Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:27](#[N:29])[CH3:28].O>N1C=CC=CC=1>[CH2:7]([CH:20]1[CH2:21][CH2:22][N:29]([S:16]([C:14]2[CH:13]=[CH:12][C:10]3[O:11][C:7]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[O:8][C:9]=3[CH:15]=2)(=[O:18])=[O:17])[CH2:27][CH2:28]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC#N
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CCC(Cc2ccccc2)CC1
Temperature: 60 °C

Procedure:
2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl chloride (93 mg, 0.25 mmol) was dissolved in pyridine (1 ml). The appropriate amine (0.25 mmol) was added and the reaction was heated to 60° C. overnight. Water was added and solids respectively oils separated. The aqueous phase was decanted and the residue was stirred with acetonitrile. A solution was obtained, which was subjected to preparative reversed phase chromatography (gradient of acetonitrile/water containing 0.1% formic acid as the eluant) to yield the product after evaporation of the eluant and drying.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([S:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)[N:16]=2)[CH:3]=1.[OH:33]O.O>C1COCC1.[Cl-].[Cl-].[Cl-].[V+3]>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:33])=[CH:22][CH:21]=3)[N:16]=2)[CH:3]=1
Reactant: OO
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(Sc5ccccc5)cc4)no3)cc2C)cc1
Agent: [V+3]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(S(=O)c5ccccc5)cc4)no3)cc2C)cc1

Procedure:
To a mechanically stirred solution of 5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-3-[4-(phenylsulfanyl)phenyl]-1,2,4-oxadiazole (Example 114, 350 mg, 0.798 mmol) in THF (3 mL) was added vanadium trichloride (6 mg, 0.04 mmol) and hydrogen peroxide (30% in water, 82 μL, 0.798 mmol). The reaction mixture was stirred at rt for 5 h, before another 40 μL (0.4 mmol) of the hydrogen peroxide solution were added. Stirring was continued at rt over night. Then water (30 mL) was added, and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent, the crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 3:1), followed by precipitation using acetonitril/water 3:1 affording a first crop of the title compound (29 mg, 8%). A second crop was obtained from the mother liquor after preparative HPLC (26 mg, 7%): 1H NMR (400 MHz, DMSO-d6) 8.39 (s, 1H), 8.18 (d, 1H), 7.96 (d, 1H), 7.81 (d, 2H), 7.78-7.74 (m, 1H), 7.60-7.50 (m, 3H), 7.18 (d, 2H), 7.12 (d, 2H), 6.94 (s, 1H), 5.44 (s, 2H), 2.32 (s, 3H), 2.28 (s, 3H); ES-MS m/z 455, HPLC RT (Method D) 2.78 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:34][C:35]1[CH:39]=[CH:38][S:37][CH:36]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH2:34][C:35]2[CH:39]=[CH:38][S:37][CH:36]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)cc2)CC1
Reactant: BrCc1ccsc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2ccsc2)c2ccc(C#N)cc2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 60.9 %

Procedure:
To a solution of 4-(4-cyano-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 106) (1.17 g, 3.89 mmol) in THF (20 mL) cooled to −78° C. was added KHMDS (0.5M, 12.0 mL, 6.0 mmol) and the mixture was stirred at −78° C. for 20 minutes. The reaction was quenched with 3-(bromomethyl)thiophene (1.06 g, 5.99 mmol) and warmed to room temperature to afford 4-[(4-cyano-phenyl)-thiophen-3-ylmethyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (941 mg, 61%) following work-up and purification.
Reaction SMILES: O=O.[O-:3][CH2:4][CH3:5].[Nb+5:6].[O-:7][CH2:8][CH3:9].[O-:10][CH2:11][CH3:12].[O-:13][CH2:14][CH3:15].[O-:16][CH2:17][CH3:18].[C:19]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Ce:29]>C(O)CCC>[O-:3][CH2:4][CH3:5].[Nb+5:6].[O-:7][CH2:8][CH3:9].[O-:10][CH2:11][CH3:12].[O-:13][CH2:14][CH3:15].[O-:16][CH2:17][CH3:18].[C:19]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Ce+3:29].[Nb:6]
Reactant: [Ce]
Agent: [Nb+5]
Agent: CC[O-]
Agent: O=O
Solvent: CCCCCC(=O)OCC
Solvent: CCCCO
Product: [Ce+3]
Product: [Nb]

Procedure:
NbxCe1-xO2 where x is from about 0.02 to about 0.05 was prepared by the following procedure. A solution of niobium ethoxide was prepared in n-butanol solvent in a low moisture and low oxygen environment to prevent hydrolysis of the niobium ethoxide with moisture present in the air. A partial solution/emulsion of cerium (III) 2-ethyl hexanoate in n-butanol was prepared. Then, the niobium ethoxide solution is admixed with the cerium 2-ethyl hexanoate solution/emulsion in an amount to provide a desired solid solution of about 2 to 5 mole percent niobium dopant. Then, the solution/emulsion mixture was then dried at about 110° C. in air to begin to transform the gel into powder. Next, the dried material was thermally decomposed by calcination at about 650° C. in air to form the solid solution of metal oxides powder agglomerate. The metal oxide powder was then deagglomerated by high frequency vibration through sonication in a MEK-ethanol solution containing a small amount of fish oil to result in an average particle size powder of about 0.8 microns.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[CH:14]([CH3:19])[CH2:15][C:16](O)=[O:17])=[CH:9][C:8]=2[N+:21]([O-:23])=[O:22])[CH2:3][CH2:2]1.O.[NH2:25][NH2:26]>C(O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]([CH3:19])[CH2:15][C:16](=[O:17])[NH:25][N:26]=3)=[CH:9][C:8]=2[N+:21]([O-:23])=[O:22])[CH2:3][CH2:2]1
Reactant: CC(CC(=O)O)C(=O)c1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(N2CCOCC2)c([N+](=O)[O-])c1

Procedure:
A mixture of 12.2 parts of 4(4-morpholino-3-nitrophenyl)-4-oxo-3-methylbutanoic acid, 3.8 parts of hydrazine hydrate in 50 parts by volume of absolute ethanol is heated at reflux for 4 hours, cooled and filtered. The solid product is collected, washed with hexane and dried at 80° C. under vacuum to give 6-(4-morpholino-3-nitrophenyl)-4,5-dihydro-5-methyl-3(2H)pyridazinone melting at 223°-225° C. Recrystallisation from a mixture of ethanol and dimethylformamide raises the melting point to 225°-227° C.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:34])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27](Cl)[C:28](OCC)=[O:29])=[CH:22][CH:21]=1)([CH3:17])[CH2:9][CH2:8]2)(=O)C.[NH2:35][C:36](N)=[S:37].S1(CCCC1)(=O)=[O:40].Cl>COCCO>[OH:4][C:5]1[C:6]([CH3:34])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]3[S:37][C:36](=[O:40])[NH:35][C:28]3=[O:29])=[CH:22][CH:21]=1)([CH3:17])[CH2:9][CH2:8]2
Reactant: O=S1(=O)CCCC1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Agent: Cl
Solvent: COCCO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Temperature: 120 °C

Procedure:
A mixture of 9.6 g of ethyl 3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]-2-chloropropionate (prepared as described in Preparation 51), 1.8 g of thiourea and 11 ml of sulfolane was heated for 3.5 hours at 120° C. under a nitrogen stream. 100 ml of ethylene glycol monomethyl ether and 70 ml of 10% w/v aqueous hydrochloric acid were then added to the reaction mixture, after which it was heated under reflux for 12 hours. The product was then purified as described in Example 27, to give the title compound. The melting point and nuclear magnetic resonance spectrum of this compound accorded with those of the compound obtained in Example 27(b).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:23]1[C:31]2[N:30]=[CH:29][NH:28][C:27]=2[C:26](=[O:32])[NH:25]/[C:24]/1=[N:33]\[NH2:34])[CH2:19][CH2:20][CH2:21][CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.O>[O:32]=[C:26]1[NH:25]/[C:24](=[N:33]\[NH:34][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][C:10]2[O:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)/[N:23]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:31]2[N:30]=[CH:29][NH:28][C:27]1=2
Reactant: O=C(O)CCCc1nc(-c2ccccc2)no1
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCn1/c(=N/NC(=O)CCCc2nc(-c3ccccc3)no2)[nH]c(=O)c2[nH]cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
A mixture of 4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanoic acid (1.44 g, 6.20 mmol), (2e)-3-pentyl-3,7-dihydro-1h-purine-2,6-dione 2-hydrazone (1.61 g, 6.82 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (3.02 g, 6.82 mmol) and triethylamine (1.73 ml, 12.4 mmol) in DMF (30 ml) was stirred at room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate (3×). The organic layer was washed with water and then brine, dried over Na2SO4, filtered and concentrated to give the desired product (2.78 g, 99% yield) as yellowish oil. LCMS calculated for C22H27N8O3 (M+H): 451.2. found: 451.1.
Reaction SMILES: [C:1]([C-:3]([C:6]#[N:7])[C:4]#[N:5])#[N:2].[K+].O.[CH2:10]([O:12]CC)[CH3:11].S(=O)(=O)(O)O>C(O)C>[NH2:2][C:1]([O:12][CH2:10][CH3:11])=[C:3]([C:6]#[N:7])[C:4]#[N:5]
Reactant: CCOCC
Reactant: N#C[C-](C#N)C#N
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(N)=C(C#N)C#N
Reaction time: 0.33 h

Procedure:
A mixture of 12.9 g of potassium tricyanomethanide from I B, 40 ml of water and 120 ml of diethyl ether was cooled to 5°. To this mixture was added 10 g of concentrated sulfuric acid dropwise at such a rate as to keep the reaction mixture temperature below 10°. Upon complete addition of sulfuric acid, the reaction mixture was stirred during 20 minutes. The mixture was then placed in a separatory funnel and the middle layer drawn off to be used in the next reaction. To 50 ml of the solution from above was added 150 ml of ethanol and volatile material was removed until the boiling temperature exceeded 50°, when the mixture was heated to reflux. The mixture was maintained at the reflux temperature for 15 hours. The white slurry was cooled to 10°, and the solid collected by filtration to give 6.5 g of 3-amino-3-ethoxy-2-cyano-2-propenenitrile, m.p. 233°. A small sample was recrystallized from ethanol without change of melting point. the nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:23])[CH2:4][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:24]([NH:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:26])[CH3:25].[O:37]1CCOCC1>C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:23])[C:4](=[O:37])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:32]4[CH:33]=[C:28]([NH:27][C:24](=[O:26])[CH3:25])[CH:29]=[CH:30][CH:31]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1CC2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: C1COCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(=O)Nc1cccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)c1
Temperature: 120 °C
Yield: 20 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H′-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-acetamidophenylboronic acid (17.9 mg, 0.1 mmol). The mixture was heated at 120° C. in a microwave reactor for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure N-(3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospir-o[chroman-4,4′-imidazole]-6-yl)phenyl)acetamide (5.8 mg, 20%). 1H-NMR (MeOD): 2.03 (s, 3H), 2.21 (t, 1H), 2.41 (t, 1H), 3.07 (s, 3H), 5.81 (d, 1H), 6.92 (d, 1H), 7.12 (t, 1H), 7.21 (t, 2H), 7.33 (t, 2H), 7.49 (m, 4H), 7.59 (d, 1H).
Reaction SMILES: Cl[C:2]1C=C(C=C[CH:11]=1)C(OO)=O.C(S[C:15]1[S:16][CH:17]=[CH:18][C:19]=1[C:20]1[N:32]([CH3:33])[C:23]2=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=[C:22]2[N:21]=1)C.C(=O)(O)[O-].[Na+].[S:39]([O-:43])([O-])(=[O:41])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:39]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[C:20]1[N:32]([CH3:33])[C:23]2=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=[C:22]2[N:21]=1)(=[O:43])=[O:41])[CH3:11]
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1sccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1sccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.20 g of 3-chloroperoxybenzoic acid (69 to 75%) was added to a mixture of 0.20 g of 2-(2-ethylthiothiophen-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine and 3 ml of chloroform, under ice cooling, and the mixture was heated to room temperature and stirred for 2 hours. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were poured to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.20 g of 2-(2-ethylsulfonylthiophen-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (Compound of Present Invention (14)).
Reaction SMILES: [C:1]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:29](Cl)(=[O:33])[C:30](Cl)=[O:31].[OH2:35]>>[C:1]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=4)=[CH:16][CH:17]=3)[C:12]([C:29](=[O:33])[C:30]([OH:35])=[O:31])=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O
Reactant: COc1cccc(-c2ccc3c(ccn3Cc3ccc(C(C)(C)C)cc3)c2)c1
Product: COc1cccc(-c2ccc3c(c2)c(C(=O)C(=O)O)cn3Cc2ccc(C(C)(C)C)cc2)c1

Procedure:
The title compound was prepared from 1-[4-(tert-butyl)benzyl]-5-(3-methoxyphenyl)-1H-indole and oxalyl chloride in substantially the same manner, as described in Step 3 of Example 25. The product was obtained as a yellow solid, mp: 86-87° C. Mass spectrum (ESI, [M+H]+) m/z 442. 1HNMR (400 MHz, DMSO-d6): δ 13.50 (br s, 1H), 8.71 (s, 1H), 8.40 (s, 1H), 7.69 (d, 1H, J=8.55 Hz), 7.58 (d, 1H, J=8.55 Hz), 7.40-7.35(m, 3H), 7.24 (d, 2H, J=8.40 Hz), 7.20(d, 1H, J=7.64 Hz), 7.14(s, 1H), 6.93 (d, 1H, J=8.25 Hz), 5.57 (s, 2H), 3.82 (s, 3H), and 1.22 ppm (s, 9H). Elemental Analysis for C28H27NO4.0.1 H2O: Calculated: C, 75.86; H, 6.18; N, 3.16. Found: C, 75.84; H, 5.91; N, 2.98.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[CH2:40]([O:42][CH:43]([O:48][CH2:49][CH3:50])[CH2:44][C:45](O)=[O:46])[CH3:41]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:40]([O:42][CH:43]([O:48][CH2:49][CH3:50])[CH2:44][C:45]([NH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:46])[CH3:41]
Reactant: CC(C)(C)OC(=O)NNc1c(N)cnc2ccccc12
Reactant: CCOC(CC(=O)O)OCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(CC(=O)Nc1cnc2ccccc2c1NNC(=O)OC(C)(C)C)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A mixture of tert-butyl N′-(3-aminoquinolin-4-yl)hydrazinecarboxylate (9.01 g, 32.9 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (7.56 g, 39.4 mmol), 4-methylmorpholine (4.34 mL, 39.4 mmol), and 4-dimethylaminopyridine (0.200 g, 1.64 mmol) in pyridine (200 mL) was chilled in an ice-water under a nitrogen atmosphere. The mixture was treated drop-wise with a solution of 3,3-diethoxypropionic acid (6.40 g, 39.4 mmol) in pyridine (50 mL). The reaction was allowed to slowly come to ambient temperature and stirred overnight. After 15 h, the reaction mixture was concentrated under reduced pressure to yield a dark red solid. The solid was dissolved in chloroform (150 mL) and transferred to a separatory funnel. The organic solution was washed with 10% Na2CO3 aqueous solution (35 mL), water (2×35 mL), and brine (35 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield 13.75 g of crude tert-butyl N′-[3-(3,3-diethoxypropionylamino)quinolin-4-yl]hydrazinecarboxylate as a dark red solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:16])[S:11][C:12]=2[CH2:13][CH2:14][Cl:15])=[CH:4][CH:3]=1.[OH:17][C:18]1([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[ClH:15].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:16])[S:11][C:12]=2[CH2:13][CH2:14][N:21]2[CH2:20][CH2:19][C:18]([OH:17])([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH2:23][CH2:22]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(-c2ccc(F)cc2)c(CCCl)s1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Solvent: Cc1ccccc1
Product: Cl
Product: O=c1[nH]c(-c2ccc(F)cc2)c(CCN2CCC(O)(c3ccc(Cl)cc3)CC2)s1

Procedure:
A mixture of 10 g of 4-p-fluorophenyl-5-β-chloroethyl-4-thiazolin-2-one, 16.4 g of 4-hydroxy-4-(p-chlorophenyl)-piperidine, and a catalytic quantity of KI in 200 cc of toluene is heated in a closed tube for 35 hours. The solid present is filtered off and the filtrate is shaken with a 1:1 solution of HCl. A solid precipitates and is dissolved in acetone and recrystallised. M.P. = 192° C (from alcohol).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35]C)[CH:6]=[CH:7][C:8]([NH:10][C:11]1[C:12](=[O:31])[O:13][C:14]2[CH:27]=[C:26]3[CH2:28][CH2:29][CH2:30][C:25]3=[CH:24][C:15]=2[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[O:9].[B].C(O)C>ClCCl.O>[OH:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[OH:35])[CH:6]=[CH:7][C:8]([NH:10][C:11]1[C:12](=[O:31])[O:13][C:14]2[CH:27]=[C:26]3[CH2:28][CH2:29][CH2:30][C:25]3=[CH:24][C:15]=2[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[O:9]
Reactant: COc1ccc(C=CC(=O)Nc2c(-c3ccccc3C)c3cc4c(cc3oc2=O)CCC4)cc1OC
Agent: [B]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccccc1-c1c(NC(=O)C=Cc2ccc(O)c(O)c2)c(=O)oc2cc3c(cc12)CCC3
Yield: 95.8 %

Procedure:
To a solution of 3-(3,4-dimethoxycinnamoylamino)-4-(2-methylphenyl)-7,8-dihydrocylopenta[g][1]benzopyran-2(6H)-one (400 mg) in dichloromethane (6 ml) was added boron tribromidedichloromethane (1:2, 1 ml) dropwise with ice-cooling and stirring. The mixture was further stirred under ice-cooling for 1 hour and, then, added gradually to ethanol (5 ml) with ice-cooling. The mixture was diluted with water and extracted with ethyl acetate, the extract was washed with water and dried (MgSO4), and the solvent was distilled off to give crystals of 3-(3,4-dihydroxycinnamoylamino)-4-(2-methylphenyl)-7,8-dihydrocyclopenta[g][1]benzopyran-2(6H)-one (361 mg, 95.8%). Recrystallization from ethanol gave light brown prisms, m.p. 295°-297° C.
Reaction SMILES: CN1C=C(CN(C)C(C2N(C3C=CC(F)=CC=3)C(S)=NC=2)=O)C(C)=N1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([C:38]([O:40]CC)=[O:39])=[CH:36][N:35]=[C:34]2[S:43][C:44]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[C:49]([F:54])[C:48]=2[F:55])([CH3:46])[CH3:45])=[CH:29][CH:28]=1.[OH-].[Li+].C1COCC1>O.CO>[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([C:38]([OH:40])=[O:39])=[CH:36][N:35]=[C:34]2[S:43][C:44]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[C:49]([F:54])[C:48]=2[F:55])([CH3:46])[CH3:45])=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1cnc(SC(C)(C)c2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: Cc1nn(C)cc1CN(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(Sc1ncc(C(=O)O)n1-c1ccc(F)cc1)c1c(F)ccc(F)c1F

Procedure:
1-(4-Fluorophenyl)-2-((2-(2,3,6-trifluorophenyl)propan-2-yl)thio)-1H-imidazole-5-carboxylic acid (76) was prepared in a similar manner as that described for the synthesis of compound 7 using ethyl 1-(4-fluorophenyl)-2-((2-(2,3,6-trifluorophenyl)propaN-2-yl)thio)-1H-imidazole-5-carboxylate (75) (0.14 g, 3.5 mmol), lithium hydroxide (15 mg, 0.64 mmol), THF (5 mL), methanol (3 mL), and water (2 mL).
Reaction SMILES: [CH3:1][NH:2][NH2:3].C([O:6][C:7](=O)[CH2:8][C:9](=O)[C:10]([CH3:13])([CH3:12])[CH3:11])C.C[O-].[Na+]>CO>[CH3:1][N:2]1[C:7]([OH:6])=[CH:8][C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:3]1
Reactant: CCOC(=O)CC(=O)C(C)(C)C
Reactant: CNN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cn1nc(C(C)(C)C)cc1O
Yield: 87.5 %

Procedure:
9.2 g (0.2 mol) of methylhydrazine were added dropwise to a mixture of 34.4 g (0.2 mol) of pivaloylacetic acid ethyl ester, 10.8 g (0.2 mol) of sodium methylate and 100 ml of methanol at 20° C. After the exothermic reaction had subsided, the mixture was heated for two hours under reflux. The reaction mixture was then concentrated, the residue was taken up in 200 ml of water and this solution was acidified to pH 6 with concentrated hydrochloric acid. The resulting precipitate was filtered off, dried and recrystallized from isopropanol. 27 g (87% of theory) of 1-methyl-3-tert.-butyl-5-hydroxy-pyrazole were obtained in the form of colorless crystals with a melting point of 150° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:26])[C:11]([CH3:25])=[C:12]([CH2:14][NH:15][C:16]3[C:17]([CH3:24])=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=3[CH3:22])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:26])[C:11]([CH3:25])=[C:12]([CH2:14][NH:15][C:16]3[C:17]([CH3:24])=[C:18]([CH:19]=[CH:20][C:21]=3[CH3:22])[O:23][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(-c2cccc(F)c2)cc(CNc2c(C)ccc(O)c2C)c1C
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(C)ccc(OCC(=O)OC(C)C)c2C)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a solution 3-[[5-(3-fluorophenyl)-2,3-dimethyl-phenyl]methylamino]-2,4-dimethyl-phenol (87.5 mg, 0.25 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (0.16 g, 0.51 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 30 min then isopropyl bromoacetate (56 mg, 0.3 mmol, 1.2 eq) was added and the reaction stirred for a further 1 h. The resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether: EtOAc, 100:1 to 30:1) to give the title compound as a colorless oil (80 mg, 69%).