous, it was cooled and added to a stirred solution of ethyl acetoacetate (260 g) and pyridine (500 mL) and left stirring at ambient temperature for 72 hours, to produce a second reaction mixture. The organic layer was then separated from the second reaction mixture and the aqueous layer was diluted with water and then extracted with methylene chloride. The combined organics were washed with 2N hydrochloric acid, followed by removal of the solvent. The residue was treated with a solution of sodium hydroxide (80 g) in water (700 mL) and ethanol (100 mL), to produce a third reaction mixture. After refluxing for 1 hour the third reaction mixture was poured into ice/water and acidified with hydrochloric acid. A cream colored precipitate formed. This precipitate was collected on a filter, washed with water and dried to give 2-methyl-3-furancarboxylic acid, 180 g. 100 g of the 2-methyl-3-furancarboxylic acid was added in portions to thionyl chloride (500 mL) and refluxed for 3 hours. Excess thionyl chloride was then distilled off to produce a residue. The residue was distilled using a water pump, to give 2-methyl-3-furanylcarboxylic chloride, bp. 62° C., 100 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:7][C:6]([CH:14]=[CH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[O:17])=[C:5]([O:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:4]=1.[ClH:37]>O1CCCC1>[ClH:37].[CH3:1][O:2][C:3]1[C:8]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:7][C:6](/[CH:14]=[CH:15]/[C:16]([C:18]2[CH:19]=[CH:20][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[O:17])=[C:5]([O:28][CH2:29][CH2:30][N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[CH:4]=1
Reactant: COc1cc(OCCN2CCOCC2)c(C=CC(=O)c2ccc(S(N)(=O)=O)cc2)cc1-c1cccs1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(OCCN2CCOCC2)c(/C=C/C(=O)c2ccc(S(N)(=O)=O)cc2)cc1-c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Th 4-{3-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide (Ex-81, 0.065 g, 0.12 mmol) was dissolved in tetrahydrofuran (5 mL) and 3 N HCl (1 mL) was added drop wise to the solution. The resulting yellow slurry was stirred in the dark at room temperature for 30 min. The precipitate was collected and dried in vacuo to yield 0.054 g (78%) of the title compound as a yellow solid, mp 235° C. (dec). 1H-NMR (300 MHz, DMSO-d6): δ 8.31–8.34 (m, 3H), 8.13 (d, 1H, J=15.0 Hz), 7.92–8.01 (m, 3H), 7.70 (d, 1H, J=4.0 Hz), 7.54 (m, 3H), 7.15–7.17 (m, 1H), 6.92 (s, 1H), 4.64 (brs, 2H), 4.03 (s, 5H), 3.72–3.79 (m, 4H), 3.56–3.60 (m, 4H). MS (ESI) m/z=529 ([M+H]+, 100%). Anal. Calcd. for C26H29ClN2O6S2: C, 55.26; H, 5.17; Cl, 6.27; N, 4.96; S, 11.35. Found: C, 55.31; H, 5.17; Cl, 6.32; N, 4.98; S, 11.20.
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([S:10]([N:13]2[C:18]3[CH:19]=[C:20]([C:23]([NH:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=4)=[O:24])[CH:21]=[CH:22][C:17]=3[O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.FC(F)O[C:39]1C=C(S(Cl)(=O)=O)C=C[CH:44]=1>>[CH2:39]([O:31][C:30](=[O:32])[C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:23]([C:20]2[CH:21]=[CH:22][C:17]3[O:16][CH2:15][CH2:14][N:13]([S:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:1])[F:35])[CH:5]=4)(=[O:11])=[O:12])[C:18]=3[CH:19]=2)=[O:24])=[CH:34][CH:33]=1)[CH3:44]
Reactant: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(OC(F)F)c2)CCO3)cc1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(OC(F)F)c2)CCO3)cc1

Procedure:
4-{[4-(3-Difluoromethoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=502.9 (M−H), was prepared as described for example 14, steps 1 to 8. Step 7 was performed using 3-difluoromethoxy-benzenesulfonyl chloride and yielded 4-{[4-(3-difluoromethoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([O:27][C:28](=[O:42])[NH:29][CH2:30][C:31](=O)[NH:32][C:33]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=1[F:40])([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([O:27][C:28](=[O:42])[NH:29][CH2:30][C:31](=[S:10])[NH:32][C:33]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=1[F:40])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1c(F)cccc1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=S)Nc1c(F)cccc1F
Yield: 63.4 %

Procedure:
A Lawesson's reagent (50 mg, 0.12 mmol) was added to a THF (2 mL) solution of [(2,6-difluorophenylcarbamoyl)methyl]carbamic acid tert-butyl ester (52 mg, 0.18 mmol) in an argon atmosphere, and the mixture was refluxed with heating overnight. After evaporating the solvent, the residue was purified by silica gel column chromatography (13 g, hexane:acetone=10:1 to 8:1) to obtain [(2,6-difluorophenylthiocarbamoyl)methyl]carbamic acid tert-butyl ester (23 mg) as a colorless crystalline substance.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:30][CH2:31][N:32]([C:14]([C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:20][CH:19]=2)=[O:16])[CH2:33][CH2:34]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: CCOC(=O)c1ccc(-n2cnc3cccnc32)cc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(-n4cnc5cccnc54)cc3)CC2)c(C)c1
Yield: 73.2 %

Procedure:
Using ethyl 4-(imidazo[4,5-b]pyridin-3-yl)benzoate (300 mg) described in Preparation Example 77 and 1-(2,4-dimethylphenyl)piperazine (214 mg) and by the reaction and treatment in the same manner as in Example 109, the title compound (338 mg) was obtained.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:33])([N:6]1[CH2:11][CH2:10][CH:9]([S:12][C:13]2[CH:14]=[CH:15][C:16]3[O:25][CH2:24][CH2:23][N:22]4[C:18](=[N:19][C:20]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)=[CH:21]4)[C:17]=3[CH:32]=2)[CH2:8][CH2:7]1)[CH3:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1>[CH3:33][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([S:12][C:13]2[CH:14]=[CH:15][C:16]3[O:25][CH2:24][CH2:23][N:22]4[C:18](=[N:19][C:20]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)=[CH:21]4)[C:17]=3[CH:32]=2)[CH2:10][CH2:11]1)([CH3:5])[CH2:3][OH:2]
Reactant: COC(=O)C(C)(C)N1CCC(Sc2ccc3c(c2)-c2nc(-c4ccccn4)cn2CCO3)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(CO)N1CCC(Sc2ccc3c(c2)-c2nc(-c4ccccn4)cn2CCO3)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of 2-methyl-2-[4-(2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl)piperidin-1-yl]propionic acid methyl ester (0.438 mmol) in THF (20 mL) was added LiAlH4 (1.0M in THF, 1.32 mL) and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added EtOAc (0.5 mL) and stirring was continued for 10 min. Volatiles were removed under reduced pressure and the resulting residue was partitioned between DCM and 10% aq. solution of Rochelle's salt. The suspension was then filtered through a pad of Celite®. The filtrate was extracted with additional DCM and the combined organic phases were washed with water, then brine, dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-13% 2M NH3/MeOH in DCM) affording 2-Methyl-2-[4-(2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl)piperidin-1-yl]propan-1-ol as a colorless gum (190 mg, 96% over two steps). LCMS: RT 1.799 min [M+H]+ 451.1
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:15])=[C:7]([C:10]([CH3:14])=[C:11]([Cl:13])[CH:12]=1)[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[S:24]([NH2:27])(=[O:26])=[O:25].ClCl>>[C:1]([C:5]1[C:6]([OH:15])=[C:7]([C:8]2[NH:27][S:24](=[O:26])(=[O:25])[C:18]3[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=3[N:16]=2)[C:10]([CH3:14])=[C:11]([Cl:13])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Reactant: Cc1c(Cl)cc(C(C)(C)C)c(O)c1C=O
Agent: ClCl
Product: Cc1c(Cl)cc(C(C)(C)C)c(O)c1C1=Nc2cc(Cl)ccc2S(=O)(=O)N1

Procedure:
From 3-tert-butyl-5-chloro-2-hydroxy-6-methyl-benzaldehyde and 2-amino-4-chlorobenzenesulfonamide; LC-MS: m/z 413/415/417 (M+H; Cl2 isotope pattern).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[H-].[Na+].[O:28]1CCC[CH2:29]1>CO.ClCCl>[Cl:1][C:2]1[C:7]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[CH:6][CH:5]=[C:4]([O:28][CH3:29])[N:3]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(Cl)nc2Cl)o1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2nnc(-c3c(-c4ccccc4)noc3C)o2)c(Cl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2,6-dichloro-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine (316 mg, 0.85 mmol) in tetrahydrofuran (3 mL) and methanol (3 mL) was added sodium hydride (55% dispersion in mineral oil, 41 mg, 0.93 mmol) and the reaction mixture was stirred for 4 h at ambient temperature. The resulting suspension was diluted with dichloromethane (10 mL) and was washed brine (half saturated, 10 mL). The aqueous layers were extracted with dichloromethane (10 mL) and dried over sodium sulfate. The filtrate was treated with tert-butylmethylether (20 mL) and the dichloromethane was distilled off. The resulting suspension was stirred for 5 min, filtered off and washed with tert-butylmethylether affording the title compound (51 mg, 16%) which was obtained as a white solid. MS: m/e=369.0 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:16]([C:17]#[N:18])=[C:15]([NH2:19])[NH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(O[CH:23](OCC)[N:24]([CH3:26])[CH3:25])C>C1(C)C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:16]([C:17]#[N:18])=[C:15]([N:19]=[CH:23][N:24]([CH3:26])[CH3:25])[NH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(OCC)N(C)C
Reactant: CC(=O)Nc1ccc(Nc2n[nH]c(N)c2C#N)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(Nc2n[nH]c(N=CN(C)C)c2C#N)cc1
Temperature: 25 °C

Procedure:
A suspension of 5.3 g (20.7 mmol) of 3-(4-acetylamino-phenylamino)-5-amino-4-cyano-pyrazole in 4.4 ml (24.9 mmol) of N,N-dimethylformamide diethyl acetal (97%) and 100 ml of toluene is heated under reflux for 4 hours. The reaction mixture is then cooled to room temperature and filtered and the filter residue is washed with toluene, yielding the title compound having a water content of 4.22%; m.p. 275-276° C. (decomp.).
Reaction SMILES: C([O:4][CH:5]1[CH2:12][CH2:11][CH:10]2[CH:6]1[CH2:7][CH2:8][CH:9]2[C:13]([OH:15])=[O:14])(=O)C.Cl.[CH3:17]O>>[OH:4][CH:5]1[CH2:12][CH2:11][CH:10]2[CH:6]1[CH2:7][CH2:8][CH:9]2[C:13]([O:15][CH3:17])=[O:14]
Reactant: CC(=O)OC1CCC2C(C(=O)O)CCC12
Reactant: CO
Agent: Cl
Product: COC(=O)C1CCC2C(O)CCC12

Procedure:
A mixture of 6-acetoxy-2-carboxybicyclo[3,3,0]octane (2.23 g; prepared as described in Reference Example 5 and predominantly in the 2β-configuration), methanol (25 ml), and concentrated hydrochloric acid (0.15 ml), was heated at reflux for 16 hours. The mixture was then concentrated under reduced pressure to a third of its previous volume, and it was then added to an excess of water. The mixture was extracted with dichloromethane. The combined dichloromethane extracts were washed with saturated aqueous sodium bicarbonate solution, and then with saturated aqueous sodium chloride solution, and then it was dried over anhydrous sodium sulphate. Concentration under reduced pressure gave crude 6-hydroxy-2-methoxycarbonylbicyclo[3,3,0]octane (1.98 g), predominantly in the 2β-configuration, and pure enough for use in the next stage.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([CH:23]5[CH2:26][N:25]([CH2:27][CH2:28][O:29]C6CCCCO6)[CH2:24]5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.O1CCOCC1>CO.C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([CH:23]5[CH2:24][N:25]([CH2:27][CH2:28][OH:29])[CH2:26]5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(CCOC4CCCCO4)C3)cc1-2
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(CCO)C3)cc1-2
Reaction time: 3 h
Yield: 32 %

Procedure:
A solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-9-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-azetidin-3-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (110 mg, 0.22 mmol) in MeOH (3 mL) and DCM (3 mL) was treated with 4N HCl/dioxan (2 mL, 8 mmol) and the mixture left to stand for 3 hours then concentrated in vacuo. The resultant residue was triturated with diethyl ether and dried under vacuum. Further purification by flash chromatography (SiO2, 0-10% 2N NH3/MeOH in DCM) gave 376 (29 mg, 32%). LCMS: RT=6.96 min, [M+H]+=412. 1H NMR δ (ppm) (CDCl3): 8.31 (1H, d, J=2.34 Hz), 7.90 (1H, s), 7.15 (1H, dd, J=8.27, 2.35 Hz), 7.01 (1H, d, J=8.26 Hz), 5.94-5.84 (1H, m), 4.40-4.34 (2H, m), 3.89-3.83 (2H, m), 3.84-3.72 (1H, m), 3.59-3.54 (2H, m), 3.41-3.36 (2H, m), 3.28-3.21 (2H, m), 2.71-2.66 (2H, m), 1.62 (6H, d, J=6.65 Hz). 1 Exchangeable proton not seen
Reaction SMILES: C([O:4][CH:5]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][N:8]=1)[CH3:6])(=O)C.[OH-].[Na+]>>[CH3:14][O:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([CH:5]([OH:4])[CH3:6])[CH:12]=1
Reactant: COc1ccnc(C(C)OC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccnc(C(C)O)c1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
114 g of (+)-1-[4-methoxy-2-pyridyl]-ethyl acetate are added dropwise at 70° C. to 220 ml of 4N sodium hydroxide solution. The mixture is then stirred for a further 2 h at 75° C., cooled and extracted with four times 200 ml of dichloromethane. The organic phase is washed with 2N sodium hydroxide solution and water, dried over sodium sulphate and concentrated to dryness. After thorough stirring with 250 ml of diisopropyl ether, this gives 64 g (72%) of the title compound of m.p. 92° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:21])=[O:5])[CH3:2].[Br:22]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21][Br:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Temperature: 25 °C
Yield: 99 %

Procedure:
4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester (1.6 g, 5.00 mmol) is dissolved into chloroform (50 mL) then N-bromosuccinimide (1.0 g, 5.5 mmol) and 2,2′-azobisisobutyronitrile (0.412 g, 2.5 mmol) are added and the reaction is heated to reflux. The reaction is monitored by TLC until no starting material remained. The reaction is allowed to cool to room temperature, then diluted with more chloroform (100 mL). Water (50 mL) is added and the two phases are separated. The organic layer is washed with brine, then dried over anhydrous sodium sulfate. The material is then concentrated and further purified using flash column chromatography to yield 1.97 g or 99% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:22])[CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:5][CH:4]=1.[CH2:23](O)[CH2:24][OH:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH2:10][N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[O:25][CH2:24][CH2:23][O:22]2)=[CH:7][CH:8]=1
Reactant: OCCO
Reactant: COc1ccc(C(=O)CN2C(=O)c3ccccc3C2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C2(CN3C(=O)c4ccccc4C3=O)OCCO2)cc1
Temperature: 25 °C

Procedure:
2-[2-(4-Methoxyphenyl)-2-oxoethyl]isoindole-1,3-dione (Preparation 37, 6.35 g, 21.5 mmol) was suspended in toluene (50 mL) and ethylene glycol (12 mL) added. p-Toluenesulfonic acid (300 mg, 1.58 mmol) was added and the resulting mixture heated under reflux for 40 h, removing water with a Dean-Stark trap. The reaction mixture was allowed to cool to rt then partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure, to give the title compound as an off-white solid. δH (d6 DMSO): 3.66 (2H, t), 3.72 (3H, s), 3.87 (4H, m), 6.88 (2H, d), 7.32 (2H, d), 7.83 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]2[N:7]([C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=3)[C:8]([C:10]([F:13])([F:12])[F:11])=[N:9][C:5]=2[CH:4]=1.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26](O)=[O:27].CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([N:7]2[C:6]3[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:9]=[C:8]2[C:10]([F:13])([F:11])[F:12])=[CH:19][N:18]=1)=[O:27]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1ccc(N)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1ccc(NC(=O)c2c(F)cccc2F)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.3 %

Procedure:
To a solution of 5-(5-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)pyridin-2-amine (80 mg, 0.25 mmol) in CHCl3 (10 ml) was added 2,6-difluorobenzoic acid (90 mg, 0.57 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (240 mg, 1.25 mmol) and 4-dimethylaminopyridine (DMAP) (160 mg, 1.31 mmol). The resultant solution was allowed to stir for 24 hours at room temperature. The reaction progress was monitored by TLC (EtOAc/petroleum ether=1:1). After the completion, the resultant solution was diluted with 30 ml of CHCl3 and washed with 30 ml of H2O. The mixture was dried and concentrated by evaporation under reduced pressure on a rotary evaporator. The crude product was purified by SGC using 1:5 EtOAc/petroleum ether as eluent to afford 90 mg (81%) of 2,6-difluoro-N-(5-(5-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)pyridin-2-yl)benzamide (Compound 163) as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[CH:4][C:3]=1[NH2:15].C(N(CC)C(C)C)(C)C.[F:25][C:26]([F:44])([F:43])[C:27]1[CH:28]=[C:29]([C:37]([CH3:42])([CH3:41])[C:38](Cl)=[O:39])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1>ClCCl>[F:25][C:26]([F:43])([F:44])[C:27]1[CH:28]=[C:29]([C:37]([CH3:41])([CH3:42])[C:38]([NH:15][C:3]2[CH:4]=[N:5][C:6]([N:8]3[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]3)=[CH:7][C:2]=2[I:1])=[O:39])[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN1CCN(c2cc(I)c(N)cn2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cc(I)c(NC(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.3 %

Procedure:
To a suspension of 1.60 g (5.03 mmol) 4-iodo-6-(4-methyl-piperazin-1-yl)-pyridin-3-ylamine and 975 mg (7.54 mmol) N,N-diisopropyl ethyl amine in 16 ml dichloromethane was added dropwise 1.76 g (5.53 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride at 0° C. The reaction mixture was stirred for 2 h at room temperature and 2 h at reflux. After cooling to room temperature the reaction mixture was washed with 20 ml of a 1 M aqueous sodium carbonate solution and 20 ml water. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 3.39 g (100%) of the crude title compound as a brown oil.
Reaction SMILES: [F:1][C:2]([F:21])([C:17]([F:20])([F:19])[F:18])[C:3]([F:16])([F:15])[C:4]1[NH:9][C:8](=[O:10])[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1.[Cl:22]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:22][C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[C:8](=[O:10])[NH:9][C:4]=1[C:3]([F:15])([F:16])[C:2]([F:1])([F:21])[C:17]([F:19])([F:18])[F:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(C(F)(F)C(F)(F)C(F)(F)F)[nH]c1=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(C(F)(F)C(F)(F)C(F)(F)F)[nH]c1=O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
16.7 g (52 mmol) of methyl 6-(heptafluoropropyl)-2-oxo-1,2-dihydropyridine-3-carboxylate were dissolved in 160 ml of N,N-dimethylformamide, and 7.08 g (52 mmol) of N-chlorosuccinimide were added at room temperature. After 3 hours of stirring at 50° C., the reaction mixture was added to water and extracted repeatedly with ethyl acetate. The organic phase was then separated off, washed with water and dried. The resulting crude product was then purified by preparative RP-HPLC. This gave 10.1 g (54% of theory) of the product as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O:37]CC)=[O:36].[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])[N:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccccc5Cl)n4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(Nc1cccc(-c2ccccc2Cl)n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(6-(2-chlorophenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.010 g, 0.0177 mmol) in 3:1 THF/ethanol (1 ml) was added 1M sodium hydroxide (0.0373 ml, 0.0373 mmol), and the reaction was stirred for 16 hours at ambient temperature. The reaction was concentrated and diluted with water. The reaction was acidified with 1M hydrochloric acid and extracted twice with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel preparative thin-layer chromatography eluting with 95:5:1 DCM/MeOH/glacial acetic acid to yield the desired compound (0.007 g, 0.0124 mmol, 70.0% yield). MS (apci) m/z=535.1 (M+H).