Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1C=CC=CC=1.O>[CH:19]1([C:25]([N:9]2[CH2:10][CH:11]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([CH2:12]3)[CH2:8]2)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: c1ccc(C23CNCC2C3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: O=C(C1CCCCC1)N1CC2CC2(c2ccccc2)C1

Procedure:
A 6.4 g. portion of 1-phenyl-3-azabicyclo[3.1.0]hexane is added to 60 ml. of benzene. A 4.2 g. portion of sodium carbonate in 40 ml. of water is added with stirring. A 5.9 g. portion of cyclohexylcarbonyl chloride in 40 ml. of benzene is added and the mixture is stirred overnight. The oily solid in the aqueous layer is extracted with chloroform. The extracts are washed with water and dilute hydrochloric acid, dried over magnesium sulfate, filtered and evaporated. The oily residue is extracted with ether giving a white solid as the product, mp 81°-82° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15](C)=[CH:14][C:13]=2[N+:19]([O-])=O)[N:4]=1.[C:22](O)(=O)C>C(OCC)(=O)C.O.[Fe]>[CH3:10][O:9][C:7]1[N:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([NH:11][C:12]2[C:13]([NH2:19])=[CH:14][CH:15]=[C:16]([CH3:22])[CH:17]=2)[N:6]=1
Reactant: CC(=O)O
Reactant: COc1nc(Nc2ccc(C)cc2[N+](=O)[O-])nc(OC)n1
Agent: [Fe]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1nc(Nc2cc(C)ccc2N)nc(OC)n1

Procedure:
N-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-2-nitroaniline (10 g) was dissolved in ethyl acetate (50 ml) and water (50 ml), and 10 g of iron power and acetic acid (2 ml) were added thereto, followed by reflux for 2 hours. Insoluble matters were removed by filtration, and the ethyl acetate layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 8.8 g of the desired product as a white powder (m.p. 180-183° C.)
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][C:10](O)=[C:5]2[C:4]([CH3:18])=[N:3]1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:10]1[CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[C:6]2[N:2]([CH3:1])[N:3]=[C:4]([CH3:18])[C:5]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nn(C)c2nc(-c3ccccc3)cc(O)c12
Product: Cc1nn(C)c2nc(-c3ccccc3)cc(Cl)c12

Procedure:
73 gms. of 1,3-dimethyl-4-hydroxy-6-phenyl-1H-pyrazolo[3,4-b]pyridine (0.31 mol.) are refluxed in 800 ml. of phosphorus oxychloride for 6 hours. The excess phosphorus oxychloride is removed in vacuo and the oily residue is treated with ice-water by which operation the compound becomes solid. The compound is extracted with ether, washed with an aqueous sodium carbonate solution (10%) and again with water. Evaporation of the dried (Na2SO4) and charcoal treated ethereal extract provides 4-chloro-1,3 -dimethyl-6-phenyl-1H-pyrazolo[3,4-b]-pyridine which is washed with absolute ethanol, yield: 55.6 gms. (69.8%) of white product melting at 89°-90° C.
Reaction SMILES: [C:1]([NH:4][NH2:5])([NH2:3])=[NH:2].Cl.[CH3:7][S:8]([OH:11])(=[O:10])=[O:9].[CH3:12][O:13][C:14]1[C:23]2[C:22](=O)[CH2:21][CH:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][C:18]=2[N:17]=[CH:16][CH:15]=1>C(O)C>[CH3:7][S:8]([OH:11])(=[O:10])=[O:9].[NH:4]([N:5]=[C:22]1[CH2:21][CH:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19][C:18]2[N:17]=[CH:16][CH:15]=[C:14]([O:13][CH3:12])[C:23]1=2)[C:1]([NH2:3])=[NH:2]
Reactant: COc1ccnc2c1C(=O)CC(c1ccccc1)C2
Reactant: N=C(N)NN
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCO
Product: COc1ccnc2c1C(=NNC(=N)N)CC(c1ccccc1)C2
Temperature: 50 °C
Reaction time: 0.42 h
Yield: 112.4 %

Procedure:
To a solution of aminoguanidine hydrochloride (0.023 g) in ethanol (10 ml) was added methanesulfonic acid (0.02 g), and the mixture was refluxed for 30 minutes. To the solution was added 4-methoxy-7-phenyl-5,6,7,8-tetrahydroquinolin-5-one (0.05 g), and the mixture was stirred at room temperature for 2 hours and 20 minutes and at 50° C. for 25 minutes. To the mixture was added methanesulfonic acid (0.02 g), and the mixture was stirred at 50° C. for 5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol-water to give 5-guanidinoimino-4-methoxy-7-phenyl-5,6,7,8-tetrahydroquinoline methanesulfonate (Compound 78) (0.09 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:12]1[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][C:11]=1[C:15]#[N:16]
Reactant: Cc1ccc(-c2[nH]c(=O)c(C#N)cc2-c2ccccc2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2nc(Cl)c(C#N)cc2-c2ccccc2)cc1

Procedure:
The mixture of 6-(4-methylphenyl)-2-oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile (1-3; 1.5 g, 5.24 mmol) in POCl3 (15 mL) was heated to 100 C for 3 h and concentrated. The residue was basified with sodium carbonate aqueous solution and extracted with CH2Cl2 (3×30 mL). The combined organic layer was dried, filtered and concentrated. The residue was purified by silica gel chromatography (5-10% EtOAc in hexane) to give 2-chloro-6-(4-methylphenyl)-5-phenylnicotinonitrile (1-4). 1H-NMR (500 MHz, CDCl3) δ 7.95 (s, 1H), 7.33-7.35 (m, 3H), 7.28 (d, J=8.3, 2H), 7.16-7.18 (m, 2H), 7.06 (d, J=7.9, 2H), 2.32 (s, 3H). LRMS m/z (M+H) Calcd: 305.2, found: 305.1.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N:12]1([CH2:17][CH2:18][CH2:19][CH2:20]N)[CH:16]=[CH:15][N:14]=[CH:13]1>>[N:12]1([CH2:17][CH2:18][CH2:19][CH2:20][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: NCCCCn1ccnc1
Reactant: O=C1NC(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1CCCCn1ccnc1

Procedure:
A mixture of 0.01 mole of phthalimide and 0.01 mole of 1H-imidazol-1-butanamine was heated in an oil bath at 140° for 1 hour. The reaction mixture was cooled to obtain the desired product.
Reaction SMILES: C(O[N:4]=[C:5]([C:7]1[N:8]=[CH:9][N:10]([C@@H:13]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]2[OH:15])[C:11]=1[NH2:12])[NH2:6])C.[C:22](=S)=[S:23]>N1C=CC=CC=1.CO>[CH:9]1[N:10]([C@@H:13]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]2[OH:15])[C:11]2[C:7](=[C:5]([NH2:6])[NH:4][C:22]([N:12]=2)=[S:23])[N:8]=1
Reactant: S=C=S
Reactant: CCON=C(N)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N
Solvent: CO
Solvent: c1ccncc1
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 65 %

Procedure:
0.45 g of 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide O-ethyl-oxime was dissolved in a mixture of 0.3 ml of pyridine, 5 ml of methanol and 0.5 ml of carbon disulfide. The resulting mixture was allowed to react in an autoclave at 120° C for 6 hours under autogenous pressure (about 10 Kg/cm2). The reaction mixture was concentrated to dryness, and the residue was dissolved in water. The aqueous solution was adjusted to a pH of 2 with hydrochloric acid to precipitate the crude product, which was then recovered by filtration. The filter cake was dissolved in aqueous ammonia, the solution was filtered, and the filtrate was adjusted to a pH of 2 with hydrochloric acid to obtain 0.31 g of pure 2-thioadenosine as crystals having a melting point of 199° C (with decomposition) in a 65% yield.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)=[CH:6][CH:5]=1.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([N:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:19])[F:20])=[CH:5][CH:6]=1)[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1)=[O:25]
Reactant: O=C(O)c1csc(Nc2ccc(OC(F)(F)F)cc2)n1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1csc(N(C(=O)c2ccccc2Cl)c2ccc(OC(F)(F)F)cc2)n1
Temperature: 50 °C
Reaction time: 48 h
Yield: 71.9 %

Procedure:
A mixture of 2.0 g (6.6 mmol) 2-(4-(trifluoromethoxy)phenylamino)-thiazole-4-carboxylic acid, 2.87 g (16.4 mmol) 2-chlorobenzoyl chloride and 0.92 g (6.6 mmol) potassium carbonate in 50 mL THF was stirred at 50° C. for 48 h. After evaporation of the volatiles the residue was partitioned between water and ethyl acetate. Organic phases were pooled, dried with MgSO4 and the solvent was removed in vacuo. Crystallisation from n-heptane yielded 2.1 g (72%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CCCc1c[nH]c2ccc(Cl)cc12)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 67.7 %

Procedure:
A mixture of 4-(5-chloroindol-3-yl)butyric acid (1.50 g), benzyl bromide (1.10 g) and potassium carbonate (0.987 in N,N-dimethylformamide (12 ml) was stirred at 25° C. for 4.5 hours. The mixture was poured into a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of solvent, the residue was chromatographed on silica gel (40 g) eluting with a mixture of hexane and ethyl acetate (10:1) to give benzyl 4-(5-chloroindol-3-yl)butyrate (1.40 g) as pale yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[CH2:6][S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:15]=[CH:16][C:3]1=2.Cl.[CH2:23](O)[CH3:24]>>[O:1]=[C:2]1[CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[CH2:6][S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18]([O:20][CH2:23][CH3:24])=[O:19])[CH:15]=[CH:16][C:3]1=2
Reactant: CC(C(=O)O)c1ccc2c(c1)SCC1CCCCC1C2=O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(C)c1ccc2c(c1)SCC1CCCCC1C2=O

Procedure:
To a solution of 2-(6,6a,7,8,9,10,10a,11-octahydro-11-oxodibenzo[b,e]thiepin-3-yl)propionic acid (10 g) in ethanol (150 ml) was added 35% hydrochloric acid (10 ml) and the mixture was heated under reflux for 4 hours. Removal of the ethanol under reduced pressure afforded the title compound (10.8 g), b.p. 205° C./0.06 mmHg. IR νmaxfilm cm-1 : 1720, 1660 (C=O). HRMS m/e: 332.1475 (M+) (Molecular weight calculated for C19H24O3S: 332.1447).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[S:28][C:29]([CH2:32][N:33]([CH3:35])[CH3:34])=[CH:30][CH:31]=2)=[CH:21][N:20]=1)([O-])=O>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[S:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[S:28][C:29]([CH2:32][N:33]([CH3:34])[CH3:35])=[CH:30][CH:31]=3)=[CH:21][N:20]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)s1
Reactant: CN(C)Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)s1
Solvent: c1ccncc1
Product: CN(C)Cc1ccc(CSCCNc2ncc(Cc3ccc(CN(C)C)s3)c(=O)[nH]2)s1

Procedure:
A solution of 2-(5-dimethylaminomethyl-2-thienylmethylthio)ethylamine (1.47 g) and 2-nitroamino-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone (2.0 g) in pyridine (10 ml) was refluxed overnight. The pyridine was removed under reduced pressure and the last traces of pyridine were removed by azeotroping with water yielding 2-(5-dimethylaminomethyl-2-thienylmethylthio)ethylamino-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone as an oil. The resultant oil was washed by decantation with water.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][N:6]=1)=[O:4].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].O>CN(C)C=O>[Cl:11][C:10]1[C:5]([C:3](=[O:4])[CH2:2][N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])=[N:6][CH:7]=[C:8]([Cl:12])[CH:9]=1
Reactant: O=C(CBr)c1ncc(Cl)cc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1ncc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 8.6 %

Procedure:
To 3.00 g of the 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone prepared in Step 2 in Synthetic Example 2 in 30 ml of N,N-dimethylformamide, 4.13 g of potassium phthalimide was added, and the mixture was stirred at 80° C. for 3 hours and then at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 150 ml of water and extracted with ethyl acetate (50 ml×2), the resulting organic layers were combined, washed with water (50 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was mixed with 40 ml of a mixture of diisopropyl ether and hexane (1:1), the insolubles were filtered off, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 15:85 to 25:75) as the eluent to obtain 0.32 g of the desired product as a dark brown resinous substance.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[N:10]([CH3:30])[CH:11]=[C:12]([C:14]3[O:18][N:17]=[C:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[N:15]=3)[N:13]=2)[CH:5]=[CH:4][N:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CCN(C(C)C)C(C)C>[CH3:30][N:10]1[CH:11]=[C:12]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[N:15]=2)[N:13]=[C:9]1[CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:35]2[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]2)[CH:7]=1
Reactant: Cn1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nc1Cc1ccnc(Cl)c1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cc(Cc3nc(-c4nc(-c5ccc(OC(F)(F)F)cc5)no4)cn3C)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.3 h
Yield: 12.8 %

Procedure:
A solution of 5-(2-((2-chloropyridin-4-yl)methyl)-1-methyl-1H-imidazol-4-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (60 mg, 0.138 mmol) and 1-methylpiperazine (2 mL) in DIPEA (2 mL) was stirred at 150° C. for 5 h. After cooled to RT, the mixture was quenched by water (5 mL), and extracted with EtOAc (2×10 mL). The combined organic phases were washed with water (5 mL) and brine (5 mL), dried (Na2SO4), filtered, and concentrated to afford the crude product, which was purified with prep-HPLC (Mobile phase:A=0.01% formic acid/water, B=acetonitrile; Gradient: B=36%-95% in 18 min; Column: XBridge C18, 5 um, 30 mm×150 mm) to give 5-(1-methyl-2-((2-(4-methylpiperazin-1-yl)pyridin-4-yl)methyl)-1H-imidazol-4-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a white solid (8.8 mg, 12.8%). MS (ES+) C24H24F3N7O2 requires: 499, found: 500 [M+H]+; 1H-NMR (500 MHz, CDCl3) δ ppm 8.20 (d, J=7.5 Hz, 2H), 8.14 (d, J=5.0 Hz, 1H), 7.63 (t, 1H), 7.32 (d, J=4 Hz, 2H), 6.58 (d, J=5 Hz, 1H), 6.47 (s, 1H), 4.53 (s, 2H), 3.79-3.74 (m, 2H), 3.63-3.58 (m, 2H), 3.56 (s, 3H), 3.29-3.25 (m, 2H), 2.92-2.87 (m, 2H), 2.79 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22]Br)[CH:7]=1)[CH3:2].[CH2:25]([SH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Na+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22][S:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CBr)c1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CSCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To [3-(2-bromomethyl-4-chloro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.15 g 0.36 mmol) and benzyl mercaptan (0.06 mL, 0.4 mmol) in 1,4-dioxane (10 mL) was added sodium hydride (60% in mineral oil; 0.05 g, 1.25 mmol), and the reaction was stirred for 1 hour at room temperature. After work-up, the crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:22])[CH2:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=O)[CH2:31][S:32][C:33]#[N:34])=[CH:26][CH:25]=1>C(O)CCC>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]=[C:33]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14](=[O:22])[CH2:15][C:16]([CH3:20])([CH3:21])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[S:32][CH:31]=2)=[CH:26][CH:25]=1
Reactant: CC(C)(CC(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)O
Reactant: N#CSCC(=O)c1ccc(Cl)cc1
Solvent: CCCCO
Product: CC(C)(CC(=O)c1ccc(-c2ccc(Nc3nc(-c4ccc(Cl)cc4)cs3)cc2)cc1)C(=O)O
Temperature: 90 °C
Yield: 6.9 %

Procedure:
In a 8-mL screw-cap vial, a mixture of 4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoic acid (60 mg, 0.20 mmol) and 2-(4-chlorophenyl)-2-oxoethyl thiocyanate (64 mg, 0.30 mmol) in 4 mL n-butanol was heated at 90° C. overnight. The solvent was removed under reduced pressure. The mixture was dissolved in 5 mL 1:4 MeOH/DMF and purified by reverse-phase HPLC to provide 6.8 mg (7%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 11.90 (br s, 1H), 10.50 (s, 1H), 7.75-8.00 (r, 10H), 7.50 (m, 3H), 3.30 (m, 2H), 1.05 (s, 6H); LC-MS m/z 491.2 (MH+), ret. time 3.83 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH:34][C:35](=[O:37])[CH3:36].[H-].[Na+]>O1CCCC1>[C:35]([N:34]([CH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=1)[C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:5]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)NCc1ccccn1
Reactant: CCCCCCCCCCCCCCOc1cc(C(=O)Cl)ccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1cc(C(=O)N(Cc2ccccn2)C(C)=O)ccc1OC
Yield: 30.6 %

Procedure:
The title compound is prepared by the procedure of Example 27 using 1.19 g of product from Example 43, 0.490 g of product from Example 12, 0,157 g of washed 50% sodium hydride and 12 ml of tetrahydrofuran. The residue is purified by column chromatography (silica gel:35% ethyl acetate/hexane) to give 0.472 g of the desired product as yellow crystals.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[C:18]([C:22]([CH3:25])=[CH:23][N:24]=3)[C:19](O)=[O:20])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32]([NH:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[CH:33]=[CH2:34]>>[CH2:32]([N:35]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C:19](=[O:20])[C:18]1[C:22]([CH3:25])=[CH:23][N:24]=[C:16]([N:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:11][CH2:12]2)[CH:17]=1)[CH:33]=[CH2:34]
Reactant: C=CCNC1CCCCC1
Reactant: Cc1cnc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)cc1C(=O)O
Product: C=CCN(C(=O)c1cc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)ncc1C)C1CCCCC1
Yield: 72.8 %

Procedure:
Step (d) of Example 107 was repeated, except that the compound (50 mg) prepared in step (d) of Example 108 and allylcyclohexylamine (34 mg) were used as the starting compounds. Thus, the title compound (47 mg) was obtained.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:14][C:15]2[CH:20]=[C:19]([N:21]3[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]3=[O:33])[C:18]([F:34])=[CH:17][C:16]=2[Cl:35])=[N:11][S:12][N:13]=1)C1C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:35][C:16]1[CH:17]=[C:18]([F:34])[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:20][C:15]=1[O:14][C:10]1[C:9]([OH:8])=[N:13][S:12][N:11]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3nsnc3OCc3ccccc3)c(Cl)cc2F)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3nsnc3O)c(Cl)cc2F)c1=O

Procedure:
A solution of 2.5 g of crude product of 4-benzyloxy-3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-1,2,5-thiadiazole in 20 ml of trifluoroacetic acid was stirred over night at room temperature. The solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.50 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-hydroxy-1,2,5-thiadiazole.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:47]1([C@@H:53]([NH2:55])[CH3:54])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:55][C@H:53]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH3:54])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](N)c1ccccc1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N[C@@H](C)c2ccccc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with (S)-(−)-1-phenylethylamine (Aldrich) to give the title product. LC-MS (ES+) 768 [(M+H)+].
Reaction SMILES: COC1C=C(C=CC=1OC)C[NH:7][C:8]1[N:29]=[CH:28][C:11]2[C:12]3[N:16]([CH2:17][CH2:18][O:19][C:10]=2[CH:9]=1)[CH:15]=[C:14]([C:20]1[N:21]([CH:25]([CH3:27])[CH3:26])[N:22]=[CH:23][N:24]=1)[N:13]=3.C(O)(C(F)(F)F)=O>>[CH:25]([N:21]1[C:20]([C:14]2[N:13]=[C:12]3[C:11]4[CH:28]=[N:29][C:8]([NH2:7])=[CH:9][C:10]=4[O:19][CH2:18][CH2:17][N:16]3[CH:15]=2)=[N:24][CH:23]=[N:22]1)([CH3:27])[CH3:26]
Reactant: COc1ccc(CNc2cc3c(cn2)-c2nc(-c4ncnn4C(C)C)cn2CCO3)cc1OC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N)cc1OCC2
Yield: 54.8 %

Procedure:
A solution of (3,4-dimethoxy-benzyl)-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl]-amine (378 mg, 0.82 mmol) and TFA (15 mL) was heated at 40° C. for 5 h. The reaction mixture was concentrated in vacuo and the residue loaded onto an SCX-2 cartridge, washing with methanol and eluting with 2M ammonia in methanol. Basic fractions were combined and then concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 453 as a white solid (140 mg, 55% total). LCMS: RT=2.09 min, [M+H]+=312. 1H NMR 400 MHz (DMSO-d6) δ: 8.93 (1 H, s), 7.88 (1 H, s), 7.80 (1 H, s), 6.19 (2 H, br, s), 5.98 (1 H, s), 5.90-5.88 (1 H, m), 4.49-4.43 (4 H, m), 1.47 (6 H, d, J=6.61 Hz)