Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=C(C=CC=1)N)([O-])=O.N[C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][C:28]=1OC)[C:15]([NH:17]C1C=CC(F)=C(F)C=1)=[O:16]>>[C:15]([NH2:17])(=[O:16])[C:14]1[CH:26]=[CH:27][CH:28]=[CH:12][CH:13]=1
Reactant: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1N
Agent: Nc1cccc([N+](=O)[O-])c1
Product: NC(=O)c1ccccc1
Yield: 43.6 %

Procedure:
The title compound was synthesized as in Example 1 using 3-nitroaniline (1.35 g, 9.8 mmol), CSI (0.85 L, 9.8 mmol), and 3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (0.39 g, 1.4 mmol) to give 0.074 g of benzamide, N-(3,4-difluorophenyl)-4-methoxy-3-[[[[[(3-nitrophenyl)-amino]carbonyl]-amino]sulfonyl]amino]-. Microanalysis: C21H17F2N5O7S.0.44 H2O; calculated: C=47.65; H=3.40; N=13.23. found: C=47.64; H=3.01; N=13.51. MS: M++1=522 Da.Mp 206-208° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[CH:9]=1)[C:5]#[N:6].[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=[O:22].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([F:17])[CH:19]=2)[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[CH:7]=1)#[N:6]
Reactant: O=C(O)c1cccc(F)c1
Reactant: N#Cc1cc(N)cc(Oc2cncnc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(NC(=O)c2cccc(F)c2)cc(Oc2cncnc2)c1
Yield: 42.2 %

Procedure:
Compound 22 (10 mg, 0.047 mmol, 1.2 eq), 3-fluorobenzoic acid (5.5 mg, 0.039 mmol, 1.0 eq), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (31 mg, 0.082 mmol, 2.1 eq), and N,N-Diisopropylethylamine (11 mg, 0.085 mmol, 2.1 eq) were dissolved in CH2Cl2 (0.43 mL) and DMF (0.09 mL) and stirred at rt overnight. The reaction was quenched with water, and the layers were separated via phase separation. The organic layer was dried on air concentrator and purified by flash chromatography on silica gel to give 5.5 mg (42%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.57 (s, 2H), 8.13 (s, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.59 (dd, J=18.9, 8.4 Hz, 2H), 7.51-7.46 (m, 1H), 7.31-7.26 (m, 1H), 7.08 (s, 1H); ES-MS [M+1]+: 335.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][NH:12][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH:14]=1.ClCCl.[C:26](OC(=O)C)(=[O:28])[CH3:27]>O>[C:26]([N:12]1[CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH:14]=[C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:10][CH2:11]1)(=[O:28])[CH3:27]
Reactant: COc1cccc(C2C=C(c3cc(F)ccc3F)CCN2)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1cccc(C2C=C(c3cc(F)ccc3F)CCN2C(C)=O)c1
Reaction time: 0.17 h

Procedure:
To a stir bar equipped flask containing 4-(2,5-difluorophenyl)-6-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridne (1-5, 0.6 g, 0.19 mmol) was added dichloromethane (15 mL) followed successively by TEA (0.14 mL, 0.19 mmol), and acetic anhydride (0.06 mL, 0.59 mmol). The resulting solution stirred for 10 min. Water was added (2 mL), and then the reaction was washed with dichloromethane (2×30 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude reside was purified by reverse phase liquid chromatography (0.1% TFA) to give 1-acetyl-4-(2,5-difluorophenyl)-6-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine (1-6). 1H NMR (300 MHz, CDCl3) δ 7.26 (m, 1H), 6.96 (m, 4H), 6.82 (m, 1H); 6.36 (m, 1H), 6.20 (m, 1H), 3.82 (s, 3H), 3.80 (m, 2H); 3.40 (dt, J=11.9, 4.2 Hz, 1H); 2.74 (m, 1H); 2.42 (dd, J=16.0, 1.0 Hz, 1H), 2.20 (s, 3H); MS 344.1 found, 343.3 (M+H+) required.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7](=O)[CH2:8][CH:9]([CH2:12][CH3:13])[CH:10]=O)=[CH:5][CH:4]=1.[S:17]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)(=[O:20])(=[O:19])[NH2:18].N>C(O)(=O)C>[CH2:12]([C:9]1[CH:8]=[C:7]([C:6]2[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:25]([C:24]2[CH:26]=[CH:27][C:21]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:22][CH:23]=2)[CH:10]=1)[CH3:13]
Reactant: CCC(C=O)CC(=O)c1ccc(OC)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: N
Solvent: CC(=O)O
Product: CCc1cc(-c2ccc(OC)cc2)n(-c2ccc(S(N)(=O)=O)cc2)c1
Temperature: 25 °C
Yield: 76.2 %

Procedure:
0.47 g (2.1 mmol) of 2-(4-methoxyphenacyl)butyraldehyde [prepared as described in step (ii) above] and 0.44 g (2.5 mmol) of 4-sulfamoylaniline were dissolved in 5 ml of acetic acid, and the resulting solution was heated under reflux for 2 hours. At the end of this time, the mixture was cooled to room temperature, concentrated aqueous ammonia was added to adjust its pH to a value of 8.0 and the mixture was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue was applied to a silica gel chromatography column, eluted with a 3:2 by volume mixture of hexane and ethyl acetate, to give 0.57 g (yield 76%) of the title compound as a pale yellow powder, melting at 154-156° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[N:23]([CH2:33][C:34](Cl)=[O:35])[N:22]=2)=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:34](=[O:35])[CH2:33][N:23]2[C:24]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[N:25][C:21]([C:18]3[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=3)=[N:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cn2nc(-c3ccc(F)cc3)nc2-c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.9 %

Procedure:
1.8 g piperazine-1-carboxylic acid tert-butyl ester was added to 3.2 g (3,5-Bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetyl chloride and 1 g triethylamine in 50 mL dichlormethane. The reaction was stirred 1 day at RT, evaporated and purified by chromatography on silica gel (petrolether/diethylether:1/1) to yield 3.1 g of the desired compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:31])[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]2[CH:9]=[C:8]([CH:16]=[CH:17][C:18]([NH:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)=[O:19])[CH:7]=[CH:6][C:5]1=2.I[CH3:33].O>CN(C=O)C>[CH3:33][N:20]([C:18](=[O:19])[CH:17]=[CH:16][C:8]1[CH:7]=[CH:6][C:5]2[C:4]([CH3:31])([CH3:3])[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]=2[CH:9]=1)[C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1
Reactant: CI
Reactant: COC(=O)c1ccc(NC(=O)C=Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(N(C)C(=O)C=Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
300 mg (10 mmol) of sodium hydride (80% in oil) and 30 ml of DMF are introduced into a three-necked flask under a stream of nitrogen. A solution of 1.8 g (4.8 mmol) of methyl 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) acryloylamino]benzoate (prepared in Example 2 (a)) in 50 ml of DMF is added dropwise and the mixture is stirred until the evolution of gas has ceased. 750 μl (12 mmol) of iodomethane are then added and the mixture is stirred at room temperature for four hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The solid obtained is triturated from hexane, filtered off and dried. 1.6 g (83%) of the expected methyl ester, with a melting point of 167-8° C., are collected.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][S:8][CH2:9][C:10]1[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH:12]=[CH:13][N:14]=1.[OH-:26].[Na+]>CO.O>[CH3:7][S:8]([CH2:9][C:10]1[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)[CH:12]=[CH:13][N:14]=1)(=[O:1])=[O:26]
Reactant: [OH-]
Reactant: CSCc1nccn1CCCCc1ccc(O)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Cc1nccn1CCCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Oxone (Trade mark; potassium peroxymonosulfate: 28.8 g) was added to a suspension of 4-[4-[2-[(methylthio)methyl]-1H-imidazol-1-yl]butyl]phenol (8.64 g) in methanol-water (2:1) (150 ml) at 0° C. and the mixture was stirred at room temperature for 3.5 hr. The reaction mixture was adjusted to pH 6 by addition of 4N aqueous sodium hydroxide solution to precipitate crystals, which were collected by filtration. The crystals were dissolved in ethyl acetate-methanol (1:4), and the insoluble was filtered off. The filtrated was concentrated and recrystallized from ethyl acetate-methanol-hexane to give the titled compound (6.53 g) as colorless needle crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].NC1C=CC2CCCC=2C=1C(OC)=O.N1C=CC=CC=1.Cl[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37].Cl>C(Cl)Cl>[CH:39]([O:38][C:36]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12])=[O:37])([CH3:41])[CH3:40]
Reactant: CC(C)OC(=O)Cl
Reactant: COC(=O)c1cc2c(cc1N)CCC2
Agent: COC(=O)c1c(N)ccc2c1CCC2
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc2c(cc1NC(=O)OC(C)C)CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of a mixture of methyl 6-aminoindane-5-carboxylate and methyl 5-aminoindane-4-carboxylate (760 mg, 3.98 mmol), and pyridine (805 uL, 9.95 mmol) in CH2Cl2 (8 mL) at 0° C. under N2 was added isopropyl chloroformate (1 M in toluene) (3.98 mL, 3.98 mmol). The resulting mixture was stirred at room temperature for 16 h. 1M HCl was added to the reaction mixture and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si, hexanes/EtOAc) to afford methyl 6-[(isopropoxycarbonyl)amino]indane-5-carboxylate. LCMS calc.=300.1; found=299.9 (M+Na)+. 1H NMR (500 MHz, CDCl3) δ 10.43 (s, 1H); 8.34 (s, 1H); 7.86 (s, 1H); 5.06-5.00 (m, 1H); 3.92 (s, 3H); 2.96 (t, J=7.5 Hz, 2H); 2.88 (t, J=7.4 Hz, 2H); 2.13-2.07 (m, 2H); 1.33 (d, J=6.2 Hz, 6H). Methyl 5-[(isopropoxycarbonyl)amino]indane-4-carboxylate was isolated as a by-product. LCMS calc.=300.1; found=299.9 (M+Na)+. 1H NMR (500 MHz, CDCl3) a 10.07 (s, 1H); 8.21 (d, J=8.4 Hz, 1H); 7.36 (d, J=8.4 Hz, 1H); 5.06-5.00 (m, 1H); 3.93 (s, 3H); 3.19 (t, J=7.5 Hz, 2H); 2.89 (t, J=7.5 Hz, 2H); 2.08-2.02 (m, 2H); 1.32 (d, J=6.2 Hz, 6H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)O)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:21])[F:1])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: FC(F)(F)c1cccc(C(Cl)c2cccc(C(F)(F)F)c2)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of bis(3-(trifluoromethyl)phenyl)methanol (1.1 g, 3.4 mmol) in CH2Cl2 (10 mL) was added dropwise thionyl chloride (0.50 ml, 6.9 mmol) at rt. The reaction was stirred at 50° C. for 4 h, concentrated under vacuum, azeotroped with toluene, and dried under vacuum to give crude chlorobis(3-(trifluoromethyl)phenyl)methane. The crude chlorobis(3-(trifluoromethyl)-phenyl)methane was added to a solution of piperazine (0.81 ml, 10 mmol) in acetonitrile (10 mL), heated to 100° C. for 18 h and concentrated under vacuum. The residue was dissolved in CH2Cl2 (150 mL) and washed with 1N NaOH (150 mL). The organic layer was dried with K2CO3, filtered, and concentrated to give 1-(bis(3-(trifluoromethyl)-phenyl)methyl)piperazine. The crude 1-(bis(3-(trifluoromethyl)phenyl)-methyl)piperazine was dissolved in acetonitrile (10 mL) and tert-butyl bromoacetate (0.55 mL, 3.4 mmol) and triethylamine (0.96 ml, 6.9 mmol) was added. The solution was stirred for 4 h, diluted with water, and extracted with CH2Cl2. The organic layer was washed with saturated NaCl solution, then dried over Na2SO4, and concentrated. The crude product was purified by ISCO using 0-50% EtOAc in haxanes to give tert-butyl 2-(4-(bis(3-(trifluoromethyl)-phenyl)methyl)piperazin-1-yl)acetate (0.86 g, 50% yield). MS (ESI, pos. ion) m/z: 503.1 (M+1), which was then converted to the title compound by proceeding as described in Example 4 above.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[C:3]=2[CH3:10])[CH2:13][CH2:12]1
Reactant: Cc1c(F)cccc1C=O
Reactant: NC1CC1
Product: Cc1c(F)cccc1CNC1CC1

Procedure:
Synthesized according to typical procedure J from 3-fluoro-2-methylbenzaldehyde and cyclopropylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:14]3[N:15]([CH3:19])[C:16](=O)[NH:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:24])=O>C(OCC)(=O)C>[Cl:24][C:16]1[N:15]([CH3:19])[C:14]2[C:9]([C:7]([C:6]3[CH:20]=[CH:21][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:8])=[CH:10][CH:11]=[CH:12][C:13]=2[N:17]=1
Reactant: COc1ccc(C(=O)c2cccc3[nH]c(=O)n(C)c23)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2cccc3nc(Cl)n(C)c23)cc1
Temperature: 100 °C
Yield: 80 %

Procedure:
A mixture of 145 mg (0.514 mmol) of 7-(4-methoxybenzoyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one was dissolved in 1.5 mL of phosphorous oxychloride and heated at 100° C. for 18 h. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue thus obtained was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo to give 124 mg (80%) of the title compound, which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C@H:14]([O:16][CH2:17][CH3:18])[CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[OH:20][C@@H:21]([CH2:51]O)[CH2:22][N:23]1[CH:27]=[CH:26][C:25]([NH:28]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:24]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:63]=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:28][C:25]1[CH:26]=[CH:27][N:23]([CH2:22][C:21]([OH:20])([CH3:51])[CH3:63])[N:24]=1)[CH2:13][C@H:14]([O:16][CH2:17][CH3:18])[CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CCO[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCO[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccn(CC(C)(C)O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
(2S,4R)-2-t-butoxycarbonylamino-4-ethoxy-pentanoic acid (273 mg, 1.04 mmol) was mixed with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 194.6 mg, 1.25 mmol) in N,N-dimethylformamide (10 mL). benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (695 mg, 1.57 mmol) and N,N-diisopropylethylamine (0.4 mL) was added at 0° C. The mixture was stirred at room temperature overnight. Solvents were evaporated and the residue was extracted with ethyl acetate and saturated sodium chloride solution. Solvents were evaporated and the crude material was purified by flash column chromatography (silica gel, 10-80% ethyl acetate/hexanes) to afford {(1S,3R)-3-ethoxy-1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-butyl}-carbamic acid t-butyl ester (306 mg, 73%) as a white solid: LR-ES-MS m/z calculated for C19H34N4O5 [M]+ 398, observed [M+H]+ 399; 1H NMR (300 MHz, CDCl3, plus drops of CD3OD) δ ppm 1.08-1.15 (m, 12H), 1.37 (s, 9H), 1.72-1.94 (m, 2H), 3.35-3.60 (m, 3H), 3.89 (s, 2H), 4.20 (m, 1H), 6.48 (br. s., 1H).
Reaction SMILES: Cl[CH:2]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:28]=[N:29][N:30]([CH2:32][CH3:33])[N:31]=3)=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)[C:3]1[CH:13]=[CH:12][C:6]([O:7][C:8]([F:11])([F:10])[F:9])=[CH:5][CH:4]=1.[F:34][C:35]([F:45])([F:44])[O:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:32]([N:30]1[N:29]=[N:28][C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][N:17]3[CH2:18][CH2:19][C:14](=[C:2]([C:3]4[CH:13]=[CH:12][C:6]([O:7][C:8]([F:11])([F:10])[F:9])=[CH:5][CH:4]=4)[O:43][C:40]4[CH:41]=[CH:42][C:37]([O:36][C:35]([F:34])([F:44])[F:45])=[CH:38][CH:39]=4)[CH2:15][CH2:16]3)=[CH:22][CH:23]=2)=[N:31]1)[CH3:33]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CCn1nnc(-c2ccc(CN3CCC(C(Cl)c4ccc(OC(F)(F)F)cc4)CC3)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nnc(-c2ccc(CN3CCC(=C(Oc4ccc(OC(F)(F)F)cc4)c4ccc(OC(F)(F)F)cc4)CC3)cc2)n1

Procedure:
A solution of {4-[chloro(1-{[4-(2-ethyl(1,2,3,4-tetraazol-5-yl))phenyl]methyl}(4-piperidyl))methyl]phenoxy}trifluoromethane, 4-(trifluoromethoxy)phenol and potassium carbonate in DMF is stirred at ambient temperature for about two hours. After this time the reaction mixture is poured into water and the mixture is extracted with ethyl acetate. The extract is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding compound 137.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[N:8][C:9]([C:14]([O:16]CC)=O)=[C:10]([OH:13])[C:11](=[O:12])[N:6]2[CH2:5][C:4](=[O:19])[N:3]1[CH3:20].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:25][NH2:26]>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:25][NH:26][C:14]([C:9]1[N:8]=[C:7]2[N:6]([C:11](=[O:12])[C:10]=1[OH:13])[CH2:5][C:4](=[O:19])[N:3]([CH3:20])[N:2]2[CH3:1])=[O:16]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N(C)N2C
Product: CN1C(=O)Cn2c(nc(C(=O)NCc3ccc(Cl)c(Cl)c3)c(O)c2=O)N1C
Yield: 74 %

Procedure:
Reaction of intermediate 22, ethyl 1,2-dimethyl-7-hydroxy-3,6-dioxo-2,3,4,6-tetrahydro-1H-pyrimido[2,1-c][1,2,4]triazine-8-carboxylate, (0.050 g, 0.177 mmol) with 3,4-dichlorobenzylamine (0.10 g, 0.57 mmol) as described in the preparation of example 1 gave 0.054 g (74% yield) of the title amide as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.28 (3H, s, NCH3), 3.32 (3H, s, NCH3), 4.59 (2H, d, J=6.7 Hz, NCH2), 4.68 (2H, s, CH2), 7.21 (1H, dd, J=2.0 Hz and J=8.0 Hz, aromatic), 7.44 (1H, d, J=2.0 Hz, aromatic), 7.46 (1H, d, J=8.0 Hz, aromatic), 7.78 (1H, broad t, NH), 11.85 (1H, s, OH). MS (ESI+) m/z 413 [M+H+].
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.O1CCCC1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:20][S:21]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (10 g) and tetrahydrofuran (100 mL) were successively added methanesulfonyl chloride (5.98 g) and triethylamme (5.53 g) at 0° C. The mixture was stirred at room temperature for 2 hrs., and the reaction mixture was diluted with ethyl acetate and washed successively with 1N aqueous sodium hydroxide solution, water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give tert-butyl 4-(methylsulfonyl)oxypiperidine-1-carboxylate as crystals. Recrystallization from ethyl acetate-hexane gave white prism crystals (13.2 g, yield 95%). melting point: 94–95° C.
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.S(=O)(=O)(O)O.[OH2:25].[CH3:26]O>>[OH:25][CH2:26][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([CH3:13])[CH:19]=1
Reactant: O
Reactant: CO
Reactant: Cc1ccccn1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Product: Cc1cc(CO)ccn1

Procedure:
Ammonium persulfate (231 g) was added to a solution of 2-methylpyridine (100 ml) in water-MeOH (350:700 ml); and then concentrated sulfuric acid (58 m,) was added. The mixture was stirred at reflux for 3 days. In this time other ammonium persulfate (20 g) and concentrated sulfuric acid (15 ml) were added. The mixture was quenched with NaOH 10% and extracted with EE (3×100 ml) and EA (3×100 ml), then the organic extracts were washed with brine (200 ml), dried and concentrated in vacuo to a yellow oil which was purified by flash chromatography (eluting with EE-EA 1:1) to give the title compound as a white solid (12.0 g).
Reaction SMILES: [Br:1][C:2]1(C(OC)=O)[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-:16].[Na+].[CH3:18][OH:19]>O>[Br:1][C:2]1[CH:11]=[C:10]([C:18]([OH:19])=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: [OH-]
Reactant: CO
Reactant: COC(=O)C1(Br)C=Cc2ccccc2N1
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Br)nc2ccccc12
Temperature: 50 °C

Procedure:
A mixture of methyl 2-bromoquinolinecarboxylate (7.2 g) and NaOH (1.1 g) in 15 mL of methanol and 15 mL of water is stirred at 50° C. until TLC indicates the disappearance of starting material. After cooling, the methanol is evaporated and the mixture is treated with 28 mL of 1N HCl, the solid is collected by filtration and dried to afford 6.1 g of 2-bromoquinoline-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10](N)[C:9]2[C:4](=[N:5]C=C(CN(C3C=CC=CC=3)C3C=CC=CC=3)N=2)[N:3]=1.[CH:27]1[C:40]2[NH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[S:32][C:31]=2[CH:30]=[CH:29][CH:28]=1.[H-].[Na+].Br.N[C:45]1C=C(N)C(CBr)=CN=1>>[NH2:1][C:2]1[N:3]=[C:4]([NH2:5])[C:9]([CH2:45][C:37]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:38]=2[NH:39][C:40]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[S:32]3)=[CH:10][N:11]=1
Reactant: Nc1cc(N)c(CBr)cn1
Reactant: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: Nc1ncc(Cc2cccc3c2Nc2ccccc2S3)c(N)n1

Procedure:
9-[(2,4-Diaminopyrimidin-5-yl)methyl]phenothiazine (Formula I: Ar=2,4-diaminopyrimidin-5-yl; W=CH2; X=N; Z=S; m=n=0) is prepared similarly to N-[(2,4-diaminopteridin-6-yl)methyl]-N,N-diphenylamine as disclosed above by using phenothiazine (159 mg, 0.8 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-5-bromomethylpyridine hydrobromide (86 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH2:13][CH3:14])[C:6]=2[C:5](=[O:18])[NH:4][C:3]1=[O:19].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27](=[O:29])[CH3:28].O>CS(C)=O>[O:29]=[C:27]([CH3:28])[CH2:26][CH2:25][CH2:24][CH2:23][N:4]1[C:5](=[O:18])[C:6]2[N:7]([C:11](=[O:17])[C:12]([CH3:15])([CH3:16])[CH2:13][CH3:14])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:19]
Reactant: CCC(C)(C)C(=O)n1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCC(C)(C)C(=O)n1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2C
Reaction time: 0.25 h
Yield: 49.7 %

Procedure:
3-Methyl-7-(methylpivaloyl)xanthine (406 mg, 1.5 mmol) was added to a stirring suspension of NaH (36 mg, 1.5 mmol) in DMSO (20 ml) and stirred for 15 min. 6-Bromo-2-hexanone (260 mg, 1.5 mmol) was added and the reaction mixture was stirred for 20 hrs. The reaction mixture was poured into 100 ml of water and extracted with 25% ethanol/dichloromethane (3×40 ml). The combined organic extracts were combined, dried with magnesium sulfate and the solvent was removed under vacuum to give a brown oil. The brown oil was chromatographed (10 g silica gel, ethyl acetate) to give 1-(5-oxohexyl)-3-methyl-7-(methylpivaloyl)xanthine (270 mg, 49% yield)