Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([C:13]1[C:14]([NH:19][CH2:20][CH2:21][CH2:22][OH:23])=[N:15][CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11]>N1C=CC=CC=1.C1C=CC=CC=1>[C:1]([O:23][CH2:22][CH2:21][CH2:20][NH:19][C:14]1[C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=[CH:16][N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccnc1NCCCO
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(OCCCNc1ncccc1[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
70 ml of benzoyl chloride are introduced dropwise into a solution of 77.8 g (0.04 mol) of 3-[(3-nitro-2-pyridyl)amino]propanol (M. ISRAEL, N. TIROSH, J. Med. Chem. 1973, 16, 520) in 48.5 ml of pyridine and 800 ml of benzene. The mixture is stirred for 2 h at ambient temperature and the precipitate is filtered. The filtrate is washed with 1N hydrochloric acid and then with water. Drying, filtering and evaporation are carried out. A crystallized product is obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH2:6][OH:7].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>N1C=CC=CC=1>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:7][CH2:6][CH2:5][CH2:4][CH:3]([C:2]([F:12])([F:13])[F:1])[CH2:8][CH2:9][CH2:10][CH3:11])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CCCCC(CCCO)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC(CCCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F

Procedure:
0.27 g (1.4 mmol) of 4-trifluoromethyloctanol was dissolved in 5 ml of pyridine and cooled with ice, and 0.27 g (1.4 mmol) of p-toluenesulfonyl chloride was added thereto under stirring, followed by reaction at 15-20° C. for 3 hours. After the reaction, the mixture was acidified with 2N-hydrochloric acid and extracted with diethyl ether. The resultant ether layer was dired on anhydrous sodium sulfate, followed by distilling-off of the solvent to obtain 4-trifluoromethyloctyl p-toluenesulfonate. Then, 0.4 g (1.1 mmol) of the 4-trifluoromethyloctyl p-toluenesulfonate was dissolved in 1 ml of ethanol and then added to a preliminarily prepared solution of 48 mg (1.1 mmol) of sodium hydroxide and 0.23 g (1.1 mmol) of p-hydroxyphenyl benzyl ether in 1 ml of ethanol. The mixture was heated to 85-90° C. for 5 hours of reaction and then cooled by standing. The reaction mixture was poured into 20 ml of 2N-hydrochloric acid and extracted with diethyl ether. The resultant ether layer was dried on anhydrous sodium sulfate and purified by silica gel column chromatography (eluent: benzene) to obtain 0.30 g (yield: 69%) of p-benzyloxy(4-trifluoromethyloctyloxy)phenyl.
Reaction SMILES: [CH:1]1[C:14]2[C@H:13]3[CH:15]([OH:18])[CH:16]([OH:17])[C@H:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)(=O)C>[CH:1]1[C:14]2[CH:13]([CH:15]=[O:18])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]([CH:16]=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OC1C(O)[C@H]2c3ccccc3[C@@H]1c1ccccc12
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Product: O=CC1c2ccccc2C(C=O)c2ccccc21
Temperature: 15 °C

Procedure:
A mixture of 2.38 g. of cis-9,10-dihydro-9,10-ethanoanthracene-11,12-diol in 40 ml. of glacial acetic acid at room temperature is treated portionwise with 4.8 g. of lead tetraacetate, with stirring over a period of 10 minutes. The mixture is cooled to 15° C. and the solid which forms is collected by filtration, washed once with glacial acetic acid, then thoroughly with water giving the desired product as colorless grains, m.p. 144°-146° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6](O)=[CH:5][C:4](=[O:9])[CH2:3]1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH:13]=O.[CH3:20][O:21][C:22](=[O:27])/[CH:23]=[C:24](\[NH2:26])/[CH3:25]>C(O)C>[CH3:20][O:21][C:22]([C:23]1[CH:13]([C:12]2[C:11]([Cl:10])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:19])[C:5]2[C:4](=[O:9])[CH2:3][N:2]([CH3:1])[CH2:7][C:6]=2[NH:26][C:24]=1[CH3:25])=[O:27]
Reactant: CN1CC(=O)C=C(O)C1
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: COC(=O)/C=C(/C)N
Solvent: CCO
Product: COC(=O)C1=C(C)NC2=C(C(=O)CN(C)C2)C1c1c(Cl)cccc1Cl

Procedure:
A mixture of 7.25 g. of 1-methyl-3-oxo-5-hydroxy-1,2,3,6-tetrahydropyridine, 8.75 g. of 2,6-dichlorobenzaldehyde, 5.94 g. of methyl-3-aminocrotonate (97%) and 135 ml. of ethanol were heated at reflux for 3 hours. The mixture was filtered and the filtrate was evaporated to dryness. The residue was slurried with ethanol and the solid was separated by filtration. The solid, m.p. 258°-260° C. dec, was suspended in ethanol and saturated with hydrogen chloride. The solution was evaporated to dryness. The residue was triturated with a small volume of ethanol and filtered. The solid was recrystallized from 95% ethanol to obtain the title compound as the hydrochloride, m.p. 260°-262° C. dec.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=[O:9])[CH:2]=1.BrN1C(=[O:18])CCC1=O.C1N2CN3CN(C2)CN1C3.Cl>C(Cl)(Cl)Cl.C(Cl)Cl.O>[CH:11]([C:1]1[CH:2]=[C:3]([CH2:7][C:8]([OH:10])=[O:9])[CH:4]=[CH:5][CH:6]=1)=[O:18]
Reactant: Cc1cccc(CC(=O)O)c1
Reactant: O=C1CCC(=O)N1Br
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=Cc1cccc(CC(=O)O)c1
Yield: 62 %

Procedure:
To a solution of 2-(m-tolyl)acetic acid in chloroform (30 mL) was added N-bromosuccinimide (2.37 g, 13.32 mmol). The mixture was heated to reflux for 8 hours and the solvent was removed in vacuo. The residue was dissolved in ethanol (30 mL) and water (30 mL) and hexamethylenetetramine (5 g, 35.7 mmol) was added. The mixture was heated to reflux for 4 hours. Concentrated HCl (5.9 mL) was added cautiously to the mixture at reflux. The mixture was heated to reflux for 30 minutes and then allowed to cool. Water (30 mL) and DCM (30 mL) were added and the organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was taken up into saturated aqueous sodium bicarbonate solution, and washed with DCM (2×15 mL). The aqueous phase was acidified with 2M aqueous HCl. The mixture was extracted with DCM (2×15 mL) and the combined organic fractions were passed through a hydrophobic frit. The solvent was removed in vacuo to afford a mixture of the title compound as an off-white solid (1.35 g, 62%). 1H NMR (400 MHz, CDCl3): δ 10.01 (s, 1H), 7.84-7.79 (m, 2H), 7.60-7.48 (m, 2H), 3.75 (s, 2H). LCMS (Method 1): [MH+]=165 at 2.77 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].B(F)(F)F>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:10]([C:19](=[O:21])[CH3:20])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cc3cccc(Cl)n3n2)cc1
Reactant: CC(=O)OC(C)=O
Agent: FB(F)F
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nn3c(Cl)cccc3c2C(C)=O)cc1
Temperature: 25 °C
Yield: 65.2 %

Procedure:
To a solution of 7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridine (1 8.7 g, 72.4 mmol) in toluene (300 mL) at room temperature was added acetic anhydride (8.2 mL, 86.9 mmol). Boron trifluoride diethyletherate (10.1 mL, 79.6 mmol) was then added dropwise and the resulting solution was heated at reflux for 4 hours. The reaction mixture was cooled to room temperature and quenched by the dropwise addition of saturated aqueous sodium bicarbonate. The reaction was extracted with ethyl acetate, and the ethyl acetate phase washed with brine, dried (magnesium sulfate), filtered and concentrated. The residue was purified by recrystallization from ethyl acetate-hexanes to give 1-[7-(chloro)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone (14.2 g, 65%) as reddish needles. 1H NMR (CDCl3): δ 8.37 (dd, 1H), 7.49 (dd, 2H), 7.39 (dd, 1H), 7.10 (dd, 1H), 6.98 (dd, 2H), 3.84 (s, 3H), 2.13 (s, 3H); MS m/z 301 (M+1).
Reaction SMILES: Cl.Cl[CH:3]([C:8]1[C:9](=[O:17])[C:10]([OH:16])=[C:11]([CH3:15])[N:12]([CH3:14])[CH:13]=1)[C:4]([F:7])([F:6])[F:5].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.Cl.CN>O.C(#N)C>[OH:16][C:10]1[C:9](=[O:17])[C:8]([CH:3]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[C:4]([F:7])([F:6])[F:5])=[CH:13][N:12]([CH3:14])[C:11]=1[CH3:15].[OH:16][C:10]1[C:9](=[O:17])[C:8]([CH:3]([NH:18][CH3:19])[C:4]([F:7])([F:6])[F:5])=[CH:13][N:12]([CH3:14])[C:11]=1[CH3:15]
Reactant: c1c[nH]cn1
Reactant: Cc1c(O)c(=O)c(C(Cl)C(F)(F)F)cn1C
Agent: CN
Agent: Cl
Solvent: O
Solvent: CC#N
Product: CNC(c1cn(C)c(C)c(O)c1=O)C(F)(F)F
Product: Cc1c(O)c(=O)c(C(n2ccnc2)C(F)(F)F)cn1C
Reaction time: 0.25 h
Yield: 64 %

Procedure:
3-Hydroxy-1,2-dimethyl-5-[2,2,2-trifluoro-1-(piperidin-1-yl)ethyl]pyridin-4(1H)-one (Apo7054) was prepared from the reaction of 5-(1-chloro-2,2,2-trifluoroethyl)-3-hydroxy-1,2-dimethylpyridin-4(1H)-one hydrochloride (304 mg, 1.0 mmol) and piperidine (2.0 mL, 20.3 mmol). The reaction was completed within 20 min, and Apo7054 was obtained as a solid product (232 mg). Yield=73%; HPLC Method 1, purity (AUC)=99.4% at 280 nm; 1H NMR (DMSO-D6) δ (ppm): 7.66 (s, 1H), 4.83-4.94 (m, 1H), 3.71 (s, 3H), 2.56 (m, 2H), 2.41 (m, 2H), 2.27 (s, 3H), 1.46 (br, 4H), 1.28 (br, 2H); MS-ESI m/z 305 [M+1]+ (100%), 220. (ii) 3-Hydroxy-1,2-dimethyl-5-[2,2,2-trifluoro-1-(1H-imidazol-1-yl)ethyl]pyridin-4(1H)-one (Apo7055) was prepared from 5-(1-chloro-2,2,2-trifluoroethyl)-3-hydroxy-1,2-dimethylpyridin-4(1H)-one hydrochloride (505 mg, 1.7 mmol) and imidazole (3.5 g, 51.4 mmol). The reaction was stopped when analysis of the HPLC chromatogram (Method 1) of the reaction mixture indicated higher than 98% conversion. The reaction mixture was concentrated to give a solid. The solid was dissolved in de-ionized water (4 mL), and the pH of the solution was adjusted to 6.5 with a 6.00 N hydrochloric acid solution. The resulting solution was repeatedly extracted with dichloromethane (15 mL×4, 30 mL×2). The organic fractions were combined, dried over sodium sulfate, filtered, and concentrated. The desired compound Apo7055 was obtained as a solid from dichloromethane (320 mg). Yield=64%; HPLC purity (AUC): 99.7% at 280 nm); 1H NMR (DMSO-D6) δ (ppm): 8.15 (s, 1H), 7.98 (s, 1H), 7.52 (s, 1H), 6.96 (s, 1H), 6.66 (q, J=9.1 Hz, 1H), 3.76 (s, 3H), 2.29 (s, 3H). MS-ESI m/z 288 [M+1]+, 220 (100%). (iii) 3-Hydroxy-1,2-dimethyl-5-[2,2,2-trifluoro-1-(methylamino)ethyl]pyridin-4(1H)-one (Apo7056) was prepared from 5-(1-chloro-2,2,2-trifluoroethyl)-3-hydroxy-1,2-dimethylpyridin-4(1H)-one hydrochloride (400 mg, 1.4 mmol) and methylamine (3.0 mL, 34.4 mmol). The reaction was essentially completed within 15 min. The reaction mixture was concentrated to give a solid. A sample of salt free Apo7056 product was obtained by purification using the Biotage instrument (C18 reversed phase; eluant: water and acetonitrile; gradient, 100:0 to 100:4). (48 mg).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:10]([Cl:11])=[CH:9][N:8]([CH2:12][CH:13]([F:15])[F:14])[N:7]=1)=[O:5].[CH3:17][Mg]Br>>[Cl:11][C:10]1[C:6]([C:4](=[O:5])[CH3:17])=[N:7][N:8]([CH2:12][CH:13]([F:15])[F:14])[CH:9]=1
Reactant: CON(C)C(=O)c1nn(CC(F)F)cc1Cl
Reactant: C[Mg]Br
Product: CC(=O)c1nn(CC(F)F)cc1Cl
Yield: 66 %

Procedure:
In a manner analogous to that described in Example 14 b), the Grignard reaction of 4-chloro-1-(2,2-difluoro-ethyl)-1H-pyrazole-3-carboxylic acid methoxy-methyl-amide with methylmagnesium bromide yielded the title compound (66% yield) as a colorless oil. MS (ISP): m/z=209.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:3]=1[C:4]#[N:5].C([Mg]Cl)(C)C.[Cl-].[Li+].[C:18]1(=[O:22])[CH2:21][CH2:20][CH2:19]1>O1CCCC1.O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:18]2([OH:22])[CH2:21][CH2:20][CH2:19]2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(I)ccc1Br
Reactant: O=C1CCC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(C2(O)CCC2)ccc1Br
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
To 2-bromo-5-iodobenzonitrile (1457 mg, 4.730 mmol) in tetrahydrofuran (10 mL) at −40° C. was added isopropyl magnesium chloride.lithium chloride (1.3M in THF, 4.4 mL, 5.7 mmol) dropwise. The mixture was stirred at −40° C. for 10 minutes, and was then treated with cyclobutanone (0.4 mL, 5.2 mmol) dropwise at −40° C. The reaction mixture was warmed to room temperature and stirred at that temperature for 16 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound which was used directly in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]2>>[O:33]=[C:28]1[CH2:27][CH2:26][C:25]2[C:30](=[CH:31][CH:32]=[C:23]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]3[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=3)[CH:24]=2)[NH:29]1
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Product: N#Cc1ccc(N(CCOc2ccc3c(c2)CCC(=O)N3)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 27B from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 15B) and 6-hydroxy-3,4-dihydro-2(1H)-quinolinone with the following exceptions: PPh3 was used instead of PBu3 and purification of the title compound consisted of flash chromatography (EtOAc/hexanes) followed by RP-HPLC (MeCN/H2O with 0.1% TFA): 1H NMR (400 MHz, acetone-D6) δ 8.96 (bs, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.49 (d, J=2.7 Hz, 1H), 7.41 (dd, J=8.9, 2.7 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 6.79 (d, J=2.6 Hz, 1H), 6.74 (dd, J=8.6 Hz, 1H), 4.62 (q, J=9.0 Hz, 2H), 4.31 (t, J=5.3 Hz, 2H), 4.16 (t, J=5.3-Hz, 2H), 2.88 (partially resolved dd, J≈7.5, 7.0 Hz, 2H), 2.44 (dd, J=8.6, 6.4 Hz, 2H).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH3:8][O:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11]>ClCCl>[OH:12][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:11])=[O:9].[CH3:8][CH:2]1[CH2:3][C:4](=[O:7])[CH2:5][CH2:6][S:1]1
Reactant: O=C1CCSCC1
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC1CC(=O)CCS1
Product: O=S(=O)(O)C(F)(F)F

Procedure:
2 mmol of tetrahydrothiopyran-4-one was dissolved in 5 ml of dichloromethane at 0° C., and about 2 mmol of methyltrifluoromethane sulfonate was slowly dripped to the mixture. The solvent was removed after about 30 minutes, and was then recrystallized with a mixture of ethyl acetate and hexane (1:2 by weight) to obtain a white solid product. The solid product was filtered and dried for 1 hour in an oven at 50° C. to obtain the following product:
Reaction SMILES: C(O)C.[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[OH-].[K+].Br[CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27]>O>[CH2:27]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)[CH2:26][CH2:25][CH:24]=[CH2:23]
Reactant: C=CCCCBr
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCCCOc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
To 400 ml ethanol is added 21.5 g of 4-hydroxy-4'-nitrobiphenyl, and the mixture heated to reflux. A solution of 7.1 g of KOH in 30 ml of water is added dropwise at reflux temperatures. After complete addition, 18 g of 5-bromo-1-pentene is added and the reaction medium is heated at reflux temperature for about 15 hours. Ethanol is removed under vacuum from the cooled mixture, and the solid residue is slurried with water in a blender, filtered, washed with water, and air dried. The product then is recrystallized from 90/10 hexane/toluene, mp 74°-76° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[C:16]([Cl:24])[CH:17]=[C:18]([Cl:23])[CH:19]=2)[NH:14][C:13]=1[S:25][CH3:26])=[O:11].[OH:27]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[C:16]([Cl:24])[CH:17]=[C:18]([Cl:23])[CH:19]=2)[NH:14][C:13]=1[S:25]([CH3:26])=[O:27])=[O:11]
Reactant: CSc1[nH]c2c(Cl)cc(Cl)cc2c(=O)c1C(=O)Nc1ccc(Cl)cc1Cl
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)c1[nH]c2c(Cl)cc(Cl)cc2c(=O)c1C(=O)Nc1ccc(Cl)cc1Cl
Temperature: 75 °C

Procedure:
6,8-Dichloro-2-methylsulfanyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (2,4-dichloro-phenyl)-amide (Compound 3 in Scheme, 1.13 g, 2.52 mmol) in acetic acid was mixed with 30% hydrogen peroxide (0.57 g, 2 eq) and heated at 70-80° C. for 2 days upon agitation. The reactants were poured into iced water, filtered, washed with water and normal hexane and dried under vacuum. The resultant was used without further purification for next steps (yield: 1.1 g, 94%): 1H NMR (DMSO-d6) δ12.66 (bs, 1H) 8.54-8.19 (m, 4H) 7.61-7.41 (m, 2H) 3.10 (s, 3H)
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][N:37]=1)[C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[CH2:28]([NH:27][C:25](=[O:26])[C:24]1[CH:35]=[CH:36][N:37]=[C:22]([NH:21][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:12]([F:11])=[CH:13][CH:14]=2)[CH:23]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Agent: O=C(Cl)c1ccccc1F
Product: O=C(NCc1ccccc1)c1ccnc(NC(=O)c2ccc(F)cc2)c1
Yield: 27 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 4-fluorobenzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(4-fluorobenzamido)isonicotinamide was obtained as a colorless solid in 27% yield: mp 170-171° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.70 (s, 1H), 8.70 (s, 1H), 8.40 (d, J=5.1 Hz, 1H), 7.95-7.88 (m, 2H), 7.57 (dd, J=5.7, 1.5 Hz, 1H), 7.37-7.26 (m, 5H), 7.20-7.14 (m, 2H), 6.78-6.65 (m, 1H), 4.64 (d, J=5.8 Hz, 2H); MS (ES+) m/z 350.5 (M+1).
Reaction SMILES: [CH:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:9]2[N:13]=[CH:12][N:11]([CH2:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:10]=2)[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][N:38]2[C:46](=[O:47])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]2=[O:48])=[CH:32][CH:31]=1.C(N(CC)CC)C>C(#N)C>[CH:21]1([C@@:7]([OH:8])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]2[N:13]=[CH:12][N:11]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH2:28][CH2:29][C:30]4[CH:31]=[CH:32][C:33]([CH2:36][CH2:37][N:38]5[C:46](=[O:47])[C:45]6[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=6)[C:39]5=[O:48])=[CH:34][CH:35]=4)[CH2:17][CH2:16]3)[N:10]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: OC(c1ccccc1)(c1ncn(CC2CCNCC2)n1)C1CCCCC1
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccc(CCBr)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(CCN2CCC(Cn3cnc([C@](O)(c4ccccc4)C4CCCCC4)n3)CC2)cc1
Temperature: 90 °C
Reaction time: 48 h
Yield: 28 %

Procedure:
Cyclohexyl-phenyl-(1-piperidin-4-ylmethyl-1H-[1,2,4]triazol-3-yl)-methanol (Preparation 4, 8.2 g, 2.98 mmol), 2-{2-[4-(2-Bromo-ethyl)-phenyl]-ethyl}-isoindole-1,3-dione (Preparation 11, 7.56 g, 21.1 mmol), and triethylamine (13.3 ml, 95.9 mmol) were dissolved in acetonitrile (100 ml). After stirring at 90° C. for 48 hours the solvent was removed in vacuo, and the residue partitioned between dichloromethane (200 ml) and water (200 mL). The organic layer was separated, dried over magnesium sulphate, filtered and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (98:2:0.2, by volume) and the resulting material then triturated in tert-butyl methyl ether to furnish title compound as a clear solid in 28% yield, 3.4 g.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18]3=[N:19][C:20]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:21][CH:22]=[C:17]3[CH2:16][N:15]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:14]2=[O:38])[CH2:9][CH2:8]1)(C)(C)C.O>FC(F)(F)C(O)=O.ClCCl>[OH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18]3=[N:19][C:20]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:21][CH:22]=[C:17]3[CH2:16][N:15]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:14]2=[O:38])[CH2:9][CH2:8]1
Reactant: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N([C@H]3CC[C@H](O)CC3)C2=O)cc1
Reaction time: 1.5 h

Procedure:
1-[trans-4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (from Example 3b supra) (139 mg, 0.25 mmol) was dissolved at 0° C. in a 50% solution of trifluoroacetic acid in dichloromethane (5 mL) that contained water (330 μL). After stirring for 1.5 hours the reaction mixture was partitioned between ethyl acetate and 1 N aqueous sodium hydroxide and the pH of the aqueous layer was adjusted to 12 by adding solid sodium hydroxide. The organic layer was then washed with water, dried over sodium sulfate, filtered and concentrated to the crude product. Purification by silica gel column chromatography with 0–100% ethyl acetate in hexanes gradient followed by a precipitation out of tetrahydrofuran with excess of pentane afforded 1-(trans-4-hydroxy-cyclohexyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as an off-white solid. (Yield 72 mg, 65%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[O:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH2:22])[CH2:17][CH2:16]1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[N+:12]([C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:22][CH2:21][CH:18]1[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1)([O-:14])=[O:13]
Reactant: NCC1CCOCC1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1

Procedure:
4-Fluoro-3-nitrobenzenesulfonamide (2.18 g), (tetrahydropyran-4-yl)methylamine (1.14 g), and triethylamine (1 g) were stirred in THF (30 mL) for 24 hours. The solution was diluted with ethyl acetate, washed with NaH2PO4 solution and brine, and dried (Na2SO4), filtered and concentrated. The product was triturated from ethyl acetate.
Reaction SMILES: [C:1](O)([CH3:4])([CH3:3])[CH3:2].Cl[S:7]([N:10]=C=O)(=[O:9])=[O:8].[CH2:13]([O:15][C:16](=[O:28])[CH2:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=1)[CH3:14].C(N(CC)CC)C>C(Cl)Cl>[CH2:13]([O:15][C:16](=[O:28])[CH2:17][N:18]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=1)[S:7]([NH:10][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:9])=[O:8])[CH3:14]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)O
Reactant: CCOC(=O)CNc1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN(c1cccc([N+](=O)[O-])c1)S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 25.7 mmol tert.butanol and 20 ml of CH2Cl2 are added 10.3 mmol of ClSO2NCO and the mixture obtained is stirred at rt for 45 minutes. The mixture obtained is slowly added to a solution of 5.14 mmol of (3-nitro-phenylamino)-acetic acid ethyl ester and 15.4 mmol of triethylamine in 50 ml of CH2Cl2 at 0° and the mixture obtained is stirred at 0° for 2.5 hours. The mixture obtained is diluted with CH2Cl2 and the dilution is extracted with HCl (0.1N). The organic layer obtained is dried, and solvent is evaporated. (3-Nitro-phenyl-N-(t-butylaminosulfonyl)amino)-acetic acid ethyl ester is obtained.