Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]2[N:16]([C:31]3[C:32]4[C@H:39]([CH3:40])[CH2:38][C@@H:37]([O:41][C:42](=[O:52])[C:43]5[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][CH:44]=5)[C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:17][C:18]3([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:11]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:53]N1C(=O)CCC1=O>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:15]([Cl:53])=[CH:14][CH:13]=[C:12]2[N:16]([C:31]3[C:32]4[C@H:39]([CH3:40])[CH2:38][C@@H:37]([O:41][C:42](=[O:52])[C:43]5[CH:44]=[CH:45][C:46]([N+:49]([O-:51])=[O:50])=[CH:47][CH:48]=5)[C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:17][C:18]3([CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:22][CH2:23]3)[C:11]=12)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c(CNC(=O)OC(C)(C)C)cccc43)c21
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c3ccc(Cl)c4CNC(=O)OC(C)(C)C)c21
Reaction time: 48 h
Yield: 27.8 %

Procedure:
To a stirred solution of tert-butyl 4-((tert-butoxycarbonylamino)methyl)-1-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (17 mg, 0.024 mmol) in DCM (0.5 mL) was added 1-chloropyrrolidine-2,5-dione (NCS) (5.7 mg, 0.043 mmol). The reaction mixture was stirred at about room temperature for 48 hours. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution and brine, dried and concentrated. The residue was purified by column chromatography (hexanes:EtOAc, 1:1) to give tert-butyl 4-((tert-butoxycarbonylamino)methyl)-5-chloro-1-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (5 mg, 28%). LCMS (APCI+) m/z 749, 751 [M+H]+; Rt=4.66 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[O:10]1[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:15]([C:12]2[CH:13]=[CH:14][O:10][CH:11]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(Cl)c1ccoc1
Reactant: Nc1ccc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Br)c1)c1ccoc1

Procedure:
3-Bromo-4-chloroaniline (150 mg), 3-furoylchloride (0.15 ml) and sodium carbonate (1 g) were stirred for 18 hours at room temperature in DCM (15 ml). The reaction was filtered, the residue washed with DCM and the combined DCM fractions reduced to dryness under vacuum to give N-(3-bromo-4-chlorophenyl)-3-furamide. NMR; δH [2H6]—DMSO 10.13,(1H, s), 8.38,(1H, s), 8.20,(1H, d), 7.81,(1H, m), 7.73,(1H, dd), 7.59,(1H, d), 6.97,(1H, m).
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[C:12]([OH:18])[CH:13]=[CH:14][C:15]=2[CH3:17])[C:10]([CH3:20])([CH3:19])[C:9]1=[O:21])C1C=CC=CC=1.[H][H].Cl>C(O)(=O)C.[C].[Pd].C(OCC)(=O)C>[OH:18][C:12]1[CH:13]=[CH:14][C:15]([CH3:17])=[C:16]2[C:11]=1[C:10]([CH3:20])([CH3:19])[C:9](=[O:21])[NH:8]2
Reactant: [H][H]
Reactant: Cc1ccc(O)c2c1N(Cc1ccccc1)C(=O)C2(C)C
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc(O)c2c1NC(=O)C2(C)C
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
41.0 g (146 mmol) of 1-benzyl-2,3-dihydro-4-hydroxy-3,3,7-trimethyl-1H-indol-2-one was dissolved in 11 of acetic acid. After the addition of 82 g of a 10% palladium-carbon catalyst, the reaction atmosphere was replaced with hydrogen and 40 ml (160 mmol) of 4N hydrogen chloride solution in ethyl acetate was added, following which the mixture was stirred for 2.5 hours over a water bath at 80° C. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography (silica gel, 4:1 mixture of chloroform and methanol) and recrystallized (ether) to obtain 27.58 g (yield, 98.9%) of colorless prisms of the title compound.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[O:5]1[C:10]2[CH:11]=[CH:12][C:13]([CH:15]=[O:16])=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1.[Cl-].[NH4+]>O1CCCC1>[OH:16][CH:15]([C:13]1[CH:12]=[CH:11][C:10]2[O:5][CH2:6][CH2:7][O:8][C:9]=2[CH:14]=1)[CH:1]=[CH2:2]
Reactant: C=C[Mg]Br
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1ccc2c(c1)OCCO2

Procedure:
To a solution of vinylmagnesiumbromide in tetrahydrofurane (29 mL 1M) maintained at a temperature below 4° C. is added portionwise 2,3-dihydrobenzo[1,4]dioxine-6-carbaldehyde (4.32 g). The mixture is further stirred at a temperature close to 0° C. for 1.75 h and hydrolized by adding an aqueous solution of ammonium chloride (36.5 mL 1M). The mixture is extracted with diethyl oxide. The organic layers are pooled, washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography over silica gel, with heptane/ethyl acetate 1/1 as eluant, affords 1.12 g of 2,3-dihydro-6-(1-hydroxyallyl)benzo[1,4]dioxine as a yellow oil used without further purification.
Reaction SMILES: C(OC(=O)C(N([S:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[C:31](=[O:45])[NH:32][CH:33]([C:38]([O:40]C(C)(C)C)=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])C(=O)C1C=C(F)C=CC=1)CC(C)C)(C)(C)C.F[C:48](F)(F)[C:49]([OH:51])=[O:50]>ClCCl.C1(OC)C=CC=CC=1>[C:49]([CH:48]([NH:32][C:31]([C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[S:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[C:31]([NH:32][CH:33]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:38]([OH:40])=[O:39])=[O:45])=[O:45])[CH2:37][CH:35]([CH3:34])[CH3:36])([OH:51])=[O:50]
Reactant: CC(C)CC(NC(=O)c1cc(F)ccc1SSN(C(=O)c1cccc(F)c1)C(CC(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(C)CC(NC(=O)c1cc(F)ccc1SSc1ccc(F)cc1C(=O)NC(CC(C)C)C(=O)O)C(=O)O

Procedure:
The general method of Preparation 20 was followed using [S-(R*,R*)]-2-[2-[[2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-4-fluorophenyldisulfanyl]-5-fluorobenzoylamino]-4-methyl pentanoic acid tert-butyl ester (1.8 g, 2.6 mmol) in 20 mL dichloromethane, anisole (2 mL), and 20 mL trifluoroacetic acid. The crude product was recrystallized from methanol/water to afford 0.9 g of the title compound.
Reaction SMILES: [OH-:1].[K+].C([O:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[N:15]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:14]([CH3:30])([CH3:29])[CH2:13]1)(=O)C1C=CC=CC=1>C(O)C>[OH:1][CH:12]1[CH2:17][C:16]([CH3:18])([CH3:19])[N:15]([O:20][CH:21]([O:20][N:15]2[C:14]([CH3:29])([CH3:30])[CH2:13][CH:12]([OH:11])[CH2:17][C:16]2([CH3:18])[CH3:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:14]([CH3:30])([CH3:29])[CH2:13]1
Reactant: [OH-]
Reactant: CCCCCCCCON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Agent: [K+]
Solvent: CCO
Product: CCCCCCCC(ON1C(C)(C)CC(O)CC1(C)C)ON1C(C)(C)CC(O)CC1(C)C

Procedure:
The title compound is prepared by basic hydrolysis (potassium hydroxide in ethanol) of the compound prepared in Example 22A.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=2)[CH2:3]1.[C:15]([SiH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])([CH3:17])[CH3:16].N1C=CN=C1.CO>CN(C)C=O>[Si:19]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=2)[CH2:3]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[SiH](c1ccccc1)c1ccccc1
Reactant: COC(=O)c1coc(N2CC(O)C2)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1coc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of 3-hydroxy-1-(4-methoxycarbonyl-1,3-oxazol-2-yl)azetidine (2.64 g, 13.4 mmol) (obtained as described in Reference Example 70(7)) in dimethylformamide (80 ml) were added t-butyldiphenylsilane (6.97 ml, 26.8 mmol) and imidazole (1.82 g, 26.8 mmol) in an ice bath and the mixture was stirred in an ice bath overnight. After checking the completion of the reaction, methanol was added to the reaction mixture and the mixture was stirred for 30 minutes. The resulting mixture was partitioned between ethyl acetate and 1 0% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (4:3→3:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-methoxycarbonyl-1,3-oxazol-2-yl)azetidine (4.95 g, yield 85%) as a pale yellow solid.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:22][F:23])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]2[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=[CH:18][C:5]=2[O:4]1>C(O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:5]2[O:4][C:3]([CH2:2][F:1])([CH2:22][F:23])[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[C:6]=2[CH:15]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccn1)=CC(CF)(CF)O2
Solvent: CCO
Product: Nc1ccc2c(c1)C(c1ccccn1)=CC(CF)(CF)O2
Yield: 85.5 %

Procedure:
A mixture of 6.2 g of 2,2-bisfluoromethyl-6-nitro-4-(2-pyridyl)-2H-1-benzopyran, 11.7 g of stannous chloride and 80 mnl of ethanol was refluxed with heating for 3 hours. The solvent was distilled off and sodium hydroxide solution was added to form an alkaline solution. The solution was extracted with methylene chloride and the organic layer was extracted with 2N hydrochloric acid. To the aqueous layer was added 2N sodium hydroxide to form a strongly alkaline solution, which was then extracted with methylene chloride. The organic layer was washed with water and dried and the solvent was distilled off to obtain 4.8 g of 6-amino-2,2-bisfluoromethyl-4-(2-pyridyl)-2H-1-benzopyran. To a mixture of 4.8 g of the above-obtained 6-amino-2,2-bisfluoromethyl-4-(2-pyridyl)-2H-1-benzopyran, 1.0 ml of concentrated sulfuric acid and 80 ml of water was added 1.20 g of sodium nitrite dissolved in 10 ml of water with stirring under ice-cooling. After the mixture was stirred for 20 minutes, 3.31 g of potassium iodide dissolved in 10 ml of water was added. After addition of 100 ml of methylene chloride, the mixture was stirred at room temperature for 2 hours. Water was added thereto and the mixture was extracted with methylene chloride. The organic layer was washed with sodium hydroxide solution and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 4.50 g of oily 2,2-bisfluoromethyl-6-iodo-4-(2-pyridyl)-2H-1-benzopyran represented by the following formula.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[N:10]#[C:11][NH2:12].[OH-].[Na+]>Cl.O>[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:11]([NH2:12])=[NH:10])=[CH:3][CH:4]=1
Reactant: N#CN
Reactant: NCc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N=C(N)Nc1ccc(CN)cc1
Yield: 15.5 %

Procedure:
p-Aminobenzylamine (6.7 g; 54.84 mmol) was suspended in 20 ml of 6N HCl and, while refluxing, 5.3 g of cyanamide—dissolved in 5 ml of H2O—were slowly added dropwise. After the reaction was complete, 50% NaOH solution was added to the solution at 0° C., and the resulting precipitate was filtered off with suction, boiled in 50 ml of ethanol and filtered. Concentration of the mother liquor and stirring of the resulting residue with diethyl ether afforded 1.4 g of yellow solid; m.p.: 255° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][N:17]([CH2:26][C:27]([F:30])([F:29])[F:28])[N:16]=2)=[C:11]([F:31])[CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[F:31][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[C:15]1[C:19]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:18][N:17]([CH2:26][C:27]([F:28])([F:29])[F:30])[N:16]=1
Reactant: Fc1cc(OCc2ccccc2)ccc1-c1nn(CC(F)(F)F)cc1-c1ccncc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(-c2nn(CC(F)(F)F)cc2-c2ccncc2)c(F)c1
Yield: 77.7 %

Procedure:
To 4-[3-(4-Benzyloxy-2-fluoro-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-4-yl]-pyridine (900 mg) was added trifluoroacetic acid (5.25 ml) and anisole (1.15 ml) and the reaction mixture heated at reflux for 18 h. The reaction mixture was quenched with 1N NaOH, extracted 3× tetrahydrofuran, dried magnesium sulfate, filtered and concentrated. Purification via Biotage MPLC eluting with 5% methanol/1% ammonium hydroxide/ethyl acetate provided the title compound (552 mg). MS: (M+H m/z=338.2).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[C:14]1(=[CH:18][C:19]([OH:21])=[O:20])[CH2:17][CH2:16][CH2:15]1>C1COCC1.CN(C=O)C>[C:1]1([S:7][C:14]2([CH2:18][C:19]([OH:21])=[O:20])[CH2:17][CH2:16][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: O=C(O)C=C1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)CC1(Sc2ccccc2)CCC1

Procedure:
A solution of thiophenol (70 mmol) in THF (10 ml) was refluxed for 1 h in the presence of K2CO3 (70 mmol) as a base. A solution of Cyclobutylidene acetic acid (intermediate 1) (35 mmol) in DMF (1.0 ml) was added to the above reaction. The reaction was monitored by TLC for completion. After 3 days the reaction was cooled and filtered. It was then neutralized with ethyl acetate saturated with hydrochloric acid and the compound was extracted with ethyl acetate. Organic layer was then separated, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was column purified to give the compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:14]([OH:16])=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(Cl)(=O)C(Cl)=O.[C:23]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].[Mg+2].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:14]([CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:23]([O:31][CH2:32][CH3:33])=[O:30])=[O:16])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: O=C(O)C1(c2ccccc2F)CCOCC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccccc2F)CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 4-(2-fluorophenyl)-tetrahydro-2H-pyran-4-carboxylic acid (1.9 g, 8.5 mmol) in DCM (50 mL) and DMF (5 mL) was carefully added oxalyl chloride (0.79 mL, 8.9 mmol). Gas evolution was observed. The reaction was stirred at room temperature for 3 hours. In a separate flask was combined IPAc (1.0 mL, 8.7 mmol), diethyl malonate (1.6 mL, 11 mmol). and anhydrous MgCl2 (1.0 g, 11 mmol). The resulting white slurry was stirred for 30 minutes, and then TEA (4.0 mL, 29 mmol) was added and the reaction was stirred for 2.5 hours. The reaction was chilled in an ice water bath for 10 minutes, and then the concentrated acid chloride oil was added via syringe over 10 minutes. The ice bath was removed, and the reaction was stirred for 16 hours at 50° C. After cooling to room temperature, the reaction was acidified with 5N HCl solution (100 mL). The aqueous layer was removed, and the organic layer was washed with saturated NaHCO3 solution (150 mL). The aqueous layer was removed, and the organic extract was washed with water. The organic layer was dried (Na2SO4), filtered and concentrated to afford a dark colored oil. The crude reaction mixture was used in the next step.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([F:15])([F:14])[F:13])=[C:9]([C:16](Cl)=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:22]=[C:23]([NH2:31])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.C(N(CC)C(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>ClCCl>[F:19][C:20]([F:32])([F:33])[C:21]1[CH:22]=[C:23]([NH:31][C:16]([C:9]2[CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:11][C:10]=2[C:12]([F:15])([F:14])[F:13])=[O:17])[CH:24]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:26]=1
Reactant: O=C(Cl)c1cc(-c2ccccc2)oc1C(F)(F)F
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.1 %

Procedure:
An excess of 5-phenyl-2-trifluoromethyl-furan-3-carbonyl chloride (1 g, 3.6 mmol) was added to a solution of 3,5-bis-trifluoromethyl-phenylamine (0.758 g, 3.3 mmol) and N,N-diisopropylethylamine (0.58 mL) in dichloromethane (50 mL). After stirring at room temperature for 1 day, the reaction underwent an aqueous acidic (dilute HCl, 2×30 mL) and basic (dilute NaHCO3, 2×30 mL) workup followed by washing with brine (saturated NaCl, 2×30 mL), drying over MgSO4, and concentration. The crude compound was purified by passing through a silica gel plug eluting with ethyl acetate/hexanes (2:1) to afford the title compound (1.42 g, 92% yield). ES-MS negative Q1 (m/z) 466.
Reaction SMILES: C([NH:11][CH2:12][C:13](=[O:37])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]CC1C=CC=CC=1)=[O:28])=[O:17])(OCC1C=CC=CC=1)=O.[ClH:38].[H][H]>[Pd].CC(O)C>[ClH:38].[NH2:11][CH2:12][C:13](=[O:37])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:17]
Reactant: O=C(CCC(=O)OCCCCCCCCC(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: NCC(=O)CCC(=O)OCCCCCCCCC(=O)O
Yield: 61.8 %

Procedure:
This compound was prepared from the product of 11c (1.4 g; 2.7 mmol), 12 M HCl (0.25 mL; 3.0 mmol), 10% Pd/C (100 mg), hydrogen gas, and 2-propanol (25 mL) using the procedure in Example 8d. 0.54 g (62%) product was obtained (white solid).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:29][CH2:28][CH:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN1CCC(CN)CC1
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(CNC(=O)c2cccc(-c3ccc4ncnc(N)c4n3)c2)CC1

Procedure:
Following the same reaction and purification procedure, the acid 14 (80 mg, 0.30 mmol) was reacted with (1-methyl-4-piperidyl)methanamine (CAS 7149-42-0) (77 mg, 0.6 mmol), HATU (129 mg, 0.33 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-((1-methylpiperidin-4-yl)methyl)benzamide 22. LC/MS (ESI+): m/z 377 (M+H). 1H NMR (400 MHz, DMSO) δ 8.48 (d, J=8.8 Hz, 2H), 8.42 (s, 2H), 8.23 (s, 1H), 8.14 (d, J=8.8 Hz, 2H), 7.96 (s, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.45 (d, J=6.9 Hz, 1H), 2.90 (s, 2H), 2.73 (d, J=52.3 Hz, 4H), 2.19 (s, 1H), 2.04 (s, 3H), 1.83 (s, 2H), 1.64 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:11][C:10]2[C:5](=[CH:6][C:7]([CH3:12])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:13].Cl[C:16]([O:18][C:19]([CH3:21])=[CH2:20])=[O:17].O>N1C=CC=CC=1>[C:19]([O:18][C:16]([N:11]1[C:10]2[C:5](=[CH:6][C:7]([CH3:12])=[CH:8][CH:9]=2)[NH:4][C:3](=[O:13])[C:2]1([CH3:14])[CH3:1])=[O:17])([CH3:21])=[CH2:20]
Reactant: C=C(C)OC(=O)Cl
Reactant: Cc1ccc2c(c1)NC(=O)C(C)(C)N2
Solvent: O
Solvent: c1ccncc1
Product: C=C(C)OC(=O)N1c2ccc(C)cc2NC(=O)C1(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3,3,7-Trimethyl-3,4-dihydroquinoxalin-2(1H)-one (0.4 g, 2.1 mmol) were dissolved in 10 ml of anhydrous pyridine, and the stirred solution was treated at room temperature with 0.24 ml (2.2 mmol) of isopropenyl chloroformate. The mixture was stirred for 6 hours at room temperature and treated with water, the precipitate which formed was filtered off with suction, washed with water and dried. This gave 0.4 g (69%) of colorless crystals of melting point 185° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].N[C:13](N)=[O:14]>>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][C:13](=[O:14])[NH:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: NC(N)=O
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2o1

Procedure:
This was prepared in a similar manner as the 5-chloro-2-hydroxyphenyl analogue, by fusing 2-amino-4-nitrophenol and urea to form 5-nitrobenzoxazolinone (m.pt. 215° C. after recrystallisation from acetone), and then heating with alcoholic dimethylamine as above: it was not recrystallised.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:16]2[CH:17]=[N:18][CH:19]=[C:14]([NH:13][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[N:15]=2)=[CH:24][CH:23]=1
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Reactant: Nc1ccc(F)cc1
Product: COc1cc(Nc2cncc(Nc3ccc(F)cc3)n2)cc(OC)c1OC
Yield: 28 %

Procedure:
Using Method R, with 200 mg of 2-(3,4,5-trimethoxyphenylamino)-6-chloropyrazine (all amounts scaled accordingly) and 4-fluoroaniline, 72 mg of title compound were obtained. Yield: 28%. 1H NMR (250 MHz, DMSO-d6) δ 3.62 (s, 9H), 6.83 (s, 2H), 7.06 (t, 2H, J=9.0 Hz), 7.51 (s, 1H), 7.57 (d, 2H, J=9.1 Hz), 9.05 (s, 1H), 9.14 (s, 1H). 13C NMR (62.5 MHz, DMSO-d6) δ 55.56, 60.12, 97.01, 114.94, 115.29, 120.38, 120.50, 121.62, 121.83, 132.29, 137.19, 137.22, 150.15, 152.84. m/z 371.2 [(M+H)+ calcd for C19H19FN4O3 370.1].
Reaction SMILES: [NH:1]1[C:10](=O)[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=[O:3].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:13].[OH-].[Na+]>N1C=CC=CC=1>[NH:1]1[C:10](=[S:13])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=[O:3]
Reactant: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=c1[nH]c(=S)c2[nH]cnc2[nH]1
Yield: 354.5 %

Procedure:
6.59 g (19 mM) of xanthine and 5.07 g (22.8 mM) of phosphorus pentasulfide were heated under reflux in 102 ml of pyridine for 3 days. At 0° C., 25.1 ml of 2N NaOH were added. The solid was filtered off and washed with pyridine. The solvents were evaporated in vacuo, the residue suspended in water, collected, redissolved in 100 ml of 1N NaOH and 50 ml of iso-propanol, treated twice with 0.3 g of charcoal, filtered and neutralized with 5N HCl to pH 7. The isopropanol was removed in vacuo and the solid collected, washed and dried to give 6.80 g (98.7%) of 6-thioxanthine, mp 188-9° C.