Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][CH:8]([C:30](=[O:33])[CH2:31][CH3:32])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2(O)[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)(C)(C)C.[SiH](CC)(CC)CC>C(Cl)Cl>[NH:19]1[CH2:20][CH2:21][CH:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][CH:8]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:7][C:6]([OH:34])=[O:5])=[CH:11][CH:12]=2)[CH2:17][CH2:18]1
Reactant: CCC(=O)C(CC(=O)OC(C)(C)C)Nc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: CCC(=O)C(CC(=O)O)Nc1ccc(C2CCNCC2)cc1
Reaction time: 18 h

Procedure:
A solution of 10-6 (0.225 g, 0.47 mmoles) in CH2Cl2 (5 ml) was treated with Et3SiH (0.33 g, 4.2 mmoles) at ambient temperature and the resulting solution was stirred for 18 hours. The solvent was removed and the residue was purified by flash chromatgraphy on silica gel eluting with EtOH(10)/H2O(1)/NH4OH(1) to give two components: 10-8 had Rf 0.25 under these conditions:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=O)=[O:9])[CH:5]=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13].P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+].[Na+].[Cl-]>C(OC)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([Cl:13])(=[O:11])=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(=O)(O)c1cncc(Br)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cncc(Br)c1
Temperature: 0 °C
Yield: 98.4 %

Procedure:
A mixture of 5-bromo-pyridine-3-sulfonic acid (Example B.2 step 1) (7.14 g, 30 mmol), phosphorus pentachloride (9.68 g, 47 mmol) and phosphorus oxychloride (20 mL) was heated to reflux for 4 h (according to J. Org. Chem. 1989, 54(2), 389. ). The reaction mixture was concentrated to dryness to give a yellow semisolid, dissolved in ice water and tert-butyl-methyl-ether, and cautiously added sat. NaHCO3-sol. until neutralized, saturated with solid NaCl, separated phases, dried organic layer over Na2SO4. Removal of the solvent in vacuum gave the title compound as a yellow solid (7.57 g, 98%). MS (EI) 254.9 [(M)+], 256.9 [(M+2)+] and 258.9 [(M+4)+]; mp 64° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C@:5]12[O:12][C@:9]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=4)[CH:14]=3)([O:10][CH2:11]1)[C@H:8]([O:30]CC1C=CC=CC=1)[C@@H:7]([O:38]CC1C=CC=CC=1)[C@@H:6]2[O:46]CC1C=CC=CC=1)[OH:4].ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[NH2:1][CH2:2][CH:3]([C@:5]12[O:12][C@:9]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=4)[CH:14]=3)([O:10][CH2:11]1)[C@H:8]([OH:30])[C@@H:7]([OH:38])[C@@H:6]2[OH:46])[OH:4]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(O)CN)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(O)CN)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 27.6 %

Procedure:
To a solution of 2-amino-1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl) methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanol 10b (205 mg, 0.28 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 25 mL) were added o-dichlorobenzene (0.16 mL, 1.42 mmol) and 10% Pd/C (32 mg, 0.03 mmol) at room temperature. The mixture was stirred at room temperature under H2 for 4 hours and filtered. The filter cake was washed with a tetrahydrofuran/methanol mixture (v/v=1/4, 10 mL×2) and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with EtOAc to give the title compound 10 as colorless oil (36 mg, 25.7%, HPLC: 98.0%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 466.0[M+H]+; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.73 (s, 2H), 7.42 (m, 2H), 7.31 (m, 1H), 7.09 (m, 2H), 6.82 (m, 2H), 5.52 (d, 2H), 5.02 (d, 2H), 3.95 (m, 5H), 3.72 (d, 1H), 3.61 (d, 1H), 3.48 (m, 2H), 3.14 (m, 1H), 2.69 (m, 1H), 1.28 (t, 3H).
Reaction SMILES: [C:1]([O:5]O)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Na+].[C:9]([O:32][CH:33]1[CH2:38][C:37]([CH3:40])([CH3:39])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]1)(=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]1[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]1)=[O:19]>[Mo](=O)(=O)=O.CC1CCCCC1>[C:9]([O:32][CH:33]1[CH2:38][C:37]([CH3:40])([CH3:39])[N:36]([O:5][C:1]2([CH3:4])[CH2:3][CH2:14][CH2:13][CH2:12][CH2:2]2)[C:35]([CH3:42])([CH3:41])[CH2:34]1)(=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]1[CH2:26][C:25]([CH3:27])([CH3:28])[N:24]([O:5][C:1]2([CH3:4])[CH2:3][CH2:11][CH2:10][CH2:9][CH2:2]2)[C:23]([CH3:29])([CH3:30])[CH2:22]1)=[O:19]
Reactant: CC(C)(C)OO
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: O=[Mo](=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC1CCCCC1
Product: CC1(ON2C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC3CC(C)(C)N(OC4(C)CCCCC4)C(C)(C)C3)CC2(C)C)CCCCC1
Temperature: 25 °C
Yield: 140.7 %

Procedure:
t-Butyl hydroperoxide (70%, 133.9 g, 1.04 mol), methylcyclohexane (250 ml), and sodium chloride (20 g) are agitated in a separatory funnel. The organic layer is dried over magnesium sulfate. The t-butyl hydroperoxidemethylcyclohexane solution is mixed with 50.0 g (104 mmol) of di-(2,2,6,6-tetramethylpiperidin-4-yl) sebacate, 3.0 g of molybdenum trioxide, and 100 ml of methylcyclohexane. The reaction mixture is heated at reflux for 4.5 hours and water is collected in a Dean-Stark trap. The reaction is cooled to room temperature and filtered. The filtrate is concentrated at reduced pressure to obtain an oil which is purified by flash chromatography (silica gel; 19:1 heptane:ethyl acetate) to obtain 51.6 g (72% yield) of a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[O:15])=[C:12]([CH3:23])[N:11]=[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:9]=2)=[CH:4][C:3]=1[N+:30]([O-])=O>[Pd].CO>[NH2:30][C:3]1[CH:4]=[C:5]([C:8]2[C:13]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[O:15])=[C:12]([CH3:23])[N:11]=[C:10]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:9]=2)[CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: Cc1nc(-c2ccccc2)nc(-c2ccc(O)c([N+](=O)[O-])c2)c1C(=O)N1CCN(C)CC1
Agent: [Pd]
Solvent: CO
Product: Cc1nc(-c2ccccc2)nc(-c2ccc(O)c(N)c2)c1C(=O)N1CCN(C)CC1
Yield: 26.9 %

Procedure:
A mixture of 4-(4-hydroxy-3-nitrophenyl)-6-methyl-5-(4-methylpiperazin-1-ylcarbonyl)-2-phenylpyrimidine (0.8 g) and 10% Palladium on carbon (0.2 g) in methanol (30 ml) was hydrogenated at room temperature under atmospheric pressure. After removal of the catalyst by filtration, the filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (100 g) and eluted with a mixture of chloroform and methanol (30:1). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give 4-(3-amino-4-hydroxyphenyl)-6-methyl-5-(4-methylpiperazin-1-ylcarbonyl)-2-phenylpyrimidine (0.2 g).
Reaction SMILES: O[Li].O.[CH2:4]([O:11][C:12]1[C:17](=[O:18])[N:16]([CH3:19])[C:15](SC)=[N:14][C:13]=1[C:22]([O:24]CC)=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:27][CH2:28][OH:29]>>[CH2:4]([O:11][C:12]1[C:17](=[O:18])[N:16]([CH3:19])[C:15]([O:29][CH2:28][CH3:27])=[N:14][C:13]=1[C:22]([OH:24])=[O:23])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCO
Reactant: CCOC(=O)c1nc(SC)n(C)c(=O)c1OCc1ccccc1
Agent: [Li]O
Solvent: O
Product: CCOc1nc(C(=O)O)c(OCc2ccccc2)c(=O)n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
To a stirred solution of LiOH.H2O (1.26 g, 30 mmol) in EtOH (100 mL) at 40° C. was added ethyl 5-(benzyloxy)-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-4-carboxylate (prepared according to the procedure in WO2004062613) (6.7 g, 20 mmol). The resulting reaction mixture was stirred at room temperature for 5 h then concentrated. The residue was taken up in aq. HCl (50 mL) and extracted with EtOAc (2×100 mL). The combined organic fractions were dried (Na2SO4), filtered and concentrated to give the desired product (6 g, 99% yield) as off-white solid which was used in the next step without purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[CH3:21][OH:22].S(=O)(=O)(O)O>O>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:21][OH:22])[CH:4]=1)#[N:2]
Reactant: CO
Reactant: N#Cc1ccncc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: N#Cc1ccnc(CO)c1
Yield: 46 %

Procedure:
A mixture of 4-cyanopyridine (31.2 g), ammonium persulphate (136.8 g), methanol (450 ml), concentrated sulphuric acid (16.2 ml), and water (210 ml) was heated under reflux for 24 hours, and the methanol was removed by distillation. Crushed ice (450 g) was added and the mixture was adjusted to pH 12 with 10 M sodium hydroxide and extracted with chloroform. The chloroform extracts were combined and evaporated and the residue was purified by elution from a silica gel column with methanol-chloroform (7.5% v/v) to give 4-cyano-2-hydroxymethylpyridine (18.5 g, 46%) m.p. 92°-94°.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]([C:12](=O)[CH:13]([CH3:15])[CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C(O)C>[NH2:1][C:2]1[S:3][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([CH:13]([CH3:15])[CH3:14])[N:4]=1
Reactant: CCOC(=O)C(Br)C(=O)C(C)C
Reactant: NC(N)=S
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1C(C)C
Yield: 40.6 %

Procedure:
A solution of thiourea (1.1 g) in ethanol (10 mL) was brought to reflux. Ethyl 2-bromo-4-methyl-3-oxopentanoate (3.0 g) was then added and the reaction mixture refluxed further for 1 h. The reaction was complete (by TLC) and was concentrated in vacuum. Flash chromatography (100% DCM→90:10 DCM:MeOH) afforded the product (1.1 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([N:11]2C(C)=CC=C2C)[CH:3]=1.Cl.NO.[OH-].[K+]>C(O)C.O>[NH2:11][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=1
Reactant: CCCc1cc(C)cc(-n2c(C)ccc2C)n1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCc1cc(C)cc(N)n1

Procedure:
By analogy to Example 56, Step B, 4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-propylpyridine was treated with 4,6 equivalents of hydroxylamine hydrochloride and 2.8 equivalents of potassium hydroxide in refluxing ethanol/water to yield 2-amino-4-methyl-6-propylpyridine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[NH2:6][C:7]1[CH:11]=[C:10](O)[NH:9][N:8]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:10]1[NH:9][N:8]=[C:7]([NH2:6])[CH:11]=1
Reactant: COCCO
Reactant: Nc1cc(O)[nH]n1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: c1ccccc1
Product: COCCOc1cc(N)n[nH]1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a mixture of 2-methoxyethanol (0.664 mL, 8.41 mmol) and 3-amino-5-hydroxypyrazole (1.00 g, 10.1 mmol) in C6H6 (50 mL) at RT was added cyanomethylenetri-n-butylphosphorane (2.03 g, 8.41 mmol). The mixture was heated to 90° C. in a pressure vessel. After 16 hrs, the solvent was removed in vacuo. The residue was taken up in CH2Cl2 and adsorbed onto silica gel prior to purification by silica gel chromatography using 2-10% MeOH in CH2Cl2 with 1% NH4OH to afford 5-(2-methoxyethoxy)-1H-pyrazol-3-amine as a yellow oil. MH+=158.2.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][N:19]([CH3:21])[CH3:20])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.[CH3:22][C:23]([OH:27])([C:25]#[CH:26])[CH3:24]>N1CCCCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([CH2:22][C:23]([CH3:24])([OH:27])[C:25]#[CH:26])[CH:10]=3)[C:6]([CH2:18][N:19]([CH3:21])[CH3:20])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: CN(C)Cc1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: C#CC(C)(O)Cc1ccc2c(CN(C)C)nn(-c3ccnc(N)n3)c2c1
Temperature: 75 °C

Procedure:
To a solution of 4-{6-bromo-3-[(dimethylamino)methyl]-1H-indazol-1-yl}pyrimidin-2-amine (80 mg, 0.23 mmol) in piperidine (2 mL) was added 2-methyl-but-3-yn-2-ol (38.8 mg, 0.461 mmol), CuI (4.4 mg, 0.023 mmol) and tetrakis(triphenylphosphine)palladium (13.3 mg, 0.012 mmol). The mixture was heated at 75° C. for 1 hr in a sealed tube. Volatiles were removed by concentration in vacuo. Purification by flash chromatography (Isolute column, 100% DCM to 5% MeOH in DCM) afforded the title compound as yellow solid: 1H NMR (500 MHz, DMSO) δ 1.53 (6H, s), 2.23 (6H, s), 3.80 (2H, s), 5.51 (1H, s), 6.93-7.09 (2H, m), 6.97-7.04 (1H, m), 7.32 (1H, d, J=8.20 Hz), 7.93 (1H, s), 8.19-8.35 (1H, m), 8.84 (1H, s); LC-MS: m/z=+351.10 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[S:9][C:8]=2[CH:10]=1
Reactant: COC(=O)c1cc2ccc(Cl)cc2s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccc(Cl)cc2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
To a solution of 630 mg (2.78 mmol) of 6-chloro-benzo[b]thiophene-2-carboxylic acid methyl ester in THF (5 ml) were added 6.95 ml of 1N LiOH-solution and the reaction mixture was stirred at RT for 4 h. The pH was then adjusted to 2-3 by addition of 1N HCl and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated to yield 579 mg (98%) of 6-chloro-benzo[b]thiophene-2-carboxylic acid as white solid. MS (ISP) 211.0 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12]O.[CH3:14][C:15]1[CH:16]=[C:17]([C:22](=O)[CH3:23])[CH:18]=[C:19]([CH3:21])[CH:20]=1.[OH-].[K+]>C1(C)C=CC=CC=1>[CH3:14][C:15]1[CH:16]=[C:17]([C:22]2[CH:23]=[CH:12][C:3]3[C:2](=[CH:7][CH:6]=[CH:5][C:4]=3[C:8]([F:11])([F:10])[F:9])[N:1]=2)[CH:18]=[C:19]([CH3:21])[CH:20]=1
Reactant: Nc1cccc(C(F)(F)F)c1CO
Reactant: CC(=O)c1cc(C)cc(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(-c2ccc3c(C(F)(F)F)cccc3n2)c1
Temperature: 25 °C
Yield: 35.3 %

Procedure:
A mixture of (2-amino-6-(trifluoromethyl)phenyl)methanol (18 g, 94 mmol), 1-(3,5-dimethylphenyl)ethanone (19.5 ml, 130 mmol), powdered potassium hydroxide (0.90 g, 16.0 mmol), and RuCl2(PPh3)3 (0.45 g, 0.47 mmol) in toluene (310 ml) was refluxed overnight. Upon cooling to room temperature, the mixture was washed with water and extracted with ethyl acetate (3 times). The crude material was coated on celite and purified by CC starting with 5% EA in Heptanes. The product Obtained was recrystallized from methanol to afford 2-(3,5-dimethylphenyl)-5-(trifluoromethyl)quinoline (10 g, 35% yield) as yellow crystals.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH2:14]([O:21][C@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:23][CH2:24][OH:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)=O>[CH2:14]([O:21][C@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:23][C:24]([OH:3])=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)=O
Reactant: CCCCCCCCCCC[C@H](CCO)OCc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCC[C@H](CC(=O)O)OCc1ccccc1

Procedure:
Jones reagent was added in portions to a mixture of alcohol 46 (3.23 g, 10.1 mmol) in acetone (50 mL) at 0° C. until the alcohol was consumed. The mixture was partitioned between 0.1M HCl (100 mL) and ethyl acetate (400 mL), and the organic phases were washed with brine (100 mL), dried, and concentrated in vacuo. The product was purified by flash chromatography to give compound 47 as an oil (Rf 0.38, silica, 25% ethyl acetate in hexane, 2.09 g, 62%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=N[CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:25]1C=CC=CC=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:25][CH:18]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Brc1ccccc1
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2)n1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2ccccc2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide (example 14) in accordance with the general method of example 20 using Bromobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=325.0 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[C:13]([C:21]#[N:22])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N=C=NC(C)C)(C)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH2:29][C:25]4[S:24][CH:28]=[CH:27][CH:26]=4)=[CH:17][CH:18]=3)[C:13]([C:21]#[N:22])=[CH:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(O)ccc32)cc1
Reactant: OCc1cccs1
Agent: CC(C)N=C=NC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(OCc4cccs4)ccc32)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-(5-hydroxy-3-cyanoindol-1-yl)benzoic acid ethyl ester and tiophene-2-methanol (0.057 g) and triphenylphosphine (0.012 g) in tetrahydrofuran (2.5 mL) was added diisopropylcarbodiimide (40% toluene solution, 0.18 mL) at room temperature, and this mixture was stirred for 3 hours. This reaction mixture was concentrated under reduced pressure. This residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/3) to give the title compound (0.10 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18]([CH3:19])=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2[CH3:20])[CH2:4][O:3]1.[CH2:22](C1C=C(C=C(C)C=1O)C#N)C>>[CH3:1][C:2]1([CH3:21])[O:6][C@@H:5]([CH2:7][O:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:17][C:18]=2[CH2:19][CH3:22])[CH2:4][O:3]1
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Reactant: CCc1cc(C#N)cc(C)c1O
Product: CCc1cc(C(=N)NO)cc(C)c1OC[C@H]1COC(C)(C)O1

Procedure:
The title compound is obtained as a yellow oil (0.77 g) in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine starting from 3-ethyl-4-hydroxy-5-methyl-benzonitrile and D-alpha-beta-isopropyliden glycerol; LC-MS: tR=0.68 min, [M+H]+=308.99.
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[C:18]([O:19][CH3:20])=[C:17]([N+:21]([O-])=O)[CH:16]=[CH:15][C:12]=2[CH:13]=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.O.[Fe]>[C:1]1([S:7]([O:10][C:11]2[C:18]([O:19][CH3:20])=[C:17]([NH2:21])[CH:16]=[CH:15][C:12]=2[CH:13]=[O:14])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1c([N+](=O)[O-])ccc(C=O)c1OS(=O)(=O)c1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(N)ccc(C=O)c1OS(=O)(=O)c1ccccc1
Yield: 66.9 %

Procedure:
The 4-nitrobenzaldehyde from Example 3 (82.0 g, 243 mM) in glacial acetic acid (323 ml) and H2O (332 ml) at 90°-95° C. was treated with iron powder (103 g, 40 mesh) added in 10-12 portions during 3/4 hour with vigorous stirring. When addition was complete the suspension was heated at 90°-95° C. for 3 hours. The reaction mixture was cooled and H2O (380 ml) added. The mixture is then filtered and the dark brown solid washed with EtOAc. Removal of solvent afforded 50 g of crude product. Crystallization from EtOAc and treatment with charcoal afforded a yellow solid, 50 g (67%), mp 280°-282° C. dec.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:18])[CH2:14][CH:15]=[C:16](O)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:18])[CH2:14][CH:15]=[C:16]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2n(c1=O)C(C)CC=C2O
Reactant: Nc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cnc2n(c1=O)C(C)CC=C2Nc1ccccc1
Yield: 46.1 %

Procedure:
0.5 g. (2.00 mmoles) of 9-hydroxy-6-methyl-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ethyl ester is dissolved in 5 ml. of anhydrous ethanol. To the solution 0.3 g. (3.00 mmoles) of aniline is added and the solution is heated under reflux for 3 hours. The reaction mixture is then cooled and the precipitated crystals are filtered and washed with some ethanol. 0.3 g. (46.1%) of 9-(phenyl-amino)-6-methyl-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ethyl ester is obtained, melting point: 119°-120° C.
Reaction SMILES: Cl[CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.Cl.[Cl:15][C:16]1[CH:17]=[N:18][C:19](=[O:22])[NH:20][CH:21]=1>ClCCl>[F:11][C:10]([F:13])([F:12])[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[O:3][CH2:2][N:20]1[CH:21]=[C:16]([Cl:15])[CH:17]=[N:18][C:19]1=[O:22]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: FC(F)(F)c1cccc(OCCl)c1
Agent: Cl
Solvent: ClCCl
Product: O=c1ncc(Cl)cn1COc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-chloromethoxy-3-trifluoromethylbenzene [see Preparation 4) (7 mmol) in dichloromethane (10 ml) was added to a solution of 5-chloropyrimidin-2-one hydrochloride (70 mmol) in dichloromethane (30 ml) and the mixture stirred at room temperature for 18 h. The solvent was then distilled off, the mixture triturated with water, the residual solid extracted with chloroform and the dried (MgSO4) chloroform solution evaporated; yield 1.88 g (94%). The product was a mixture of the N- and O-isomer in the ratio 3:1. The isomers were separated by the difference in their solutilities in tetrachloromethane, the O-isomer being the more solunble. The title compound, the N-isomer was isolated in a non-crystalline form. 1H NMR (CDCl3) δ 5.82 (CH2), 7.1-7.3 (Ph), 7.85 (H-4, J4,6 3 Hz), 8.45 (H-6).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH:12]=1)[CH2:10][OH:11].[N+]([O-])(O)=O>[N+](C)([O-])=O.O>[Cl:1][C:2]1[CH:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH:12]=1)[CH:10]=[O:11]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1CO
Solvent: C[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: O
Product: O=Cc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 50.5 %

Procedure:
100 g of 5-(2-chloro-4-trifluoromethyl-phenoxy)-2-nitrobenzyl alcohol were dissolved in 370 ml of nitromethane. A mixture of 86.4 g of 65% strength nitric acid and 43.2 g of water was then added dropwise in the course of 90 minutes to this solution, at 60° to 65° C., and the mixture was stirred for 8 hours at 60° to 65° C. It was then diluted with 4 liters of water, and the product was filtered off. 50.2 g (50% of theory) of 5-(2-chloro-4-trifluoromethyl-phenoxy)-2-nitro-benzaldehyde, of melting point 95° C., were obtained.