Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=1[CH:12]=O)([O-:3])=[O:2].[C:14]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:16][CH2:17][CH3:18])=[O:15]>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[CH:19]=[CH:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:12]=[CH:19][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]=1[N+:1]([O-:3])=[O:2])[CH3:18]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(C=O)c1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cccc(C=CC(=O)OCC)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
The 2-nitro-1,3-benzenedialdehyde (3.4 g, 0.019 mole) is dissolved in toluene (60 ml) and carbethoxymethylene triphenylphosphorane (19.2 g, 0.06 mole) is added. The mixture is heated at 60° C. for eight hours, cooled, and concentrated at reduced pressure. Diethyl ether (100 ml) is added and the mixture is filtered. The filtrate is concentrated and purified by flash chromatography over silica (elution with 4:1 hexane:ethyl acetate) to afford, after concentration, pure 2-nitro-1,3-benzenediacrylic acid diethyl ester, mp 114°-115° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2=[O:12].[OH-].[K+].BrC[C:17](=O)[C:18]([OH:20])=[O:19].Cl>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][C:5]([OH:12])=[C:17]2[C:18]([OH:20])=[O:19]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: O=C(O)C(=O)CBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1c(O)cnc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 144 h
Yield: 56 %

Procedure:
A solution of 5-bromoisatin (2.26 g, 10 mmol) and potassium hydroxide (4.48 g, 80 mmol) in water (10 mL) was warmed until the materials were dissolved then cooled to room temperature, treated with bromopyruvic acid (2.3 g, 14 mmol), stirred for 6 days, adjusted to pH <7 with concentrated HCl, and filtered. The solid was washed with water and ethanol and dried to provide the desired product (1.5 g, 58%). MS (DCI/NH3) m/e 269 (M+H)+.
Reaction SMILES: [C:1]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:49])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:48])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:47])[NH:34][CH2:35][CH2:36][CH2:37][N:38](C(OC(C)(C)C)=O)[CH3:39])=[CH:29][CH:28]=2)[CH3:19])[CH2:12][CH2:11]1.[ClH:56].CO.C1(C)C=CC=CC=1>ClCCl>[ClH:56].[ClH:56].[ClH:56].[C:1]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:49])[O:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[C:20](=[O:48])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33](=[O:47])[NH:34][CH2:35][CH2:36][CH2:37][NH:38][CH3:39])=[CH:31][CH:32]=2)[CH2:14][CH2:15]1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(C(=O)NCCCN(C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CNCCCNC(=O)c1ccc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compound (135 mg, 0.178 mmol) obtained in Example 73d was dissolved in 2.0 mL of dichloromethane, 2.0 mL of a 2 N hydrochloric acid-methanol solution was added, and the mixture was stirred at room temperature for 16 hours. 10 mL of toluene was added to the reaction mixture, and then the solvent was evaporated under reduced pressure to give a crude title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:9]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH2:19])=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: Nc1ccccc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-amino-6-bromopyrazine-2-carboxylic acid (140 g, 0.64 mol), o-phenylenediamine (70 g, 0.65 mol) and TBTU (247 g, 0.77 mol) in DMF (1.5 L) at 0° C. was added drop wise DIPEA (166 g, 1.29 mol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water and the resultant precipitate isolated by filtration and washed with water. The precipitate was dried at 50° C. to give the sub-title compound as a brown solid that was used in the next step without further purification product (140 g, 70% Yield). 1H NMR (400 MHz, DMSO) δ 4.95 (br s, 2H), 6.59 (m, 1H), 6.79 (d, 1H), 6.95 (m, 1H), 7.30 (d, 1H), 7.70 (bs, 2H), 8.40 (s, 1H) and 9.65 (s, 1H) ppm; MS (ES+) 307.8.
Reaction SMILES: CC1CC(C)CNC1.Cl.[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[S:17]1[CH2:22]CCC(C=O)[CH2:18]1.[OH2:25]>>[S:17]1[CH2:22][CH2:11][CH2:12][CH:13]([CH:14]=[CH:15][C:10](=[O:25])[CH3:16])[CH2:18]1
Reactant: O=CC1CCCSC1
Reactant: Cc1ccccc1
Reactant: O
Agent: CC1CNCC(C)C1
Agent: Cl
Product: CC(=O)C=CC1CCCSC1
Reaction time: 5 h
Yield: 88.2 %

Procedure:
The aqueous solution of sodium acetoacetate which was obtained by hydrolysis of aqueous sodium hydroxide solution of methylacetoacetate according to the method of Example 1 was 32% in concentration. 93.0 g (0.24 moles) of the aqueous solution was placed in a redaction vessel of 200 ml in inside volume, 2.26 g (0.02 moles) of 3,5-dimethylpiperidine was added, and pH was adjusted to 7.0 with concentrated hydrochloric acid. Into the resulting solution were added 20 ml of toluene and 26.0 g (0.20 moles) of 3-tetrahydrothiopyrane carbaldehyde, and a mixture of toluene and water was distilled by aspirator under reduced pressure at an inside temperature of 40° C. During the distillation, the pH was adjusted to 7.0 to 7.5 with concentrated hydrochloric acid and the same amount of toluene as that of toluene distilled was continuously added into the reaction vessel so that the amount of toluene in the vessel was always about 20 ml. After 5 hours, the same post treatment as that used in Examaple 4 was carried out to give the intended product of 4-(3-tetrahydrothiopyranyl)-3-butene-2-one with yield of 88.2%.
Reaction SMILES: CN(C)C=O.S(Cl)([Cl:8])=O.[OH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][N:19]=2)[N:14]=[CH:13][C:12]=1[C:21]([OH:23])=O>C1C=CC=CC=1>[ClH:8].[OH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][N:19]=2)[N:14]=[CH:13][C:12]=1[C:21]([Cl:8])=[O:23]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnc2cccnc2c1O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cl
Product: O=C(Cl)c1cnc2cccnc2c1O
Reaction time: 3 h
Yield: 147.5 %

Procedure:
To a mixture of dimethylformamide (0.73 g) and thionyl chloride (1.56 g) in benzene, there was added dropwise 4-hydroxy-1,5-naphthyridine-3-carboxylic acid (1.9 g) while stirring, and the reaction was carried out at 40° to 85°C for 3 hours. The crystals were collected by filtration, washed with benzene and dried under reduced pressure to give the objective compound (2.37 g). Purity, 96.3%. M.P.>350°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[C:11](Cl)(=[O:13])[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][C:8]=1[C:11](=[O:13])[CH3:12]
Reactant: COc1cccc(OC)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(C)=O)c(OC)c1

Procedure:
Using a Perrier modification, Perrier, Chem. Ber., Vol. 33, pp. 819 et seq. (1900), and Perrier, Bull. Soc. Chim. France, pp. 859 et seq. (1904), 1,3-dimethoxybenzene (138.0 g) (which may be obtained from Aldrich Chemical Company, Inc., Milwaukee, Wis.) is reacted with acetyl chloride (72.0 g), methylene chloride (500 ml), and aluminum chloride (145.0 g) to provide 2',4'-dimethoxy-acetophenone, which may then be purified using standard vacuum fractional distillation.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=1)[C:5](=O)[CH3:6].C([O-])([O-])=O.[K+].[K+].Cl.[NH2:24][C:25]([NH2:27])=[NH:26]>CN(C=O)C>[CH3:6][C:5]1[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=2)=[CH:3][N:24]=[C:25]([NH2:27])[N:26]=1
Reactant: CSc1nccc(C(=CN(C)C)C(C)=O)n1
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nccc(-c2cnc(N)nc2C)n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution of 4-Dimethylamino-3-(2-methylsulfanyl-pyrimidin-4-yl)-but-3-en-2-one (18) (1.02 g, 4.30 mmol) in DMF (14 mL) was added K2CO3 (1.782 g, 12.89 mmol) and Guanidine HCl (0.616 g, 6.45 mmol) and the resulting suspension was stirred at 120° C. for 1 hour. The DMF was evaporated and the crude residue partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried with sodium sulfate, and concentrated. The crude residue was purified by flash chromatography with a gradient of 1-12% MeOH in DCM to give the desired product as a light yellow solid (800 mg, 80%). MS (ES+): m/z=234.3/235.4 (100/20) [MH+]. HPLC: tR=1.01 minutes over 3 minutes. Purity: 70% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [P:1]([O-:10])([O:6][CH2:7][CH2:8][Cl:9])[O:2][CH2:3][CH2:4][Cl:5].C(Cl)(Cl)(Cl)[Cl:12]>C(N(CC)CC)C>[P:1]([Cl:12])(=[O:10])([O:6][CH2:7][CH2:8][Cl:9])[O:2][CH2:3][CH2:4][Cl:5]
Reactant: ClC(Cl)(Cl)Cl
Reactant: [O-]P(OCCCl)OCCCl
Solvent: CCN(CC)CC
Product: O=P(Cl)(OCCCl)OCCCl

Procedure:
A total of 0.84 mole of bis(2-chloroethyl) phosphite was reacted with 1.56 moles of carbon tetrachloride in the presence of 2 mls. of triethylamine. The bis(2-chloroethyl) phosphorochloridate thus formed was reacted with 0.4 mole of resorcinol in the presence of 0.84 moles of pyridine. The procedure of Example 3 was followed in isolating a 76% yield of product which was identified by IR as tetrakis(2-chloroethyl) m-phenylene diphosphate. This product had a refractive index (nD25) of 1.5050; and, on analysis, was found to contain 28.61% chlorine and 11.85% phosphorus (as compared to theoretical calculated percentages in C14H20Cl4O8P2 of 27.31% chlorine and 11.92% phosphorus).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:18]4[CH:28]=[CH:27][C:21](/[CH:22]=[CH:23]/[C:24](O)=[O:25])=[CH:20][CH:19]=4)[CH:14]=[CH:15][C:16]=3[OH:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH2:29].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.Cl.[NH2:53]O>CN(C=O)C>[C:1]12([C:11]3[CH:12]=[C:13]([C:18]4[CH:28]=[CH:27][C:21](/[CH:22]=[CH:23]/[C:24]([NH:53][OH:29])=[O:25])=[CH:20][CH:19]=4)[CH:14]=[CH:15][C:16]=3[OH:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)/C=C/c1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Reactant: O
Reactant: NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1)NO
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.7 %

Procedure:
To a solution of E-4-(3-(1-adamantyl)-4-hydroxyphenyl)cinnamic acid (2 g, 5.34 mmol) in 80 ml of DMF were added hydroxybenzotriazole hydrate (866 mg, 5.34 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (1130 mg, 6.94 mmol). The mixture was stirred at room temperature for 4 h. After addition of hydroxylamine hydrochloride (1856 mg, 26.7 mmol), followed by 3.7 ml (26.7 mmol) of TEA, the mixture was stirred at room temperature overnight. DMF was removed under reduced pressure and the residue was washed with water to obtain 5 g of a crude product. Purification by flash chromatography on silica gel (phosphate buffered) using as eluent dichloromethane/methanol 95:5 afforded 950 mg of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH2:23][CH2:24][CH3:25])[N:14]([CH2:15][CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[CH:27]([B-](F)(F)F)=[CH2:28].[K+]>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH2:23][CH2:24][CH3:25])[N:14]([CH2:15][CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH:27]=[CH2:28])=[CH:5][C:4]=2[N:3]=1
Reactant: C=C[B-](F)(F)F
Reactant: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCNS(C)(=O)=O
Agent: [K+]
Product: C=Cc1ccc2c(c1)nc(N)c1nc(CCCC)n(CCNS(C)(=O)=O)c12

Procedure:
N-[2-(4-Amino-7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamide was coupled with potassium vinyltrifluoroborate according to the procedure described in Part D of Examples 440-455 and recrystallized from acetonitrile to provide N-[2-(4-amino-2-butyl-7-vinyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamide as an off-white solid.
Reaction SMILES: CCC(=O)CC(=O)CC.[CH3:10][CH:11]([C:13](=[O:20])[CH2:14][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH3:12]>>[CH3:18][CH:16]([CH:15]([OH:19])[CH2:14][CH:13]([OH:20])[CH:11]([CH3:12])[CH3:10])[CH3:17]
Reactant: CC(C)C(=O)CC(=O)C(C)C
Agent: CCC(=O)CC(=O)CC
Product: CC(C)C(O)CC(O)C(C)C
Yield: 90 %

Procedure:
Synthesis procedure was similar to that described in synthetic example 19(1), except that 3,5-heptandione was replaced by 2,6-dimethyl-3,5-heptandione, and finally the product was purified by distilling under reduced pressure. 2,6-dimethyl-3,5-heptandiol as a colorless liquid was obtained with a yield of 90%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O.O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cn2)CC1
Temperature: 100 °C
Yield: 83.3 %

Procedure:
A mixture of 0.678 g (3 mmol) of 2-bromo-5-(trifluoromethyl)pyridine, 0.901 g (4.5 mmol) of tert-butyl 4-aminopiperidine-1-carboxylate and 0.829 g (6 mmol) of potassium carbonate in 5 ml of dimethyl sulphoxide is heated at 100° C. for 20 hours. The mixture is cooled to ambient temperature and then 50 ml of ethyl acetate and 15 ml of water are added. The organic phase is separated by settling and washed twice with 15 ml of water and then with 15 ml of a saturated aqueous sodium chloride solution. It is dried over sodium sulphate and evaporated under vacuum. The product is purified by chromatography on silica gel, elution being carried out with a 20:80 and then 30:70 mixture of ethyl acetate and cyclohexane in order to obtain 0.864 g (2.5 mmol) of product in the form of a white solid.
Reaction SMILES: Br.[CH2:2]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][C:12]=1N(C)C)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:24][C:25]1[CH:33]=[C:29]([C:30]([OH:32])=[O:31])[C:28]([OH:34])=[CH:27][CH:26]=1>C(O)(=O)C>[C:30]([C:29]1[CH:33]=[C:25]([N:24]2[C:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]=3[CH:2]=[C:3]2[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:26]=[CH:27][C:28]=1[OH:34])([OH:32])=[O:31]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: CN(C)C1=C(CC(=O)c2ccccc2)c2ccccc2CC1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O
Temperature: 75 °C
Reaction time: 4.5 h

Procedure:
A mixture of 10.0 g of 1-phenacyl-2-dimethylamino-3,4-dihydronaphthalene hydrobromide and 4.1 g of 5-aminosalicylic acid in 50 ml of acetic acid is vigorously stirred at 75° C for 4.5 hours. The reaction mixture is then cooled to 20° C, filtered and the precipitate collected, washed successively with one 20 ml portion of acetic acid and five 20 ml portions of hexane and then dried for 20 hours under vacuum to give 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([C:17]#[N:18])[CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:6]([CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25](SC)=[CH:24][CH:23]=2)[NH:5][N:4]=1)[CH3:2].O[O:31][S:32]([O-:34])=O.[K+].[CH3:36]O>O>[CH2:1]([C:3]1[C:7]([O:8][C:9]2[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=[C:11]([CH:10]=2)[C:17]#[N:18])=[C:6]([CH2:19][CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([S:32]([CH3:36])(=[O:34])=[O:31])=[CH:26][CH:27]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: CCc1n[nH]c(CCOc2ccc(SC)cc2)c1Oc1cc(C#N)cc(C#N)c1
Reactant: CO
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CCc1n[nH]c(CCOc2ccc(S(C)(=O)=O)cc2)c1Oc1cc(C#N)cc(C#N)c1

Procedure:
To a stirred solution of the sulfide from Example 1 (90 mg, 0.22 mmol) in methanol (2 ml) at 0° C. was added a solution of oxone (205 mg, 0.33 mmol) in water (2 ml). The viscous suspension was further diluted with methanol (2 ml). After 4 hours the reaction mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (20 ml) and water (20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (50:50, by volume) to give the title compound (70 mg) as a white powder, m.p. 88–90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH:11][C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([OH:28])([C:24]([F:25])([F:26])[F:27])[C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(NCCc1ccc(Cl)c(Cl)c1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OC(c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of 680 mg N-[2-(3,4-dichloro-phenyl)-ethyl]-4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-benzamide (1.48 mmol) in 10 ml of THF was added dropwise to 5.9 ml of a 1 molar solution of BH3-THF complex in THF at 0° C. The reaction mixture was stirred for 1 h at rt and then heated to reflux over night. Then 2 ml of 6 N HCl solution were added very carefully at ambient temperature and the mixture was heated again to reflux for 1.5 h. After cooling to rt, the pH was adjusted to 8-9 by addition of 1 N sodium hydroxide solution and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried with magnesium sulfate, filtered and concentrated. Final purification (silica gel; DCM/methanol 95:5) yielded 647 mg (98%) of [2-(3,4-dichloro-phenyl)-ethyl]-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-benzyl]-amine as a white solid.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.[CH3:29][NH:30][NH2:31]>C(O)C>[CH3:29][N:30]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[N:7][C:6]=3[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4](=[O:18])[C:3]=2[C:19]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[N:31]1
Reactant: CNN
Reactant: O=C(CCc1ccncc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: CCO
Product: Cn1nc(CCc2ccncc2)c2c(=O)n(-c3ccccc3)c3ncccc3c21
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(pyridin-4-yl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (100 mg, 0.27 mmol, prepared in Synthetic Example 1) in ethanol (2 ml) was added methylhydrazine (40 μl, 0.75 mmol, 2.8 eq.) and the mixture was stirred at room temperature to form a solution which was then stirred for 30 minutes. After it was perceived that precipitation started, the mixture was heated under reflux for 3 hours and cooled to room temperature. Next, to the liquid mixture was added additional methylhydrazine (40 μl, 0.75 mmol, 2.8 eq.) and the resultant mixture was heated overnight with stirring at 70° C. The liquid reaction mixture was cooled to room temperature, and then filtered to give precipitates which were dried to obtain 1-methyl-5-phenyl-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (94 mg, 92%).
Reaction SMILES: Cl[C:2]([N:4]=[C:5]=[O:6])=[O:3].[CH:7]1([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C.[NH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1>O1CCCC1>[CH:14]1([N:13]([CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[C:2]([NH:4][C:5]([NH:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)=[O:6])=[O:3])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=C=NC(=O)Cl
Reactant: Nc1nccs1
Reactant: C1CCC(NC2CCCCC2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC(=O)N(C1CCCCC1)C1CCCCC1)Nc1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Prepared as described in General Procedure 2. To chlorocarbonyl isocyanate (0.2 g) in tetrahydrofuran at −20-0° C. was added dicyclohexylamine (1 equivalent) and triethylamine (0.27 mL). After 20 min 2-aminothiazole (0.2 g) was added and the reaction allowed to warm to room temperature over 3 h and stirred overnight at room temperature. The reaction mixture was partially concentrated. The crude product was then dissolved in tetrahydrofuran and purified by flash chromatography (Eluant 20 dichloromethane:1 methanol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O)[C:6](=O)[CH3:7])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]=1[CH3:7])=[O:19])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)c1ccc(F)cc1)C(C)=O
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)n(-c2ccccc2)c1C
Yield: 79.9 %

Procedure:
A mixture of 2-[2-(4-fluoro-phenyl)-2-oxo-ethyl]-3-oxo-butyric acid ethyl ester (6.979 g, 26.21 mmol)), aniline (2.9 mL, 31.45 mmol) and p-toluenesulfonic acid (TsOH) monohydrate (249 mg, 1.31 mmol) in toluene (60 mL) was refluxed overnight while the generated water was separated with Dean-Stark distillation head. Then the reaction mixture was diluted with EtOAc, washed with saturated sodium hydrogen carbonate aqueous solution, and saturated sodium chloride aqueous solution, respectively, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, the residue was purified with column chromatography to give the title compound (6.768 g); The title compound, ESI MS (m/z): 324 (M+H+).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C@@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:37]4[CH2:38][CH2:39][C@@H:35]([F:34])[CH2:36]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: F[C@@H]1CCNC1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CC[C@@H](F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and (R)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 5.43-5.56 (1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 426 [M+H]
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1)[CH3:10]
Reactant: CCN
Reactant: ClCc1cncnc1
Solvent: C1CCOC1
Product: CCNCc1cncnc1

Procedure:
prepared by reaction of the 5-chloromethyl-pyrimidine (Russell M. G. N et al J. Med. Chem. 2005, 48, 5, 1367-1383) with 2M ethylamine in THF.