Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28]Br)[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:31]1([C:37]2([C:43]([NH2:45])=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][N:40]3[CH2:39][CH2:38][C:37]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)([C:43]([NH2:45])=[O:44])[CH2:42][CH2:41]3)[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(CN2CCC(CCBr)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1cc(CN2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare according to the method of example 57.8 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-3-yl]-ethyl-bromide (5 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[NH2:12][OH:13].[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:12][OH:13])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 25 g (0.18 mol) of 4-methoxybenzaldehyde in 100 ml of ethanol was added dropwise under ice cooling to a solution of 15.3 g (0.22 mol) of hydroxylamine hydrochloride and 11.0 g (0.28 mol) of sodium hydroxide in 100 ml of water. After completion of the dropwise addition, the resulting mixture was stirred at room temperature for 30 minutes and ethanol was distilled off under reduced pressure. An insoluble solid was then collected by filtration. The solid was washed with water and hexane. The washings were combined with the filtrate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, whereby 4-methoxybenzaldoxime was obtained as a colorless liquid. Its yield was 23.7 g (85%). It was then provided for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:21][N:22]1[C:29](=[O:30])[CH2:28][C:26](=[O:27])[N:25]([CH3:31])[C:23]1=[S:24].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:31][N:25]1[C:26](=[O:27])[CH:28]([C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([O:7][C:6]3[CH:17]=[CH:18][C:3]([C:2]([F:19])([F:20])[F:1])=[CH:4][CH:5]=3)=[CH:9][CH:10]=2)=[O:16])[C:29](=[O:30])[N:22]([CH3:21])[C:23]1=[S:24]
Reactant: CN1C(=O)CC(=O)N(C)C1=S
Reactant: O=C=Nc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN1C(=O)C(C(=O)Nc2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)C(=O)N(C)C1=S

Procedure:
4-(4'-Trifluoromethylphenoxy)phenyl isocyanate (3.7 g.) was added to a stirred mixture of 1,3-dimethyl-2-thiobarbituric acid (2.3 g.) and triethylamine (1.7 ml.) in dry benzene (30 ml.). The mixture was refluxed for 12 hours. The mixture was evaporated in vacuo. Diethyl ether (10 ml.) was added to the gummy residue and the mixture was acidified with 1N hydrochloric acid. The mixture was filtered and the solid was washed with water and then ethanol.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][OH:11].CS(O[CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)=O.O>COCCOC>[C:21]1([CH2:20][O:19][CH2:18][CH2:17][O:11][CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)OCCOCc1ccccc1
Reactant: OCCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: c1ccc(COCCOCCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.4 %

Procedure:
Sodium hydride (80% dispersion in oil, 1.68 g) was added portionwise to a solution of 2-pyridineethanol (6.88 g) in 1,2-dimethoxyethane (50 ml) and stirred under nitrogen for 18 h at room temperature. A solution of 2-(phenylmethoxy)ethanol methanesulphonate (8.25 g) in 1,2-dimethoxyethane (100 ml) was added and the mixture stirred at room temperature for 7 h, then poured into water (400 ml) and extracted with diethyl ether (3×200 ml). The ethereal extracts were washed with 2N hydrochloric acid (250 ml). The aqueous phase was re-extracted with diethyl ether (100 ml) and the aqueous phase carefully basified with 8% sodium bicarbonate to pH8. Extraction with diethyl ether (2×200 ml) and drying and evaporation in vacuo of the organic extracts gave an oil. Purification by FCC eluting with System F (4.1→1.1) gave the title compound (2.71 g) as an oil. T.l.c. (diethyl ether) Rf 0.54
Reaction SMILES: [NH:1]1[C:9](=[O:10])[C:8]2[NH:7][CH:6]=[N:5][C:4]=2[N:3]=[CH:2]1.[CH2:11]1[O:13][CH:12]1[CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>>[NH:1]1[C:9](=[O:10])[C:8]2[N:7]=[CH:6][N:5]([CH2:11][CH:12]([OH:13])[CH2:14][OH:15])[C:4]=2[N:3]=[CH:2]1
Reactant: OCC1CO1
Reactant: O=c1[nH]cnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=c1[nH]cnc2c1ncn2CC(O)CO

Procedure:
Hypoxanthine is treated as in the procedure of Example 1 with glycidol in the presence of potassium carbonate to give 1-(hypoxanthine-9-yl)-2,3-propandiol. The resulting 1-(9-hypoxanthine)-2,3-propandiol is treated with dimethoxytrityl chloride in pyridine as in Example 2 to give 1-(9-hypoxanthine)-3-O-dimethoxytrityl-2-propanol. The resulting 1-(9-hypoxanthine)-3-O-dimethoxytrityl-2-propanol is phosphitylated with chloro-β-cyanoethoxy-N,N-diisopropylaminophosphine as per Example 3 to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1)[CH2:9][CH3:10].[N:21]1([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29](O)=[O:30])[CH:25]=[CH:24][CH:23]=[CH:22]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.O1CCCC1>[CH3:20][C:2]([CH3:19])([CH3:1])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([N:21]3[CH:25]=[CH:24][CH:23]=[CH:22]3)[CH:27]=2)[CH:13]=1)[CH2:9][CH3:10]
Reactant: O=C(O)c1cccc(-n2cccc2)c1
Reactant: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(N)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(NC(=O)c2cccc(-n3cccc3)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.6 %

Procedure:
83 mg of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-aminobenzylamine and 100 mg of 3-(1-pyrrolyl)benzoic acid were dissolved in a mixture of 1 ml of methylene chloride and 2 ml of tetrahydrofuran, and 92 mg of N,N'-dicyclohexylcarbodiimide (DCC) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated under reduced pressure, and the residue was dissolved in methylene chloride. The insoluble material was separated by filtration, and washed successively with a 5% aqueous solution of sodium hydrogen carbonate, 5% hydrochloric acid and a saturated aqueous solution of sodium chloride. It was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography [Wakogel C-200, 20 g; eluting solvent: hexane/-ethyl acetate =10/1 → 3/1] to give 98 mg (yield 61%) of the captioned compound as a pale yellow oil.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH2:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22]2)[CH3:18]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:22]1[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([CH2:17][CH3:18])[CH:20]=2)[NH:24][C:23]1=[O:28])([CH3:3])[CH3:2]
Reactant: CCc1ccc2c(c1)CC(=O)N2
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: CCc1ccc2c(c1)C(=Cc1cc(C(C)C)c(OC)c(C(C)C)c1)C(=O)N2

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-ethyl-2-oxindole to give 0.3 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-5-ethyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:24]=[CH:25][C:26]=1[C:27]1([OH:30])[CH2:29][CH2:28]1>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:32]([NH:31][C:23]3[CH:24]=[CH:25][C:26]([C:27]4([OH:30])[CH2:28][CH2:29]4)=[C:21]([F:20])[CH:22]=3)=[O:33])=[CH:12][C:11]([C:16]([F:17])([F:18])[F:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: O=C(Nc1ccc(C2(O)CC2)c(F)c1)Oc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(C2(O)CC2)c(F)c1
Reaction time: 8 h
Yield: 43.2 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (0.141 mg, 0.45 mmol, 1.0 eq) in DCM (5 mL) was added TEA (0.137 mg, 1.35 mmol, 3.0 eq) followed by phenyl 3-fluoro-4-(1-hydroxycyclopropyl)-phenylcarbamate (0.130 mg, 0.45 mmol, 1.0 eq) at RT and stirred overnight. The reaction mixture was diluted with DCM (20 mL), washed with water (10 mL), brine (5 mL), dried over anhydrous Na2SO4 and the solvents evaporated under vacuum. Crude product was purified by CC by using EtOAc/PE (1:1) to get 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(1-hydroxycyclopropyl)-phenyl)urea (0.0912 g; 43%) as pale yellow solid (TLC system: EtOAc/PE (3:1); Rf: 0.45).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O[CH:29]1CCCNC1.CCN(C(C)C)C(C)C>CC(O)C>[Br:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:29][CH2:25][CH:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=1)=[O:8]
Reactant: OC1CCCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC(O)C2)c(Br)c1
Temperature: 25 °C

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Example 35, 1 g, 2.53 mmol), 3-hydroxypiperidine (307 mg, 3.03 mmol) and DIPEA (883 μL, 5.06 mmol) in iPrOH (2528 μL) were added to a MW vial and subjected to MW irradiation at 140° C. for 60 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure, treated with 0.5 M HCl (25 mL) and extracted with EtOAc. The combined extracts were washed with HCl 0.5 M, brine, dried over MgSO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (Silica gel column, 24 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1)), from 15% to 60% EtOAc-EtOH+0.1% NH4OH (9:1)) to afford the title compound as a white foam. UPLC-MS (condition 1) tR=2.89 min, m/z=460.0-462.0 [M+H]+, m/z=458.0-460.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.27-1.45 (m, 1H) 1.46-1.66 (m, 1H) 1.73-1.87 (m, 1H) 1.89-2.01 (m, 1H) 2.74 (dd, J=12.23, 9.29 Hz, 1H) 2.92 (t, J=10.64 Hz, 1H) 3.56-3.70 (m, 1H) 3.70-3.81 (m, 1H) 3.91 (dd, J=12.10, 3.30 Hz, 1H) 4.87 (d, J=4.40 Hz, 1H) 7.36 (d, J=8.56 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.42 (d, J=1.96 Hz, 1H) 8.76 (d, J=1.96 Hz, 1H) 10.37 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[C:15]([O:17]C)[C:14]([Cl:19])=[C:13]([Cl:20])[C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>O>[Cl:19][C:14]1[C:15]([OH:17])=[CH:16][C:9]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:12][S:11][C:10]=2[C:13]=1[Cl:20]
Reactant: COc1cc2c(-c3ccc(Cl)cc3)csc2c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1cc2c(-c3ccc(Cl)cc3)csc2c(Cl)c1Cl
Yield: 78.2 %

Procedure:
A mixture of 200 mg of 3-(4-chlorophenyl)-6,7-dichloro-5-methoxybenzo[b]thiophene and 1.77 g of pyridine hydrochloride is stirred and heated at 195°-205° for two and one half hours. The reaction is cooled and 20 ml of water is added. The resulting solid is collected on a filter and washed with 1N hydrochloric acid. The product is chromatographed on a silica gel-hexane column using 3:1 hexane/ether as elutent. The product is isolated and recrystallized from acetone-hexane to give 150 mg of 6,7-dichloro-3-(4-chlorophenyl)-5-hydroxybenzo[b]thiophene as a white powder, mp 174°-176°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5](N(OC)C)=[O:6].Br[Mg][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([F:25])[CH:18]=1>>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:5]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([F:25])[CH:18]=2)=[O:6])[CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc([Mg]Br)cc1F
Reactant: CON(C)C(=O)c1cccc(Cl)c1F
Product: COc1ccc(C(=O)c2cccc(Cl)c2F)cc1F

Procedure:
Prepared according to Method A step B from 3-chloro-2-fluoro-N-methoxy-N-methylbenzamide (4.0 g, 18.4 mmol) and bromo(3-fluoro-4-methoxyphenyl)magnesium (100 mL, 2M in diethyl ether). The title compound was obtained as a white solid (1.65 g, 5.85 mmol, 32%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].C(N(CC)CC)C.[C:19]([C:23](Cl)=[O:24])([Cl:22])([Cl:21])[Cl:20]>C1COCC1>[Cl:20][C:19]([Cl:22])([Cl:21])[C:23]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5])=[O:24]
Reactant: COc1cccc(N)c1C=O
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)C(Cl)(Cl)Cl)c1C=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 2-Amino-6-methoxy-benzaldehyde (6.00 g, 0.04 mol) and triethylamine (4.4 g, 0.044 mol) is dissolved in THF (20 mL) and cooled to 0° C., then CCl3COCl (7.95 g, 0.044 mol) is added and stirred at 25° C. for 24 h. The mixture is extracted from water with ethylacetate to give the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17][SH:18])=[CH:13][CH:12]=1.CC[O-].[Na+]>C(O)C>[CH2:17]([S:18][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1)[C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: SCc1ccccc1
Reactant: Cc1nc(Cl)nc(C)c1Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(SCc2ccccc2)nc(C)c1Br
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 94 %

Procedure:
2-Chloro-4,6-dimethyl-5-bromopyrimidine (10 mmol) was added to a solution of benzylthiol (11 mmol) and 0.138 M NaOEt in ethanol (80 ml). The mixture was stirred at room temperature for 70 min and then heated under reflux for 40 min. The solvent was then distilled off, the residue extracted with chloroform (50 ml), the chloroform solution washed with 2 M NaOH and the dried (MgSO4) solution evaporated to leave the sulfide which was purified by distillation; yield 94%, b.p. 232°-234° C./15 mmHg. 1H NMR (Cl3CF): δ2.50 (Me-4, Me-6), 4.26 (CH2), 7.20 (Ph).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1ccc(-c2nc(-c3cccnc3)no2)c(F)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,4-difluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.23-7.36 (m, 2 H), 7.64 (ddd, J=8.1, 5.0, 0.8 Hz, 1 H), 8.35 (td, J=8.5, 6.4 Hz, 1 H), 8.56 (dt, J=7.8, 1.9 Hz, 1 H), 8.74 (dd, J=5.1, 1.7 Hz, 1 H), 9.30 (dd, J=2.2, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[O:5][CH2:6][CH2:7][NH:8][CH:9]([CH3:11])[CH3:10].[C:16](Cl)([Cl:18])=[O:17].C1C=CC=CC=1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[O:5][CH2:6][CH2:7][N:8]([CH:9]([CH3:11])[CH3:10])[C:16]([Cl:18])=[O:17]
Reactant: O=C(Cl)Cl
Reactant: CC(C)NCCOc1cc(Cl)cc(Cl)c1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCl
Solvent: c1ccccc1
Product: CC(C)N(CCOc1cc(Cl)cc(Cl)c1)C(=O)Cl

Procedure:
A solution of 4.53 g (0.018 mole) of 2-(3,5-dichlorophenoxy)-N-(1-methylethyl)ethanamine (oil obtained in Preparation 1), 3.92 g (0.040 moles) phosgene in 21 ml solution of benzene and 3.92 g (0.018 mole) of 1,8-bis(dimethylamino)naphthalene (proton sponge) in 200 ml of methylene chloride was stirred overnight at room temperature. The reaction mixture was extracted with 1N sulfuric acid and the methylene chloride layer thereafter dried over sodium sulfate-sodium carbonate. Evaporation of solvent gave an oil which, when triturated with hexane, gave 1.91 g (34.2%) g of solid. The solid forms a gum on exposure to air which prevents measurement of melting point by conventional means.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)P(N(C)C)(N(C)C)=O.[OH-].[Na+]>[CH2:17]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:11][C:2]1=[O:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CC(C(=O)O)c1cc(=O)[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CC(C(=O)O)c1cc(=O)n(Cc2ccccc2)c2ccccc12
Yield: 39 %

Procedure:
α-(1,2-Dihydro-2-oxoquinol-4-yl)propionic acid (217 mg.) was dissolved in a mixture of hexamethylphosphoramide (2 ml.) and 2N-sodium hydroxide (2 ml.). A solution of benzyl bromide (0.528 ml.) in hexamethylphosphoramide (2 ml.) was added dropwise to the stirred solution during 2 hours. The mixture was then poured into water (10 ml.), and the resulting mixture washed with chloroform (3 × 5 ml.). The aqueous solution was acidifed to pH 1 with concentrated hydrochloric acid, and the resulting mixture was filtered and the white solid residue washed with water and dried in vacuo over phosphorus pentoxide. The solid was crystallised from ethanol to give α-(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)propionic acid, m.p. 178°-180° C. (decomposition), in 39% yield.
Reaction SMILES: [F:1][C:2]1[N:3]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1.C([Li])(C)(C)C.C1(C)C=CC(S([N:40]=[N+:41]=[N-:42])(=O)=O)=CC=1.Cl[Si](C)(C)C>C1COCC1.C1(C)C=CC=CC=1>[N:40]([C:5]1[N:6]=[C:2]([F:1])[N:3]([C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:4]=1)=[N+:41]=[N-:42]
Reactant: Fc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: C[Si](C)(C)Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=Nc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
A solution of 2-fluoro-1-triphenylmethylimidazole in THF was treated with t-butyllithium at -70° for 2 hours. A solution of toluene-p-sulphonyl azide in toluene was added, followed after 10 minutes by chlorotrimethylsilane, and the mixture allowed to come to 0°. Work-up and chromatography on magnesium silicate gave 4-azido-2-fluoro-1-triphenylmethylimidazole. This was dissolved in ether and treated with triphenylphosphine at 25°, to precipitate 2-fluoro-1-triphenylmethyl-4-(triphenylphosphimino)imidazole. A solution of this compound in EtOAc was treated for 10 minutes at 25° with propionyl chloride. Aqueous work-up, followed by magnesium silicate chromatography gave 2-fluoro-4-propionylamino-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 1.05 (t, 3H); 2.2 (q, 2H); 6.95 (s, 1H); 7.05-7.4 (m, 15H); 9.05 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:27][C:28]([NH2:30])=[S:29])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1.C(OCC)C>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:27][C:28]2[S:29][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=3)[N:30]=2)[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: COc1cccc(C(=O)CBr)c1
Solvent: CCOCC
Solvent: CCO
Product: COc1cccc(-c2csc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)n2)c1
Yield: 100.2 %

Procedure:
The title compound was prepared in analogy to example 1 step e) from 77 mg (0.33 mmol) 2-bromo-3′-methoxyacetophenon and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The solvent was evaporated under reduced pressure and the crude reaction was stirred with diethyl ether and little ethanol for 15 minutes at room temperature. The product was filtered off and dried to yield 118 mg (100%) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-(3-methoxy-phenyl)-thiazol-2-yl]-amine as a light green solid. MS ISP (m/e): 393.2 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.72 (s, 1H), 9.31 (s, 1H), 8.06 (s, 1H), 7.69 (s, 1H), 7.54-7.51 (m, 4H), 7.35 (t, 1H), 7.28 (d, 1H), 6.90 (d, 1H), 3.93 (s, 3H), 3.81 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:25])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:11]=[CH:10][CH:9]=2)=[O:4].[NH2:26][C@H:27]([C:29]([OH:31])=[O:30])[CH3:28].C[O-].[Na+]>COCCO>[CH:20]1([CH2:19][CH2:18][CH2:17][O:16][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[C:14]([OH:15])=[C:5]([C:3]([NH:26][C@@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:4])[C:6](=[O:25])[O:7]3)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)c1c(O)c2c(OCCCC3CCCC3)cccc2oc1=O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: C[C@H](NC(=O)c1c(O)c2c(OCCCC3CCCC3)cccc2oc1=O)C(=O)O
Yield: 77 %

Procedure:
A mixture of 5-(3-cyclopentyl-propoxy)-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (110 mg, 0.32 mmol) and L-alanine (424 mg, 4.76 mmol) in 2-methoxyethanol (9 mL) was added sodium methoxide (207 mg, 3.84 mmol). Resulting mixture was refluxed overnight and concentrated. Residue was dissolved in water (75 mL) and extracted with (1/1) EtOAc/hexanes which was discarded. The aqueous layer was acidified using 1 N HCl to pH=3-4 and extracted with EtOAc. Organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated to provide the title compound (99.4 mg). MS ESI(−) m/e: 402.10 (M−1).
Reaction SMILES: [CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[S:15])[NH:7][C:6]3[C:16]([CH3:20])=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:3][CH2:2]1.[H-].[Na+].IC.[CH2:25](O)C>CN(C)C=O>[CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8]([S:15][CH3:25])=[N:7][C:6]3[C:16]([CH3:20])=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:3][CH2:2]1
Reactant: Cc1ccnc2c1NC(=S)c1cccnc1N2C1CC1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSC1=Nc2c(C)ccnc2N(C2CC2)c2ncccc21
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a warm (40° C.) solution of 1.0 g (3.54 mmol) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-thione in 25 mL of dry dimethylformamide under argon was added 200 mg (4.43 mmol) of a 60% sodium hydride on mineral oil dispersion. The suspension was heated at 60° for 30 min., cooled to 40° C., and 0.3 mL (4.43 mmol) of iodomethane was added in one portion. After stirring the mixture for 1 hr at room temperature, ethanol was added dropwise until bubbling ceased. The mixture was then poured over 200 mL of water, and the product was extracted with 2×200 mL of ethyl ether. The combined organics were washed with 300 mL of water, dried (Na2SO4), and concentrated. The resulting reddish solid was flash chromatographed over silica gel (eluted with 83% methylene chloride/ethyl acetate) to give a yellow solid. Recrystallization from ethyl ether/petroleum ether gave 350 mg of the title compound, m.p. 173°-177° C.