Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)(=[O:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[C:2]([C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)(=[O:4])[CH3:3]
Reactant: CC(=O)c1ccc(O)c2ncccc12
Reactant: ClCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)c2ncccc12
Reaction time: 4.5 h
Yield: 57.1 %

Procedure:
27 g of 5-acetyl-8-hydroxyquinoline hydrochloride are dissolved in 540 ml of anhydrous dimethylformamide and 50 g of powdered potassium carbonate are added thereto. 18.4 g of benzyl chloride are added to the mixture at 50° C. under an argon atmosphere, and the mixture is stirred at the same temperature for 4.5 hours and then further stirred at room temperature for 1.5 hours. After the reaction, water is added to the mixture, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, a saturated sodium chloride solution, dried and then evaporated under reduced pressure to remove ethyl acetate. The residue is recrystallized from ethanol. 19.1 g of 5-acetyl-8-benzyloxyquinoline are obtained as brownish prisms. 6.35 g of said product are further recovered from the mother liquor.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH:12]1([C:18]2[CH:23]=[CH:22][C:21]([NH:24][CH2:25][C:26]3[CH:39]=[CH:38][C:29]([C:30]([NH:32][C:33]4[N:34]=[N:35][NH:36][N:37]=4)=[O:31])=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>ClC(Cl)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:11])[N:24]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([NH:32][C:33]3[N:34]=[N:35][NH:36][N:37]=3)=[O:31])=[CH:38][CH:39]=2)[C:21]2[CH:20]=[CH:19][C:18]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:23][CH:22]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: O=C(Nc1nn[nH]n1)c1ccc(CNc2ccc(C3CCCCC3)cc2)cc1
Reactant: N#Cc1cccc(N=C=O)c1
Solvent: CC(Cl)Cl
Product: N#Cc1cccc(NC(=O)N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)c2ccc(C3CCCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
200 μmol 3-cyanophenylisocyanate dissolved in 500 μL dichloroethane was added to the above resin bound 4-[(4-cyclohexylphenylamino)methyl]-N-(2H-tetrazol-5-yl)benzamide (50 mg). Shaking the mixture for 5 hours at 25° C. followed by filtration and washing of the resin with 2×1 mL dichloromethane, 4×1 mL DMF, 2×1 mL H2O, 3×mL THF and 3×1 mL dichloromethane afforded the resin bound title compound.
Reaction SMILES: [CH3:1]C1C=CC(S(O)(=O)=O)=CC=1.[C:12]1(/[C:18](/[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C[O-].[Na+]>[CH3:1][O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]/[CH:19]=[C:18](\[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)/[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COCCCCC/C=C(\c1ccccc1)c1cccnc1
Reaction time: 72 h
Yield: 75 %

Procedure:
p-Toluenesulfonate of (E)-7-phenyl-7-(3-pyridyl)-6-hepten-1-ol (0.2 g, 0.5 mmole) was dissolved in a methanolic solution (1 ml) of 28% sodium methoxide and the solution was allowed to stand at room temperature for 3 days. To the reaction mixture was added water (10 ml) and the product was extracted twice with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography using isopropyl ether-ethyl acetate (1:1) as the developing solvent to give (E)-1-methoxy-7-phenyl-7-(3-pyridyl)-6-heptene (0.1 g, 75%) (Compound I-37) as an oil.
Reaction SMILES: [NH2:1]/[C:2](=[N:16]\[OH:17])/[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH2:18]([O:25][C:26]([NH:28][C@H:29]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:30](O)=[O:31])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[NH2:1]/[C:2](/[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[N:16]\[O:17][C:30](=[O:31])[C@@H:29]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH:28][C:26](=[O:27])[O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(N[C@@H](C(=O)O)c1ccccc1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1/C(N)=N/O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1/C(N)=N/OC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccccc1

Procedure:
The title compound was prepared by a similar method to Preparation 5 from tert-butyl (Z)-(2S)-2-[amino(hydroxyimino)methyl]-1-piperidinecarboxylate [see Preparation 4] and (2R)-2-{[(benzyloxy)carbonyl]amino}-2-phenylethanoic acid to afford tert-butyl (2S)-2-[(Z,5R)-1-amino-4,7-dioxo-5,9-diphenyl-3,8-dioxa-2,6-diaza-1-nonen-1-yl]-1-piperidinecarboxylate as an oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:36][CH:37]2[CH2:39][CH2:38]2)[C:6]2[N:11]=[C:10]3[N:12]([CH3:16])[C:13]([CH3:15])=[N:14][C:9]3=[CH:8][C:7]=2[CH2:17][N:18]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:19]#[N:20])[CH2:3][CH2:2]1.[N-:40]=[N+:41]=[N-:42].[Na+].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[F:35][C:32]([F:33])([F:34])[C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=1)[CH2:21][N:18]([CH2:17][C:7]1[CH:8]=[C:9]2[N:14]=[C:13]([CH3:15])[N:12]([CH3:16])[C:10]2=[N:11][C:6]=1[N:5]([CH2:4][CH:1]1[CH2:2][CH2:3]1)[CH2:36][CH:37]1[CH2:39][CH2:38]1)[C:19]1[N:40]=[N:41][NH:42][N:20]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nc2cc(CN(C#N)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c(N(CC3CC3)CC3CC3)nc2n1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc2cc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nn[nH]n3)c(N(CC3CC3)CC3CC3)nc2n1C
Temperature: 90 °C
Yield: 926.6 %

Procedure:
A mixture of [5-(bis-cyclopropylmethyl-amino)-2,3-dimethyl-3H-imidazo[4,5-b]pyridin-6-ylmethyl]-(3,5-bis-trifluoromethyl-benzyl)-cyanamide (0.220 g, 0.04 mmol), sodium azide (0.130 g, 2 mmol.) and ammonium chloride (0.106 g, 2 mmol) were taken in DMF (15 mL) and heated at 90° C. for 2 h. The reaction mixture was taken in ethyl acetate (250 mL) and washed with water (250 mL×4) and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 0.220 g of colorless gummy liquid.
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([NH:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1)=[O:4].[CH3:19]I>>[CH3:1][N:2]([CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([N:5]([CH3:19])[C:6]1[CH:10]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[O:8][N:7]=1)=[O:4]
Reactant: CCCCN(C)C(=O)Nc1cc(C(C)(C)C)on1
Reactant: CI
Product: CCCCN(C)C(=O)N(C)c1cc(C(C)(C)C)on1

Procedure:
The reaction is effected as in Example 171 by using 1-methyl-1-butyl-3-(5-t-butyl-3-isoxazolyl)urea and methyl iodide to give 1,3-dimethyl-1-butyl-3-(5-t-butyl-3-isoxazolyl)urea as an oil boiling at 130° to 135° C (bath temperature)/0.25 mm Hg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](F)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([NH2:19])[CH2:17][NH2:18]>>[Br:1][C:2]1[N:3]=[C:4]([NH:18][CH2:17][CH2:16][NH2:19])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(F)nc(Br)c1
Reactant: NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(Br)nc(NCCN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-bromo-6-fluoro-4-methyl-pyridine (380 mg, 2 mmol) was added potassium carbonate (552 mg, 4 mmol) followed by ethylenediamine (3 ml) and the resulting mixture was stirred art room temperature for two hours. The mixture was filtered through kieselguhr and the filtrate was evaporated to dryness under reduced pressure to yield 256 mg (1.11 mmol, 56%) MS(ESI) m/z=230.0 [M+1]+.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([N:19]=[C:20]=[S:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[C:1]1([N:7]2[CH2:8][C:9](=[O:11])[N:19]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:20]2=[S:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CNc1ccccc1
Reactant: S=C=NCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C1CN(c2ccccc2)C(=S)N1Cc1ccccc1
Reaction time: 8 h
Yield: 20 %

Procedure:
A mixture containing 30.2 g (0.2 M) of N-phenyl glycine, 37.2 g (0.25M) of benzylisothiocyanate and 80 ml of toluene was refluxed for 5 hours and allowed to stand at room temperature overnight. The product was washed with toluene and recrystallized from ethanol to produce 12 g (0.04 mole) of the above-identified product having a melting point of 103° C.
Reaction SMILES: O.OO.N[C:5]([NH2:7])=[O:6].[OH-].[Na+].[C:10]([O:14][C:15]([N:17]1[CH2:42][CH2:41][C:20]2([CH2:23][N:22]([C@H:24]3[C:32]4[C:27](=[CH:28][C:29]([C:33]5[CH:34]=[N:35][C:36](C#N)=[CH:37][CH:38]=5)=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[CH2:21]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CCO>[C:10]([O:14][C:15]([N:17]1[CH2:42][CH2:41][C:20]2([CH2:23][N:22]([C@H:24]3[C:32]4[C:27](=[CH:28][C:29]([C:33]5[CH:34]=[N:35][C:36]([C:5](=[O:6])[NH2:7])=[CH:37][CH:38]=5)=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[CH2:21]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: NC(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-c4ccc(C#N)nc4)ccc31)C2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-c4ccc(C(N)=O)nc4)ccc31)C2
Temperature: 25 °C
Yield: 60.2 %

Procedure:
To a solution of water (150 mL) and urea hydrogen peroxide (916 mg, 9.45 mmol) was added sodium hydroxide (220 mg, 5.51 mmol) and the reaction was stirred at room temperature. Once a clear solution was obtained, the reaction was placed in an ice bath and fitted with an addition funnel. A solution of 2-[(R)-5-(6-cyano-pyridin-3-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (4-1c, 700 mg, 1.58 mmol) in 50 mL EtOH was added dropwise via the funnel over 30 minutes. The reaction was warmed to room temperature and was stirred overnight. The reaction mixture (a white suspension) was filtered and the solids were washed with 50 mL water and air-dried to give 440 mg (60%) of the title compound as an off-white powder. MS (ES+) 463.1 (M+H)+. 1H NMR (DMSO-d6) δ 1.39 (s, 9H), 1.54-1.62 (m, 4H), 1.81-1.91 (m, 1H), 2.06 (dd, 1H), 2.76-2.87 (m, 1H), 2.94-3.02 (m, 3H), 3.10 (d, 2H), 3.24 (br s, 4H), 3.86 (dd, 1H), 7.40 (d, 1H), 7.55 (d, 1H), 7.62-7.68 (m, 2H), 8.09 (d, 1H), 8.12 (br s, 1H), 8.22 (dd, 1H), 8.89 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>ClCCCl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:3]=1
Reactant: C1CCNC1
Reactant: O=Cc1cncc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Brc1cncc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-3-pyridinecarboxaldehyde in 20 mL of 1,2-dichloroethane are successively added, under argon, 4.55 g of sodium triacetoxyborohydride and 0.94 mL of pyrrolidine. The reaction mixture is stirred at room temperature for 3 hours and then washed with saturated sodium hydrogen carbonate solution, with water and with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of ethyl acetate and cyclohexane (80/20 by volume) to give 1.4 g of 3-Bromo-5-pyrrolidin-1-ylmethylpyridine in the form of a pale yellow oil.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.[OH:30][CH2:31][CH:32]1[CH2:35][NH:34][CH2:33]1>C(Cl)Cl.C(Cl)(Cl)Cl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([N:34]1[CH2:35][CH:32]([CH2:31][OH:30])[CH2:33]1)=[N:6]2
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: OCC1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(CO)C3)nc2c1C#N
Yield: 73.4 %

Procedure:
Under nitrogen atmosphere, 2-chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (240 mg, 0.84 mmol) was dissolved in methylene chloride (10 ml), then diisopropylethylamine (584 μl, 3.35 mmol) and 3-hydroxymethylazetidine (206 mg, 1.67 mmol) dissolved in methylene chloride (5 ml) were added, followed by heating under reflux in a sealed tube for 5 hours. After cooling, diluting with chloroform and washing with water, the organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography. The eluate with chloroform/methanol (10:1, v/v) gave the entitled compound (208 mg, 74%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][CH:6]=[CH:5]2.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1cc2ncccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4cccnc4cc3OC)c2cc1OC
Temperature: 155 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
6-Hydroxy-7-methoxyquinoline (65 mg), 4-chloro-6,7-dimethoxyquinoline (100 mg), and 4-dimethylaminopyridine (148 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 155° C. overnight. The reaction solution was cooled to room temperature. Water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (134 mg, yield 100%).
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@@H:22]([C:24](=[O:38])[N:25]([CH:35]4[CH2:37][CH2:36]4)[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=4[Cl:34])[CH2:21][C@@H:20]([NH2:39])[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.Cl.[C:41]([CH2:45][C:46](Cl)=[O:47])([CH3:44])([CH3:43])[CH3:42]>CC#N>[CH:35]1([N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[C:24]([C@H:22]2[CH2:21][C@@H:20]([NH:39][C:46](=[O:47])[CH2:45][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:19][NH:18][CH2:23]2)=[O:38])[CH2:36][CH2:37]1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: N[C@@H]1C[C@H](C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Agent: Cl
Solvent: CC#N
Product: CC(C)(C)CC(=O)N[C@H]1CNC[C@@H](C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)C1

Procedure:
The title compound is prepared analogously as described in Example 61 using (3R*,5S*)-3-amino-5-[cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester; hydrochloride and tert-butyl acetyl chloride. MS (LC-MS): 440.5/442.4 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.28 min.
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:16])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[CH2:18][C:19]([C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20]>ClCCl>[C:8]([O:16][CH2:18][C:19]([C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccccc1
Reactant: CN(C=O)c1ccccc1C(=O)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C=O)c1ccccc1C(=O)COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (362.8 ml) was added to a stirred mixture of benzoic acid (239.1 g) and dichloromethane (1120 ml) at 0° and the resultant solution was added dropwise over a period of 1 hour to the solution of 2'-(2-chloroacetyl)-N-methylformanilide under nitrogen whilst maintaining the temperature below 5°. The resulting solution was stirred overnight at ambient temperature, washed with water (2×1250 ml), dried over magnesium sulphate and the solvent removed by distillation at 50° to give a solid residue. Trituration with petroleum ether (b.p. 60°-80°, 1 1) gave the novel compound 2-[2-(N-methylformamido)phenyl]-2-oxoethyl benzoate, m.p. 100°-102°.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[NH:31]1[CH2:36][CH2:35][S:34][CH2:33][CH2:32]1>>[C:24]1([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[N:6]=[CH:5][C:4]([C:3]([N:31]5[CH2:36][CH2:35][S:34][CH2:33][CH2:32]5)=[O:2])=[CH:9][CH:8]=4)[CH:14]=3)=[C:19]([C:20]([F:22])([F:23])[F:21])[O:18][N:17]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Reactant: C1CSCCN1
Product: O=C(c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1)N1CCSCC1
Yield: 51 %

Procedure:
As described for Example 18, 6-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-nicotinic acid methyl ester (70 mg, 0.17 mmol), was converted, using thiomorpholine instead of cyclopropanemethylamine, to the title compound (42 mg, 51%) which was obtained as a colourless oil. MS: m/e=486.0 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:23]=[CH:22][C:11]([O:12][CH2:13][C:14]([NH:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)=[O:15])=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C.I.[NH2:34][C:35]1[C:36]([C:43]([NH:45][C:46](=[NH:49])SC)=[O:44])=[N:37][C:38]([Cl:42])=[C:39]([NH2:41])[N:40]=1>C(O)C.CO>[NH2:34][C:35]1[C:36]([C:43]([N:45]=[C:46]([NH2:49])[NH:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13][C:14]([NH:16][C:17]3[NH:21][CH:20]=[CH:19][N:18]=3)=[O:15])=[CH:10][CH:9]=2)=[O:44])=[N:37][C:38]([Cl:42])=[C:39]([NH2:41])[N:40]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCCCc1ccc(OCC(=O)Nc2ncc[nH]2)cc1
Agent: Cl
Agent: I
Solvent: CCO
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)NCCCCc1ccc(OCC(=O)Nc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.5 %

Procedure:
A solution of 2-[4-(4-aminobutyl)phenoxy]-N-(1H-imidazol-2-yl)acetamide dihydrochloride 35 (99 mg, 0.27 mmol) and diisopropylethylamine (0.27 mL, 1.53 mmol) in absolute ethanol (4 mL) and anhydrous methanol (3 mL) was stirred at 70° C. for 30 min, after which 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (130 mg, 0.34 mmol) was added in one portion. The reaction mixture was stirred for 3 h and then cooled to room temperature. The yellow insolubles were removed by suction filtration and the liquid filtrate was concentrated by rotary evaporation. The crude residue was purified by flash silica gel column chromatography eluting with dichloromethane/methanol/concentrated ammonium hydroxide (200:10:0, 200:10:1, 150:10:1, and 100:10:1, v/v) to give 2-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}phenoxy)-N-(1H-imidazol-2-yl)-acetamide as a yellow solid (44 mg, 29% yield). The free base thus obtained was dissolved in methanol and treated with 4 drops of 4 N aqueous HCl. The solution was concentrated under reduced pressure and further dried under vacuum to give the final compound 36. mp 172–174° C. 1H NMR (300 MHz, CD3OD) δ 1.61–1.77 (m, 4H), 2.58–2.70 (m, 2H), 3.32-3.40 (m, 2H), 4.80 (s, 2H), 7.00 (d, 2H), 7.18 (d, 2H), 7.20 (s, 2H). m/z (ESI): 501 [C21H25ClN10O3+H]+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:18])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25].[H-].[Na+]>CN(C)C=O>[C:1]1([C:7]2[NH:8][C:9](=[O:18])[N:10]([CH2:20][C:21]3[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=3)[C:24]#[N:25])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: N#Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(Cn2c(-c3ccccc3)c(-c3ccccc3)[nH]c2=O)c1

Procedure:
In a manner similar to Preparation 1 above, 2,3-dihydro-4,5-diphenyl-1H-imidazol-2-one (1.2 g, 5 mmol) was reacted with 3-(bromomethyl)benzonitrile (0.39 g, 2 mmol) and sodium hydride (0.18 g, 5 mmol) in dimethylformamide (20 mL) to give 3-[(2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl)methyl]benzonitrile after chromatography on silica; NMR (DMSO-d6) 11.02 (s,1), 7.4 (m,4), 7.3 (m,2), 7.2 (m,7), 4.75 (s,2) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][S:16][C:17]3[NH:18][CH:19]=[C:20]([CH2:24][C:25]4[CH:26]=[N:27][C:28]([O:31]C)=[N:29][CH:30]=4)[C:21](=[O:23])[N:22]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].B1(Br)OC2C(=CC=CC=2)O1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][S:16][C:17]3[NH:18][CH:19]=[C:20]([CH2:24][C:25]4[CH:30]=[N:29][C:28](=[O:31])[NH:27][CH:26]=4)[C:21](=[O:23])[N:22]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:33]([F:35])([F:36])[F:34]
Reactant: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Agent: BrB1Oc2ccccc2O1
Solvent: ClCCl
Product: O=c1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)c[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.3 %

Procedure:
A mixture of 2-{[(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]thio}-5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-4(1H)-pyrimidinone and B-bromocatecholborane (357 mg, 1.795 mmol) in DCM (10 mL) was stirred at room temperature for 24 h. Purification via MDAP then afforded the title compound (24 mg, 25.3% yield). LCMS: rt=3.01 min, [M+H+]=521
Reaction SMILES: [C:1]([C:5]1[C:6]([O:18][CH2:19][CH3:20])=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Zn+2:36]>CO>[C:1]([C:5]1[C:6]([O:18][CH2:19][CH3:20])=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8]([O-:10])=[O:9])([CH3:4])([CH3:2])[CH3:3].[Zn+2:36].[C:1]([C:5]1[C:6]([O:18][CH2:19][CH3:20])=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8]([O-:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1c(C(=O)O)cc(C(C)(C)C)cc1C(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOc1c(C(=O)[O-])cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Five parts of 3,5-di-t-butyl-2-ethoxybenzoic acid was dissolved in 80 parts of methyl alcohol, followed by the addition of an aqueous solution of 1.1 parts of 96% potassium hydroxide in 10 parts of water. The resulting mixture was heated to 60° C. An aqueous solution of 2.6 parts of zinc sulfate heptahydrate in 10 parts of water was dropped into the resulting mixture over a period of 15 minutes. After the completion of the dropping, the obtained mixture was stirred at that temperature for 2 hours, cooled to a room temperature and filtered to recover a white crystalline precipitate. This precipitate was dispersed in 60 parts of water, washed therewith and filtered. The filter cake was dried to give 3.9 parts of a white crystal. The melting point thereof was 178° to 180° C.