Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].Cl.[F:20][C:21]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][NH:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:20][C:21]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][N:25]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Fc1ccc2c(c1F)CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c1ccc(F)c2F
Yield: 55.8 %

Procedure:
The product is prepared according to the procedure described in example 5, but using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, 383 mg of 4,5-difluoro-2,3-dihydro-1H-indole hydrochloride, and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.32 ml of pyridine and 4 ml of N,N-dimethylformamide. 210 mg of 2-[2-(4,5-difluoro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pale pink, powdery solid, the characteristics of which are the following:
Reaction SMILES: CC([O:4][C:5]([C:7]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[O:18])=[CH:15][CH:16]=1)([CH3:9])[CH3:8])=[O:6])C.[OH-].[Na+].Cl>C(O)(C)C.O>[CH3:9][C:7]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:18])=[CH:15][CH:16]=1)([C:5]([OH:6])=[O:4])[CH3:8]
Reactant: CC(C)OC(=O)C(C)(C)Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 75 °C
Yield: 96.6 %

Procedure:
Fenofibrate (200.0 g, 0.5543 mol) was suspended in 900 mL of isopropanol. A solution of NaOH (33.0 g NaOH, 0.825 mol, 1.49 eq) in 400 mL of water was added and the mixture heated to reflux for 2 hours. The solution was cooled to approximately 75° C. A solution of hydrochloric acid (652 g of a 5.0% solution, 32.8 g of HCl, 0.894 mol, 1.6 eq) was added maintaining the temperature above 55° C., and the product crystallized from solution. The slurry was cooled to 28° C. over 3.5 hours. The product was filtered and rinsed twice with 500 mL of water. The product was dried in a vacuum oven at 60° C. with a nitrogen purge for approximately 16 hours. The dry weight was 170.7 g, or 96.6% yield.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:7]([O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][NH:4][CH2:3]1.C1C=CC(C(O[C@@H](C(O)=O)[C@@H](OC(C2C=CC=CC=2)=O)C(O)=O)=O)=CC=1>CCOC(C)=O>[CH3:1][C@@H:2]1[C@@H:7]([O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: C[C@@H]1CNCC[C@H]1OC(=O)C(C)(C)C
Agent: O=C(O[C@@H](C(=O)O)[C@@H](OC(=O)c1ccccc1)C(=O)O)c1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H]1CNCC[C@@H]1OC(=O)C(C)(C)C

Procedure:
Racemic 19 (62.7 g, 314.4 mmol) is dissolved in EtOAc (300 ml) and a solution of L-(−)-O,O′-Dibenzoyl tartaric acid (56.3 g, 157.2 mmol) in EtOAc (450 ml) is added. The formed solid is filtered off, washed with cold EtOAc and dried. It is then re-crystallized from hot methanol (400 ml). The crystals are collected and the free base is liberated by treatment with 1N—NaOH and extraction with ether.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O)([O-:11])=[O:10]>C(O)C>[N+:9]([C:12]1[CH:13]=[C:14](/[CH:15]=[N:8]/[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:17]=[CH:18][CH:19]=1)([O-:11])=[O:10]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: Cc1ccc(N)cc1
Solvent: CCO
Product: Cc1ccc(/N=C/c2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a stirred solution of p-tolylamine (21.43 g, 0.2 mol) in ethanol (300 mL) was added 3-Nitro-benzaldehyde (30.22 g, 0.2 mol). The mixture was stirred overnight at room temperature. After filtration, the yellow solid was dried under infrared lamp, and the filtrate was concentrated, treated with ethanol again. The precipitated solid was filtered to afford 44.5 g of [1-(3-nitro-phenyl)-meth-(E)-ylidene]-p-tolyl-amine (Yield: 93%).
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[C:10]([O:15]C)[N:11]=[CH:12][CH:13]=3)[N:8]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([C:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[N:8]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:21][CH:22]=3)[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nccc2c(C3CCCC3)nn(-c3ccc(S(N)(=O)=O)cc3)c12
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(-n2nc(C3CCCC3)c3cc[nH]c(=O)c32)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 92.8 %

Procedure:
To a solution of 4-(3-cyclopentyl-7-methoxy-1H-pyrazolo[3,4-c]pyridin-1-yl)benzenesulfonamide (22.4 mg) in acetonitrile (10 mL) were added sodium iodide (18.0 mg) and chloro(trimethyl)silane (52.1 mg), and the mixture was stirred at 80° C. for 5 hr. To the reaction mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (20 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7](Cl)=[O:8].N1C=CC=CC=1.[C:16]([C:18]1[CH:19]=[C:20]([NH:30][C:31]([C:33]2[CH:34]=[N:35][N:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[C:37]=2[CH3:38])=[O:32])[CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)#[N:17]>O>[C:16]([C:18]1[CH:19]=[C:20]([NH:30][C:31]([C:33]2[CH:34]=[N:35][N:36]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[C:37]=2[CH3:38])=[O:32])[CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][N:27]([C:7]([C:3]2[CH:4]=[N:5][O:6][C:2]=2[CH3:1])=[O:8])[CH2:26][CH2:25]1)#[N:17]
Reactant: Cc1c(C(=O)Nc2ccc(N3CCNCC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Reactant: Cc1oncc1C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1oncc1C(=O)N1CCN(c2ccc(NC(=O)c3cnn(-c4ccc(F)cc4)c3C)cc2C#N)CC1
Reaction time: 1 h
Yield: 58.7 %

Procedure:
5-Methylisoxazole-4-carbonyl chloride (1.4 g) synthesized according to the method described in J. Chem. Soc. Perkin Trans. I, pp. 1875–1879 (1988) was added to a pyridine solution (20 ml) containing N-[3-cyano-4-(piperazin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide (4 g) under ice-cooling, and the mixture was stirred for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under pressure. Diisopropyl ether was added to the obtained residue to allow crystallization. The crystals were recrystallized from hydrous dimethylformamide to give the title compound (2.9 g), melting point: 208° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:9]=1[C:10]([O:12]C)=[O:11].FC(F)(F)S(O[CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])(=O)=O>CC(=O)CC>[F:7][C:8]1[CH:17]=[C:16]([O:18][CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH:15]=[CH:14][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1ccc(O)cc1F
Reactant: O=S(=O)(OCCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(O)c1ccc(OCCC(F)(F)F)cc1F
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 40 %

Procedure:
Potassium carbonate (663 mg) was added to a 2-butanone (6 mL) solution of methyl 2-fluoro-4-hydroxybenzoate (compound described in U.S. Pat. No. 5,990,142 A1, 340 mg) and 3,3,3-trifluoropropyl trifluoromethanesulfonate (compound described in Tetrahedron, (1988), 44, 5375-5388, 590 mg). The mixture was stirred at 75° C. for 1.5 hours, and then the solvent was evaporated. To the obtained residue were added methanol (8 mL) and a 2 M sodium hydroxide aqueous solution (2 mL). The mixture was stirred at 60° C. for 1.5 hours, and the solvents (mainly methanol) were evaporated. To the residue was added water (15 mL), and the mixture was changed to acidic by adding 1 M hydrochloric acid thereto while stirring. The precipitated crystalline solid was collected by filtration, washed with water, and dried under reduced pressure to give 203 mg of the title compound (white crystal, yield: 40%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O.[BH4-].[Na+]>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([NH:1][CH2:23][C:19]3[O:18][CH:22]=[CH:21][CH:20]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1NCc1ccco1
Yield: 38 %

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide (100 mg) was suspended in EtOH (4 mL) and 2-Furaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr. Resulting imine (100 mg) was suspended in 5 mL MeOH and sodium borohydride (10 eq.) was added. HPLC confirmed reaction was complete (absence of imine). After completion (1 hr), precipitate was filtered to obtain D96 as a light yellow powder. Product was washed with deionized water to remove excess sodium borohydride. Product was allowed to dry under vacuum for 18 hrs. 40 mg (38% yield) of final product was obtained.
Reaction SMILES: [NH2:1][C:2](=O)[C@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].ClC1N=C(Cl)N=C(Cl)N=1.O>CN(C)C=O>[C:2]([C@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:4])#[N:1]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(N)=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](C#N)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To a solution of benzyl [(1R)-2-amino-1-methyl-2-oxoethyl]carbamate (10 g, 45 mmol) in 50 mL of N,N-dimethylformamide was added 2,4,6-trichloro-1,3,5-triazine (4.15 g, 22.5 mmol). After 2 h, 100 mL of water was added and the mixture was filtered. The solids were washed with 100 mL aqueous sodium bicarbonate (2×) and dried under vacuum to give pure benzyl [(1R)-1-cyanoethyl]carbamate (7.2 g). MS 205.2 ((M+1).
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[N:11][CH:12]=1)=[O:5].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[OH:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[O:35][C:2]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[N:11][CH:12]=1)=[O:5]
Reactant: COc1ccc(O)c(OC)c1
Reactant: COC(=O)c1ccc(NC(=O)c2cc(C(F)(F)F)ccc2F)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(NC(=O)c2cc(C(F)(F)F)ccc2Oc2ccc(OC)cc2OC)cn1
Temperature: 100 °C

Procedure:
To methyl 5-[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate (51.3 mg, 0.15 mmol) in N-methylpyrrolidinone (1 mL) was added 2,4-dimethoxyphenol (23.1 mg, 0.45 mmol), cesium carbonate (146.6 mg, 0.45 mmol) and the mixture was heated at 100° C. for 50 minutes to yield methyl 5-(2-(2,4-dimethoxyphenoxy)-5-(trifluoromethyl)benzamido)picolinate that was taken into the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH2:22][CH2:23][CH:24]1[CH:29]([OH:30])[CH2:28][CH2:27][NH:26][CH2:25]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:27][CH2:28][CH:29]([OH:30])[CH:24]([CH2:23][NH2:22])[CH2:25]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: NCC1CNCCC1O
Product: NCC1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCC1O
Yield: 52.8 %

Procedure:
The condensation of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with 3-aminomethyl-4-hydroxy-piperidine was carried out in a similar manner as described in example 1, gave the titled product. Yield 52.8%, m.p 202–04° C., C19H22F2N4O4, m/z 409 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]([C@@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:18]=[CH2:19])=[N:14][N:15]=2)=[C:7]([N+:28]([O-:30])=[O:29])[CH:6]=1.C([O:36]C(N[C@@H](CC=C)C(O)=O)=O)(C)(C)C.CCOC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:31])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:15][NH:14][C:13](=[O:12])[C@@H:16]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:17][CH:18]=[CH2:19])=[O:36])=[C:7]([N+:28]([O-:30])=[O:29])[CH:6]=1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1nnc(-c2ccc(NC(=O)OC)cc2[N+](=O)[O-])o1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)c1ccc(NC(=O)OC)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
{4-[5-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1,3,4-oxadiazol-2-yl]-3-nitro-phenyl}-carbamic acid methyl ester: 168B (0.3 g, 0.393 mmol) and (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (0.085 g, 0.393 mmol) were dissolved in DMF (2 mL) in a 15 mL rbf and TEA (0.274 mL, 1.967 mmol) was added. Mixture was stirred under nitrogen at room temperature while propane phosphonic acid anhydride (T3P), 50% in EtOAc (0.293 mL, 0.983 mmol) was added dropwise. The flask was fitted with a reflux condenser, and the resulting mixture was stirred in an 80° C. oil bath for 5 h. Reaction mixture was poured into ice water and extracted 3× with EtOAc. Combined extracts were washed with sat'd aq. NaHCO3, water and brine, dried over anh. Na2SO4, filtered and evaporated to provide {4-[N′-((S)-2-tert-butoxycarbonylamino-pent-4-enoyl)-hydrazinocarbonyl]-3-nitro-phenyl}-carbamic acid methyl ester, (0.46 g, 86%) as a light yellow solid which was used without further purification. The solid (0.46 g, 1.019 mmol) was dissolved in anhydrous THF (20 mL) under argon and the solution transferred to a 75 mL pressure flask. Burgess reagent (1.33 g, 5.58 mmol) was added, the flask was sealed with a pressure relief cap and then heated in a 75° C. oil bath for 2 h behind a blast shield then left standing overnight at room temperature. Reaction mixture was evaporated on rotary evaporator. Residue was purified by normal phase chromatography to give 168C as a light yellow foam (0.315 g, 71.3%). MS (ESI) m/z: 434.3 (M+H)+ 378.3 (M+H−tBu)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:20]([CH3:21])=[N:19][C:12]3[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:4][C:3]=1[NH2:22].[CH3:23][O:24][CH2:25][CH2:26][NH2:27].O>CN(C=O)C>[NH2:22][C:3]1[C:2]([F:1])=[CH:7][C:6]([CH3:8])=[C:5]([C:9]2[C:20]([CH3:21])=[N:19][C:12]3[N:13]=[C:14]([NH:27][CH2:26][CH2:25][O:24][CH3:23])[N:15]=[CH:16][C:11]=3[CH:10]=2)[CH:4]=1
Reactant: CSc1ncc2cc(-c3cc(N)c(F)cc3C)c(C)nc2n1
Reactant: COCCN
Solvent: CN(C)C=O
Solvent: O
Product: COCCNc1ncc2cc(-c3cc(N)c(F)cc3C)c(C)nc2n1
Temperature: 100 °C
Yield: 85.4 %

Procedure:
Treat a solution of 2-fluoro-4-methyl-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)benzenamine (0.300 g, 0.954 mmol) in DMF (1 mL) with 2-methoxyethanamine (0.430 g, 5.73 mmol) in a screw-capped vial and heat at 100° C. for 20 h. Cool the mixture to RT, treat with H2O and extract with EtOAc (2×). Wash the combined organics with brine, dry over Na2SO4 and concentrate to dryness to afford the title compound as a dark semi-solid (278 mg, 85% yield). MS (m/z): 342.2 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:23])=[O:12])[N:3]=1.[C:24]([O-:27])([O-])=[O:25].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:23][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([F:22])([F:21])[F:20])[C:13]=1[C:11]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:24](=[O:25])[O:27][CH2:2]3)=[N:3]1)=[O:12]
Reactant: O=C(c1c(Cl)cccc1C(F)(F)F)n1nc(Br)c2ccccc21
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1OCc2cc(-c3nn(C(=O)c4c(Cl)cccc4C(F)(F)F)c4ccccc34)ccc21
Temperature: 100 °C

Procedure:
(0.97 g, 2.48 mmol), (3-bromo-1H-indazol-1-yl)(2-chloro-6-(trifluoro methyl)phenyl)methanone (1.0 g, 2.48 mmol), K2CO3 (1.03 g, 7.44 mmol) and Pd(PPh3)4 (0.143 g, 0.12 mmol) were suspended in 1,4-dioxane (15 mL) and H2O (3 mL). The reaction mixture was heated at 100° C. in a microwave reactor for 2 h. The reaction mixture was cooled to rt and diluted with H2O. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (PE:EA=4:1) to afford the title compound as a pale yellow oil. LCMS (ESI) calc'd for C23H13ClF3N2O3 [M+H]+: 457. found: 457.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][CH2:15][N:16]3[C@H:21]4[CH2:22][CH2:23][C@@H:17]3[CH2:18][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:20]4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:34][C:35]1[CH:43]=[C:42]([F:44])[C:41]([S:45]([NH:48][CH2:49][CH3:50])(=[O:47])=[O:46])=[CH:40][C:36]=1[C:37](O)=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[Cl:34][C:35]1[C:36]([C:37]([N:11]2[CH2:10][CH2:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)([CH2:14][CH2:15][N:16]3[C@H:21]4[CH2:22][CH2:23][C@@H:17]3[CH2:18][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:20]4)[CH2:13][CH2:12]2)=[O:38])=[CH:40][C:41]([S:45]([NH:48][CH2:49][CH3:50])(=[O:46])=[O:47])=[C:42]([F:44])[CH:43]=1
Reactant: CCNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCNS(=O)(=O)c1cc(C(=O)N2CCC(CCN3[C@@H]4CC[C@H]3CC(n3c(C)nc5ccccc53)C4)(c3cccc(F)c3)CC2)c(Cl)cc1F
Yield: 44 %

Procedure:
0.103 g (0.23 mmol) 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole and 0.129 g (0.46 mmol) 2-chloro-5-[(ethylamino)sulfonyl]-4-fluorobenzoic acid were combined following the HATU general procedure in Example 5. This compound was purified by flash chromatography on a 0-100% gradient of 1N methanolic ammonia in ethyl acetate in ethyl acetate. 0.76 g obtained (44% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.04-8.14 (m, 1H), 7.86-7.89 (d, 1H J=9.83 Hz), 7.72-7.79 (m, 3H), 7.41-7.51 (m, 3. H), 7.21-7.26 (m, 2H), 7.09-7.15 (m, 1H), 5.00-5.11 (m, 1H), 4.03-4.14 (m, 2H), 3.87-3.99 (m, 1H), 3.19-3.38 (m, 2H), 2.96-3.05 (m, 1H), 2.85-2.94 (m, 3H), 2.69-2.80 (m, 4H), 2.51-2.64 (m, 2H), 1.93-2.26 (m, 11H), 1.73-1.88 (m, 2H), 0.94-1.12 (m, 3H). LC/MS m/z (M+H): 710.
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])([CH2:9][CH2:10][CH3:11])[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[CH2:19](I)[CH3:20].[OH-].[Na+]>CN(C)C=O>[OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][CH3:20])([CH2:9][CH2:10][CH3:11])[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: CCI
Reactant: CCCC(O)(Cn1ccnc1)c1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCC(O)(Cn1ccnc1)c1ccccc1OCC
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.1 %

Procedure:
34 mg of 1-[2-hydroxy-2-(2-hydroxyphenyl)pentyl]imidazole (Compound 18) was dissolved into 10 ml of dimethylformamide, and 33 mg of ethyl iodide and 10 mg of sodium hydroxide was added to this solution. The mixture was stirred at room temperature for 20 hours. The reaction mixture, after being charged into ice water, was subjected to extraction with ether. The ether layer was then washed with water, followed by drying over anhydrous magnesium sulfate. The extract thus obtained was purified by means of silica gel column chromatography (eluent: methylene chloride) to produce 22 mg of the title compound at a yield of 58%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:29][C:30]([F:33])([F:32])[F:31])(=O)=O>CC(C)=O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH2:29][C:30]([F:33])([F:32])[F:31]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CNS(=O)(=O)c1ccc(O)c(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)OC)c1
Temperature: 60 °C

Procedure:
To 3.3 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and 3.3 mmol potassium carbonate in 50 ml acetone was added dropwise 4.9 mmol 2,2,2-trifluoro-ethyl trifluoromethanesulfonate, and the mixture was heated at 60° C. for 16 h. The mixture was then concentrated in vacuo. The residue was suspended in dichloromethane and filtered. The filtrate was concentrated in vacuo, and the residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 3:7) to afford the title compound. MS (m/e): 328.0 (M+H+, 100%)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=4)[C:11]=3[CH:22]=2)=[N:4][N:3]=1.[H-].[Na+].[CH3:25][S:26][CH2:27]Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:16]=[CH:17][C:18]([O:21][CH2:25][S:26][CH3:27])=[CH:19][CH:20]=4)[C:11]=3[CH:22]=2)=[N:4][N:3]=1
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(O)cc4)c3c2)o1
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSCOc1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a solution of 4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]phenol (1.17 g, 4.00 mmol) in N,N-dimethylformamide (15 mL) was added sodium hydride (60% in oil, 0.320 g, 8.00 mmol) at room temperature, and the resulting mixture was stirred for 15 min. (Chloromethyl) methyl sulfide (90%, 0.744 mL, 8.00 mmol) was added to the reaction mixture, and the resulting mixture was further stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=2/1) and recrystallized from methanol to give the title compound (1.22 g, yield 87%) as colorless crystals.