Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[S:11][C:7]=2[CH:6]=1)=[NH:4].[C:23](Cl)(=O)[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>C(O)(=O)C>[CH:18]([N:15]1[CH2:14][CH2:13][N:12]([C:10]2[S:11][C:7]3[CH:6]=[C:5]([C:3]4[N:4]=[C:23]([C:24]5[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=5)[O:1][N:2]=4)[CH:22]=[CH:21][C:8]=3[N:9]=2)[CH2:17][CH2:16]1)([CH3:19])[CH3:20]
Reactant: CC(C)N1CCN(c2nc3ccc(C(=N)NO)cc3s2)CC1
Reactant: O=C(Cl)c1ccncc1
Solvent: CC(=O)O
Product: CC(C)N1CCN(c2nc3ccc(-c4noc(-c5ccncc5)n4)cc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.6 %

Procedure:
To a solution of N-hydroxy-2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carboxamidine (1.30 g, 4.07 mmol) in acetic acid (50 mL) was added isonicotinoyl chloride (1.42 g, 10.0 mmol). The reaction mixture was stirred overnight at room temperature and then heated at refluxed for 8 h. The reaction mixture was concentrated in vacuo and the residue was dissolved into 0.5 N hydrochloric acid (40 mL). The aqueous solution was extracted with diethyl ether (3×15 mL). The organic extracts were discarded and the aqueous phase was basified to pH 13 with 4 N sodium hydroxide and then extracted with ethyl acetate (4×10 mL). The combined organic extracts were evaporated and the residue was recrystallized from a mixture of CH2Cl2 and MeOH to give 175 mg (11%) of 2-(4-isopropylpiperazin-1-yl)-6-(5-pyridin-4-yl-[1,2,4]oxadiazol-3-yl)benzothiazole.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:5]=[N:4][C:3]1=2.[CH2:25]([O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)[CH3:26].CC(C)=O>CS(C)=O>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:35][C:32]3[CH:31]=[CH:30][C:29]([C:28]([O:27][CH2:25][CH3:26])=[O:36])=[CH:34][CH:33]=3)=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(NC(=O)CCn2cnc3c(=O)[nH]cnc32)cc1
Yield: 30 %

Procedure:
165 mg (0.50 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) and 84 mg (0.50 mmol) of 4-aminobenzoic acid ethyl ester were heated together in 1.5 ml of dimethylsulfoxide at 35°-40° C. for 72 hours. A white precipitate was observed at the bottom of the flask. 10 ml acetone was added and the solid was collected by Buchner vacuum filtration. The solid was washed twice with acetone and was allowed to dry. This yielded 53 mg of 4-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]amino]benzoic acid, ethyl ester (AIT-0079) as a white solid. m.p. 265°-269° C. Yield: 30%.
Reaction SMILES: [NH2:1][CH:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1.CCOC(C)=O>[CH:9]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]([CH2:4]3)[CH:2]1[NH:1][C:12](=[O:14])[CH3:13])[CH2:8]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)NC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
A solution of 2-aminoadamantane (20 g, 108 mmol) in dry pyridine (120 mL) was treated with acetic anhydride (12 mL, 128 mmol) and stirred overnight at rt. The mixture was dilute with EtOAc and washed with water, 1 N aq phosphoric acid and brine. The organic layer was dried, filtered and concentrated to give N-(2-adamantyl)acetamide (12.5 g, 60%). 1H NMR (400 MHz, CDCl3): δ=1.57 (m, 2H), 1.67 (m, 3H), 1.72 (m, 1H), 1.77 (m, 6H), 1.85 (m, 2H), 1.94 (s, 3H), 3.97 (t, 1H), 5.78 (br, 1H).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]([C:20]2[C:21]([CH2:32][CH:33]=O)=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=O)[N:9]=[N:8]1.C([O-])(=O)C.[NH4+:48]>C(O)(=O)C>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:40])([F:39])[F:41])[CH:37]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([C:18]2[C:20]3=[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[O:23][N:22]=[C:21]3[CH:32]=[CH:33][N:48]=2)[N:9]=[N:8]1
Reactant: [NH4+]
Reactant: O=CCc1noc(-c2ccccc2Cl)c1C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(Cn2nnc(-c3nccc4noc(-c5ccccc5Cl)c34)c2-c2ccccc2)cc(C(F)(F)F)c1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
Combine [4-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbonyl]-5-(2-chloro-phenyl)-isoxazol-3-yl]-acetaldehyde (0.401 g, 0.65 mmol) and acetic acid (4.5 mL), add ammonium acetate (0.25 g, 3.2 mmol) and stir at 65° C. for 90 minutes. Concentrate, neutralize with saturated aqeous NaHCO3, extract with ether, dry over MgSO4, filter and concentrate under vacuum. Purify on chromatotron, using EtOAc/Hexane (10%-85%) to give the title compound: Exact mass 599.1, MS (IS) 600.1 (M+1), 1H NMR (CDCl3): δ 8.15 (d, J=6.6 Hz, 1H), 7.85 (s, 1H), 7.60 (m, 1H), 7.52-7.38 (m, 8H), 7.17 (m, 2H), 5.54 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Si](C)(C)C)=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:23].[I:24]Cl>ClCCl>[NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([I:24])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:23]
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)cc2)c(C)c(N)c1Cl
Reactant: ClI
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccc(I)cc2)c(C)c(N)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.4 %

Procedure:
To methyl 4-amino-3-chloro-5-methyl-6-(4-(trimethylsilyl)phenyl)picolinate (0.95 g, 2.72 mmol) in dichloromethane (9 mL) was added iodine monochloride (920 mg, 5.67 mmol) in dichloromethane (4.5 mL) dropwise. The reaction was stirred at room temperature for 4 h, then quenched with saturated aqueous sodium thiosulfate, diluted with water, and extracted with dichloromethane (3×). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography (0-30% ethyl acetate/hexanes) afforded the title compound as a red-orange solid (618 mg, 56%).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][CH3:10])[S:7][CH:8]=1.[CH:11]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[ClH:2].[ClH:1].[ClH:2].[CH:11]([N:24]1[CH2:29][CH2:28][N:27]([CH2:3][C:4]2[N:5]=[C:6]([NH:9][CH3:10])[S:7][CH:8]=2)[CH2:26][CH2:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNc1nc(CCl)cs1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1
Temperature: 70 °C
Yield: 44.5 %

Procedure:
A mixture of 4-chloromethyl-2-methylaminothiazole monohydrochloride (2.2 g), 1-benzhydrylpiperazine (2.5 g) and potassium carbonate (2.7 g) in N,N-dimethylformamide (15 ml) was stirred at 70° C. for an hour. After the reaction mixture was poured into ice-water, it was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and then evaporated to dryness to give an oil, which was transformed into its hydrochloride in a conventional manner, followed by recrystallization from a mixture of methanol and diethyl ether to obtain white crystals (1.2 g) of 4-(4-benzhydrylpiperazin-1-ylmethyl)-2-methylaminothiazole trihydrochloride, mp 225°-228° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Cl[CH2:45][C:46]1[CH:50]=[CH:49][O:48][CH:47]=1>>[CH3:43][O:42][C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:29]([CH2:45][C:46]4[CH:50]=[CH:49][O:48][CH:47]=4)[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reactant: ClCc1ccoc1
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4Cc4ccoc4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 35.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and 3-(chloromethyl)furan (J. Am. Chem. Soc. 72, 2195-2199 (1950)) to give the title compound.
Reaction SMILES: [Na].Cl.[F:3][C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[C:12](#[N:16])[C:13]([CH3:15])=[CH2:14].C>CCCCCC.C(O)C>[NH2:16][C:12]1[CH:13]([CH3:15])[CH2:14][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=2)[N:11]=1
Reactant: C=C(C)C#N
Reactant: NNc1cccc(F)c1
Agent: Cl
Agent: [Na]
Solvent: CCCCCC
Solvent: CCO
Product: CC1CN(c2cccc(F)c2)N=C1N

Procedure:
A 1.38 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 8.1 g. of m-fluorophenylhydrazine hydrochloride is added followed by 3.9 g. of methacrylonitrile. The reaction mixture is refluxed for 5 hours, then is evaporated to dryness in vacuo. Water is added to give a dark semi-solid precipitate. The aqueous is decanted then more water is added and the solid is collected by filtration. The solid is dissolved in dichloromethane and the solution is passed through a short column of a hydrous magnesium silicate. The effluent is evaporated to give an oil. The oil is dissolved in hexane, treated with activated charcoal and filtered and evaporated to give a solid. The solid is recrystallized from hexane to give 0.65 g. of the desired product as light orange prisms, m.p. 78°-80° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16](Br)[N:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)#[N:39]>C1COCC1>[NH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([C:38]#[N:39])[CH:45]=3)[N:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Nc1cc2cccnc2c(Br)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2nc(N)cc3cccnc23)c1
Temperature: 80 °C

Procedure:
To a mixture of THF (80 ml) and 2N sodium carbonate (34 ml, aqueous) is added 6-amino-8-bromo-1,7-naphthyridine (4.007 g), triphenylphosphine (0.37 g) and 3-cyanophenyl-boronic acid (3.23 g). The mixture is degassed under argon three times and then bis(di-benzylidene-acetone)palladium (0) (0.4 g) is added and the mixture is degassed under argon three more times. The mixture is heated at 80° C. under argon for 16 hours then cooled and filtered. The mixture is diluted with ethyl acetate and washed with 2N sodium hydroxide then brine. After drying over sodium sulfate the organic layer is evaporated and suspended in ether. The solid precipitate thus obtained is the title compound, which is filtered off.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([CH3:13])[CH2:8][N:7]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:21]=1.[H-].[Na+].[CH3:24]I>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:24])[C:10](=[O:12])[C:9]([F:14])([CH3:13])[CH2:8][N:7]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:21]=1
Reactant: CC1(F)CN(C2CCCCC2)c2nc(Cl)ncc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C(C)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-9-cyclohexyl-7-fluoro-7-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (313 mg, 2.85 mmol) in 10 mL of DMA was added sodium hydride (60% dispersion in mineral oil, 44 mg, 1.1 mmol) at 0° C., followed by the dropwise addition of methyl iodide (0.07 mL, 1.1 mmol). The reaction mixture was warmed up to rt and stirred for 1 h. The whole was poured into ice-water, extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4. The solution was concentrated in vacuo and used for next step reaction (330 mg). [M+H] calc'd for C15H20ClFN4O, 327. found 327.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].O[C:10](=[C:13]1C(=O)OC(C)(C)[O:15][C:14]1=O)[CH2:11][CH3:12].CCOCC>CCCCCC>[CH2:11]([C:10]1[NH:1][C:2]([CH3:8])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:14](=[O:15])[CH:13]=1)[CH3:12]
Reactant: COC(=O)/C=C(/C)N
Reactant: CCC(O)=C1C(=O)OC(C)(C)OC1=O
Solvent: CCCCCC
Solvent: CCOCC
Product: CCc1cc(=O)c(C(=O)OC)c(C)[nH]1
Temperature: 120 °C
Reaction time: 18 h
Yield: 11.8 %

Procedure:
A mixture of methyl 3-aminocrotonate (5 g) and 5-(1-hydroxypropylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10 g) (obtained as described in J. Org. Chem., 1978, 43, 2087) was heated at 120° C. for 1 hour. The residue was cooled to ambient temperature and treated with a mixture of ether and hexane (1:6 v/v; 35 ml) and allowed to stand for 18 hours. The solvent was removed by decanting and the insoluble residue purified by flash chromatography, eluting with methanol/dichloromethane (1:9 v/v) to give methyl 1,4-dihydro-6-ethyl-2-methyl-4-oxopyridine-3-carboxylate (1 g), as a yellow solid, m.p. 176°-180° C.; NMR (CDCl3): 1.2(t,3H); 2.45(s,3H), 2.45(q,2H), 3.8(s,3H), 6.3(s,1H); mass spectrum (chemical ionisation, ammonia): 196(M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=1)[C:17]([NH2:19])=[O:18].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=2)[C:17]([NH2:19])=[O:18])=[O:10])=[CH:11][CH:12]=1
Reactant: O=C(O)COc1ccc(Br)cc1
Reactant: NC(=O)c1ccnc(N)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)c1ccnc(NC(=O)COc2ccc(Br)cc2)c1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
To solution of (4-bromo-phenoxy)-acetic acid (100 mg, 0.43 mmol), 2-amino isonicotinamide (89.39 mg, 0.65 mmol) and DMAP (106 mg, 0.86 mmol) in DMF 5 ml was added PyBOP (452 mg, 0.86 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by PLC (EtoAC:Hexane:MeOH=3:6:1˜2:4:1) to afford 2-[2-(4-bromo-phenoxy)-acetylamino]-isonicotinamide as a colorless solid (0.083 g, 55% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6].C([O-])([O-])=O.[K+].[K+].[N+:14]([C:17]1[NH:18][CH:19]=[CH:20][N:21]=1)([O-:16])=[O:15]>CN(C)C=O.C(OCC)C>[CH3:6][C:5]([CH3:7])=[CH:4][CH2:3][CH2:2][N:18]1[CH:19]=[CH:20][N:21]=[C:17]1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: CC(C)=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)=CCCn1ccnc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 48 h

Procedure:
5-Bromo-2-methyl-2-pentene (25 g, 0.154 mol) was dissolved in dry dimethylformamide (DMF) (200 mL). To the solution was added K2CO3 (21.3 g, 0.154 mol) and 2-nitroimidazole (17.4 g, 0.154 mol). The mixture was stirred under N2 atmosphere at 75° C. for 48 hours. DMF was evaporated on a rotary evaporator. The yellow gummy residue was stirred with water (150 mL) to give yellow solid, which was dissolved in diethyl ether (150 mL), dried over Na2SO4 and evaporated on a rotary evaporator to yield the title product. Yield 27.8 g (92%). mp: 49-51° C. MS: (M+H)+=196, M+=195. 1H NMR (CDCl3) δ1.45 and 1.68 (s, 6H, gem-di-CH3), 2.52 (q, 2H, CH2CH═), 4.43 [t, 2H, CH2-(2-nitroimidazolyl)], 5.08 (t, 1H, CH2CH═), 7.05 and 7.14 (s, 2H, 2-nitroimidazolyl-H).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:12](Cl)(=[O:15])[CH:13]=[CH2:14].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:15])[CH:13]=[CH2:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc2ccccc12
Reactant: C=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc2c(F)cccc2c1
Yield: 195 %

Procedure:
1-fluoronaphthalene (146 mg), acryloyl chloride (110 mg), and aluminium chloride (150 mg) were reacted in dichloromethane (1 mL) at from −15° C. to room temperature for 2 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (390 mg).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][O:12][CH2:13][CH2:14][NH2:15]>CC(O)C>[CH3:11][O:12][CH2:13][CH2:14][NH:15][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: COCCN
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: CC(C)O
Product: COCCNc1ccc(C(=O)O)cn1
Yield: 19.3 %

Procedure:
A microwave vial is charged with 6-chloronicotinic acid (1 g, 6.35 mmol), 2-methoxyethylamine (1.214 mL, 13.96 mmol) and IPA (3.5 mL) sealed and irradiated in a microwave synthesizer at 180° for 40 min. The reaction was cooled, concentrated and purified by SiO2 chromatography eluting with a MeOH/DCM gradient (5% to 10% MeOH containing 0.5% HOAc) to afford 0.24 g of 6-(2-methoxy-ethylamino)-nicotinic acid (330) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH3:14])=[O:5].[C:20](=O)(OC(Cl)(Cl)Cl)[O:21]C(Cl)(Cl)Cl>C1COCC1.C(Cl)Cl>[Br:13][C:9]1[C:8]([CH3:14])=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:18]([Cl:19])[CH:17]=[CH:16][CH:15]=3)[NH:1][C:20]2=[O:21])[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(Br)cccc1NC(=O)c1cccc(Cl)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(Br)cccc1-n1c(=O)[nH]c2c(Cl)cccc2c1=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 95.1 %

Procedure:
A solution of 2-amino-N-(3-bromo-2-methylphenyl)-3-chlorobenzamide (780 mg, 2.30 mmol) in THF (20 mL) was treated with bis(trichloromethyl) carbonate (1.02 g, 3.45 mmol) and the solution stirred at room temperature for 21 h. The mixture was diluted with DCM and washed sequentially with saturated aqueous NaHCO3, water and brine. The organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (gradient from 25-50%), to give 3-(3-bromo-2-methylphenyl)-8-chloroquinazoline-2,4(1H,3H)-dione as a white solid (800 mg, 95% yield). Mass spectrum m/z 365, 367 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:29]=[C:30]([C:32]3([C:37]#[N:38])[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:31]=2)[C:26](O)=[O:27])=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:39][C:40]1[CH:45]=[CH:44][C:43]([C@H:46]([NH2:48])[CH3:47])=[CH:42][CH:41]=1.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(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:29]=[C:30]([C:32]3([C:37]#[N:38])[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:31]=2)[C:26]([NH:48][C@@H:46]([C:43]2[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=2)[CH3:47])=[O:27])=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](N)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@](C)(Cc1ccccc1)c1nnc(-c2cc(C(=O)O)cc(C3(C#N)CCCC3)c2)o1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)cc(C2(C#N)CCCC2)c1)c1ccc(F)cc1

Procedure:
A solution of 3-(5-((2R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1-cyanocyclopentyl)benzoic acid (20 mg, 0.039 mmol), (R)-1-(4-fluorophenyl)ethanamine (0.017 mL, 0.13 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (24 mg, 0.05 mmol) and diisopropylethylamine (0.024 mL, 0.14 mmol) in 0.4 mL DMF was stirred at rt overnight. Purification by reverse phase preparative HPLC (5-95% MeCN/H2O containing 0.1% TFA, C18 PRO YMC 20×150 mm) gave 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1-cyanocyclopentyl)-N—((R)-1-(4-fluorophenyl)ethyl)benzamide. 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.16 (m, 1H), 8.10 (d, J=1.5 Hz, 1H), 7.39 (m, 2H), 7.28 (m, 3H), 7.06 (m, 4H), 6.56 (d, J=7.5 Hz, 1H), 5.33 (m, 1H), 5.07 (bs, 1H), 3.59 (d, J=13.6 Hz, 1H), 3.40 (d, J=13.6 Hz, 1H), 2.55 (m, 2H), 2.16-1.98 (m, 6H), 1.72 (s, 3H), 1.64 (d, J=7.0 Hz, 3H), 1.41 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2([C:34]([O:36]CC)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1.[S:41]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[N:43]=[CH:42]1>>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[CH2:17][O:16][C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH2:6][C:5]3[CH:39]=[CH:40][C:2]([C:44]4[N:43]=[CH:42][S:41][CH:45]=4)=[CH:3][CH:4]=3)[C:8]([CH2:28][C:29]3([C:34]([OH:36])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]3)=[N:9][C:10]=2[CH:15]=1
Reactant: CC1(C)OB(c2cscn2)OC1(C)C
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)CCCC1
Product: O=C(O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(-c3cscn3)cc2)CCCC1

Procedure:
The title compound was prepared using similar methods to those in Example 97 using ethyl 1-((1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate and thiazole-4-boronic acid pinacol ester in Step A. MS (ESI): mass calcd. for C34H30N4O3S, 574.20; m/z found, 575.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.90-8.86 (m, 1H), 8.21 (d, J=8.5 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.88 (d, J=8.3 Hz, 2H), 7.86-7.82 (m, 1H), 7.78-7.72 (m, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.59-7.54 (m, 1H), 7.54-7.51 (m, 1H), 7.40-7.35 (m, 1H), 7.22-7.17 (m, 1H), 7.13-7.05 (m, 3H), 5.43 (s, 2H), 5.38 (s, 2H), 3.14 (s, 2H), 2.38-2.28 (m, 2H), 1.76-1.67 (m, 2H), 1.58-1.49 (m, 4H).