Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])(=[O:5])[CH3:4].[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26]Cl>CN(C=O)C>[C:3]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:26][CH2:25][CH2:24][N:23]([CH3:28])[CH3:22])(=[O:5])[CH3:4]
Reactant: CN(C)CCCCl
Reactant: CC(=O)N1c2ccccc2SC1c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccccc2SC1c1ccccc1OCCCN(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To the suspension of 0.26 g of sodium hydride in anhydrous DMF, the soution of 1.36 g of 3-acetyl-2-(2-hydroxyphenyl)-benzothiazoline in 5 ml of anhydrous DMF is added dropwise under nitrogen atmosphere at room temperature. After the addition, the reaction mixture is stirred for 20 minutes at room temperature. To the reaction mixture, the solution of 0.61 g of 3-dimethylaminopropyl chloride in 10 ml of anhydrous DMF is added. The reaction mixture is stirred for 2 hours at 80° C., and washed with n-hexane after cooling and poured into ice-water. The separated oil is extracted with ethyl acetate. The organic layer is washed with N--NaOH solution, water and saturated sodium chloride solution in the order named and dried over anhydrous magnesium sulfate. Ethy acetate is removed off in vacuo to give 1.0 g (56%) of the titled compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH2:7])([O-:3])=[O:2].N1C=CC=CC=1.[C:20](Cl)(=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>ClC(Cl)C>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:20](=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CCCCCCCCC(=O)Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
3,5-Dinitroaniline, 10.0 g (0.055 mole), is dissolved in 200 ml dichloroethane, containing 25 ml pyridine. The solution is stirred at room temperature while nonanoyl chloride, 10.3 g (0.058 mole), is added slowly. The solution is stirred for 2 hours. Excess pyridine is removed by washing the product with 4N hydrochloric acid. The product is obtained by crystallization at -20° C. and recrystallized from 95% ethanol. There is obtained N-(3,5-Dinitrophenyl) nonanamide (M.P. 72.5°-73.0° C.). Analysis shows 12.69% nitrogen as against a calculated value of 12.61% for C15H21N3O5.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:18]([C:19](=[O:25])[C:20]=2[O:21][CH2:22][O:23][CH3:24])=[CH:17][CH:16]=[C:15]([O:26][CH2:27][O:28][CH3:29])[CH:14]=3)=[CH:7][C:6]=1[O:30][CH2:31][O:32][CH3:33].CCN(C(C)C)C(C)C.[CH3:43][C:44]1[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1>CCOCC>[CH3:43][C:44]1[CH:49]=[CH:48][C:47]([S:50]([O:1][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[O:12][C:13]4[C:18]([C:19](=[O:25])[C:20]=3[O:21][CH2:22][O:23][CH3:24])=[CH:17][CH:16]=[C:15]([O:26][CH2:27][O:28][CH3:29])[CH:14]=4)=[CH:7][C:6]=2[O:30][CH2:31][O:32][CH3:33])(=[O:52])=[O:51])=[CH:46][CH:45]=1
Reactant: COCOc1ccc2c(=O)c(OCOC)c(-c3ccc(OCCO)c(OCOC)c3)oc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc2c(=O)c(OCOC)c(-c3ccc(OCCOS(=O)(=O)c4ccc(C)cc4)c(OCOC)c3)oc2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To 2-(4-(2-hydroxyethoxy)-3-(methoxymethoxy)phenyl)-3,7-bis(methoxymethoxy)-4H-chromen-4-one (18 mg, 0.039 mmol) and DIPEA (15 mg, 0.11 mmol) was added 4-methylbenzene-1-sulfonyl chloride (11 mg, 0.058 mmol). The mixture was stirred at rt for 15 h under Ar atmosphere and diluted with ether (30 mL). It was washed with 0.5 M HCl(2×30 mL) and water (50 mL), and dried over MgSO4 and concentrated. The crude product was chromatographed to afford 2-(4-(3,7-bis(methoxymethoxy)-4-oxo-4H-chromen-2-yl)-2-(methoxymethoxy)phenoxy)ethyl 4-methylbenzenesulfonate (AD-C-001P-WZ01079) as a yellow wax (20 mg, 83%). 1H NMR (400 MHz, CDCl3) δ 8.15 (dd, J=8.8, 2.0 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.76 (dd, J=8.4 Hz, 2.0 Hz, 2H), 7.73 (dd, J=8.4, 2.0 Hz, 1H), 7.36 (d, J=6.8 Hz, 2H), 7.27 (d, J=2.0 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 7.05 (dd, J=8.8, 2.0 Hz, 1H), 6.94 (dd, J=8.8, 2.0 Hz, 1H), 5.29 (d, J=1.6 Hz, 2H), 5.22 (d, J=2.0 Hz, 4H), 4.42 (t, J=3.0 Hz, 2H), 4.32 (t, J=3.0 Hz, 2H), 3.53 (d, J=2.4 Hz, 3H), 3.52 (d, J=2.0 Hz, 3H), 3.20 (d, J=2.4 Hz, 3H), 2.46 (s, 3H); MS (ESI) m/z 617 (M+H+).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>CN(C=O)C.CCOC(C)=O>[C:9]1([C:6]2[C:5]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)=[C:4]([NH:3][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[O:8][N:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1onc(-c2ccccc2)c1-c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C(=O)Nc1onc(-c2ccccc2)c1-c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (18 mg 0.45 mmol) is added to the solution of 2-[4-(5-Amino-3-phenyl-isoxazol4-yl)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol in DMF at 0° C. under argon atmosphere. The reaction mixture is stirred at room temperature under argon atmosphere for 30 minutes before adding isobutyryl chloride (23.8 ul, 0.23 mmol). The solution is allowed to stir for 8 hours and diluted with EtOAc. The organic layer is washed with H2O brine and dried over MgSO4. Concentration and purification by preparative TLC afford the title compound. 1HNMR 1.11 (s, 3H), 1.12 (s, 3H), 2.60 (m, 1H), 7.26 (d, 2H), 7.4 (m, 5H), 7.72 (d, 2H); ESIMS: m/z 471 (M−H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]2=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=[C:7]2[CH:6]=[N:5]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>CN(C=O)C>[CH3:3][N:4]1[C:8]2=[C:9]3[CH:15]=[CH:14][N:13]([S:22]([C:19]4[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=4)(=[O:24])=[O:23])[C:10]3=[N:11][CH:12]=[C:7]2[CH:6]=[N:5]1
Reactant: Cn1ncc2cnc3[nH]ccc3c21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnn(C)c23)cc1
Reaction time: 2 h
Yield: 43.8 %

Procedure:
To a solution of NaH (60% dispersion in mineral oil, 0.209 g, 5.23 mmol) in DMF (10 mL) at about 0° C. was added a solution of 1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.60 g, 3.5 mmol) in DMF (5 mL). The cooling bath was removed and after about 20 min, p-toluenesulfonyl chloride (0.996 g, 5.23 mmol) was added. After about 2 h at room temperature, water was added (15 mL) and the mixture was extracted with EtOAc (3×20 mL). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 5-45% EtOAc in heptane to give 1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.50 g, 44%): LC/MS (Table 2, Method d) Rt=2.20 min; MS m/z: 327 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)[CH:3]([F:5])[F:4].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[CH3:54][O:55][NH:56][CH3:57]>CN(C=O)C>[CH3:54][O:55][N:56]([CH3:57])[C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([O:6][C:2]([F:1])([F:16])[CH:3]([F:4])[F:5])[CH:8]=1
Reactant: O=C(O)c1cccc(OC(F)(F)C(F)F)c1
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cccc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(1,1,2,2-tetrafluoroethoxy)benzoic acid (10 g, 42.0 mmol) was dissolved in DMF (200 mL) and Hunig's Base (20.54 mL, 118 mmol). Benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphonium hexafluorophosphate (BOP, 27.9 g, 63.0 mmol) and N-methoxy-N-methylamine hydrochloride (4.51 g, 46.2 mmol) were added to the reaction flask, and the resulting reaction mixture was stirred at 25° C. overnight. Crude reaction mixture was concentrated and purified on a silica gel column (340 g cartridge 0-10% EtOAc/Hexanes gradient) to afford N-methoxy-N-methyl-3-(1,1,2,2-tetrafluoroethoxy)benzamide. 1H NMR (400 MHz, CDCl3) δ 3.38 (s, 3H), 3.57 (s, 3H), 5.95 (t, J=52.9, 2.9 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.58 (s, 1H), 7.63 (d, J=7.7 Hz, 1H).
Reaction SMILES: [CH:1]([N:14]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=[CH:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]=[O:24]>>[CH:1]([N:14]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=[C:15]1[CH2:23][OH:24])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=O
Reactant: COC(=O)c1cncn1C(c1ccccc1)c1ccccc1
Product: COC(=O)c1cnc(CO)n1C(c1ccccc1)c1ccccc1

Procedure:
2.9 g (0.01 mol) of 1-benzhydryl-5-methoxycarbonyl-imidazole (Example 8) and 25 cc of 50% methanolic formaldehyde solution were heated for 36 hours to 135° C. 3.15 g of 1-benzhydryl-2-hydroxymethyl-5-methoxycarbonyl-imidazole, m.p. 160° C., were obtained from the reaction mixture in an almost quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([Cl:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl.C(OCC)C>O1CCCC1>[Cl:13][C:8]1[CH:9]=[C:10]([O:11][CH3:12])[C:2]2[NH:1][C:15](=[O:17])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(Cl)cc(C(=O)O)c1N
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(Cl)cc2c(=O)oc(=O)[nH]c12
Temperature: 25 °C

Procedure:
To 2-amino-5-chloro-3-methoxybenzoic acid (0.72 g, 3.57 mmol) in anhydrous tetrahydrofuran (15 mL) was added triphosgene (0.53 g, 1.8 mmol). The mixture was heated to refluxed under a nitrogen atmosphere for 2.5 hours. The resulting solution was cooled to ambient temperature, diethyl ether (10 mL) was added, which caused a solid to precipitate. The solid was collected by filtration and washed with more diethyl ether to yield 6-chloro-8-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione. MS (m/z): 226.3, 228.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]1([CH:18]([C:21]2[CH:26]=[CH:25][N:24]=[N:23][CH:22]=2)[CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:21]1[CH:26]=[CH:25][N:24]=[N:23][CH:22]=1)=[O:6]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: NCC(c1ccccc1)c1ccnnc1
Product: O=C(NCC(c1ccccc1)c1ccnnc1)c1ccc(Cl)cc1Cl

Procedure:
From 2,4-dichlorobenzoic acid and 2-phenyl-2-(pridazin-4-yl)ethanamine. LCMS (MH+): m/z=372.1, tR (minutes, Method G)=2.09
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][N:64]([CH3:73])[CH2:65][CH2:66][CH:67]1[CH2:72][CH2:71][CH2:70][CH2:69][NH:68]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:68]1[CH2:69][CH2:70][CH2:71][CH2:72][CH:67]1[CH2:66][CH2:65][N:64]([CH3:63])[CH3:73])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CN(C)CCC1CCCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3CCN(C)C)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-(2-dimethylamino-ethyl)-piperidine in DMSO at ambient temperature.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16])=[O:4].C(N(CC)CC)C.[CH3:40][O:41][C:42](Cl)=[O:43]>C1COCC1>[CH3:17][CH:15]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[C:6]=1[NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:42](=[O:43])[O:41][CH3:40])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:21][CH:20]=1)[CH3:16]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a coded (0° C.) solution of (S)-α-amino-N-[2,6-bis(1-Methylethyl)phenyl]-4-(phenylmethoxy)benzenepropanamide (4.50 g, 10.5 mmol) and triethylamine (1.75 mL, 12.5 mmol) in THF (125 mL) was added methylchloroformate (0.97 mL, 12.5 mmol). The resulting slurry was stirred (1 hr, 0° C.) then filtered, and the filtrate was concentrated. The residue was taken up in ethyl acetate (300 mL), washed with water (1×mL), washed with saturated sodium bicarbonate (1×100 mL), washed with brine (1×100 mL), then dried (MgSO4) and concentrated in vacuo. The resulting solid was recrystallized from ethyl acetate to yield 3.0 g (59%) of the title compound, mp 179°-182° C.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][N:13]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[N:15]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:14]1=[O:37].CN1CCOCC1.Cl[S:46]([CH2:49][C:50]([O:52][CH2:53][CH:54]1[C:66]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:60]2[C:55]1=[CH:56][CH:57]=[CH:58][CH:59]=2)=[O:51])(=[O:48])=[O:47]>ClCCl>[CH:56]1[C:55]2[CH:54]([CH2:53][O:52][C:50](=[O:51])[CH2:49][S:46]([NH:12][N:13]3[CH2:17][CH:16]([C:18]4[CH:23]=[CH:22][C:21]([CH:24]5[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[N:15]([CH2:27][CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)[C:14]3=[O:37])(=[O:47])=[O:48])[C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:60]=2[CH:59]=[CH:58][CH:57]=1
Reactant: COc1ccc(CCN2C(=O)N(N)CC2c2ccc(C3CC3)cc2)cc1
Reactant: O=C(CS(=O)(=O)Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(CCN2C(=O)N(NS(=O)(=O)CC(=O)OCC3c4ccccc4-c4ccccc43)CC2c2ccc(C3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1-amino-3-[2-(4-methoxyphenyl)ethyl]-4-(4-cyclopropylphenyl)-2-imidazolidinone p-toluenesulfonic acid salt (2.61 g, 0.0050 mol), dichloromethane (12 mL), and N-methylmorpholine (1.53 mL, 0.014 mol) is added a solution of 9H-fluoren-9-ylmethyl chlorosulfonylacetate, 14, (1.76 g, 0.0052 mol) in dichloromethane (7 mL) slowly over 7 minutes at 15° C. to 20° C. The reaction is stirred at ambient temperature for 45 minutes, and then washed twice with 0.1 N HCl and water. The organic phase is dried (sodium sulfate) and concentrated to a foamy solid. The residue is purified over silica (0%-50% ethyl acetate/hexanes gradient) to afford 2.1 g of the desired compound. 1H NMR (CDCl3) δ 7.81 (d, J=7.5 Hz, 2H), 7.69 (d, J=7.5 Hz, H), 7.45 (m, 2H), 7.36 (m, 2H), 7.27 (s, 1H), 7.17 (m, 2H), 7.10 (m, 2H), 7.02 (m, 2H), 6.82 (m, 2H), 4.63 (m, 2H), 4.45 (t, J=8.4 Hz, 1H), 4.35 (m, 3H), 3.94 (t, J=8.4 Hz, 1H), 3.78 (s, 3H), 3.65 (m, 1H), 3.38 (t, J=8.1 Hz, 1H), 2.92 (m, 1H), 2.74 (m, 1H), 2.64 (m, 1H), 1.94 (m, 1H), 1.03 (m, 2H), 0.74 (m, 2H). MS 652 (MH+). Anal. calcd. for C37H37N3O6S ¾H2O: C, 66.80; H, 5.83; N, 6.32. Found: C, 66.78; H, 5.72; N, 6.30.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:9](=[O:20])[CH2:10][C:11]2[NH:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[N:12]=2)[CH:6]=[CH:7][CH:8]=1.C[O-].[Na+].[C:24](OC)(=[O:27])[C:25]#[CH:26]>>[F:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([C:10]1[CH:26]=[CH:25][C:24](=[O:27])[N:15]2[C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[NH:12][C:11]=12)=[O:20]
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1cccc(F)c1
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: O=C(c1cccc(F)c1)c1ccc(=O)n2c3c([nH]c12)CCCC3

Procedure:
The compound is prepared as described in example 25 with 200 mg (0.51 mmol) of 1-(3-Fluorophenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone hydrochloride (example XXXXVI), 55.2 mg (1.02 mmol) of sodium methylate and 42.9 mg (0.51 mmol) methyl propiolate.
Reaction SMILES: [OH:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.[CH:8]1([CH2:11][CH2:12][NH:13][C:14]([C:16]2[N:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1>>[CH:8]1([CH2:11][CH2:12][NH:13][C:14]([C:16]2[N:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:5]([C:2]4([OH:1])[CH2:4][CH2:3]4)=[O:7])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: O=C(O)C1(O)CC1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)C3(O)CC3)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 1-hydroxycyclopropanecarboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (53.4% yield). 1H NMR (500 MHz, CDCl3) δ8.07, 8.03, 7.01, 3.98-3.73, 3.58, 1.53, 1.16, 1.02, 0.76, 0.48, 0.10. MS (ES+) m/z 360 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccnc1Cl
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1cccnc1-c1ccc(F)cc1

Procedure:
A mixture of methyl 2-chloropyridin-3-carboxylate (6.8 g.), 4-fluorobenzeneboronic acid (7.2 g.), 1M. aqueous sodium carbonate (40 ml.), Pd(dppb)Cl2(1.2 g.), ethanol(10 ml.) and toluene(150 ml.) was stirred at reflux under an inert atmosphere for 5 hr. The reaction was then cooled, the oganic layer separated, the aqueous extracted with toluene and then the Icombined extracts dried and evaporated to dryness. The product was purified by flash column chromatography eluting wth ethyl acetate/iso-hexane(9:1,8:2,7:3) to give methyl 2-(4-fluorophenyl)pyridin-3-carboxylate as a white solid(7.5 g.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:23](OCC)=[O:24])[N:11]([CH2:21][CH3:22])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:4][CH:3]=1.[NH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[N:29]1([NH:28][C:23]([C:10]2[N:11]([CH2:21][CH3:22])[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=2)=[O:24])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: NN1CCCCC1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1CC
Product: CCn1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1Cl
Temperature: 90 °C

Procedure:
A mixture of ethyl 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1-ethylimidazole-2-carboxylate (25 mg, 0.06 mmol) from Step B in neat 1-aminopiperidine (2 mL) was heated at 90° C. for 72 hr. Most of the amine was evaporated under a stream of nitrogen and the residue was purified by Prep TLC (1 mm, silica) (25% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH:6]1[O:8][CH2:7]1)([CH3:3])[CH3:2].[CH3:9][C:10]([NH2:21])([CH3:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>>[OH:8][CH:6]([CH2:5][O:4][CH:1]([CH3:2])[CH3:3])[CH2:7][NH:21][C:10]([CH3:20])([CH3:9])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: CC(C)OCC1CO1
Product: COc1ccc(CC(C)(C)NCC(O)COC(C)C)cc1
Yield: 17.9 %

Procedure:
Using the method of Example 15, supra, isopropylglycidyl ether (126 μL, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 53 mg of the title compound as a clear, colorless oil; GC/EI-MS, m/z (rel. int.) 296 (M+1, 0.2), 280 (1.4), 222 (1.5), 174 (100), 132 (12), 121(24); 1H-NMR (CDCl3) 7.03 (2H, d, J=8.4), 6.77 (2H, d, J=8.4), 3.72 (3H, s), 3.70 (1H, m), 3.53 (1H, m), 3.38 (2H, m), 2.80 (1H, broad s), 2.73 (2H, m), 2.58 (4H, m) 1.09 (6H, m), 1.01 (3H, s), 0.99 (3H, s); 13C-NMR (CDCl3) δ 157.9, 131.2, 129.9, 113.2, 73.4, 71.2, 69.0, 54.9, 53.1, 46.2, 44.5, 31.5, 26.6, 26.4, 19.1, 13.8.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:15](Cl)(=[O:20])[C:16](C)([CH3:18])[CH3:17]>ClCCl>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:15](=[O:20])[CH:16]([CH3:18])[CH3:17]
Reactant: Nc1ccccn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
EX-5A) A solution of 2-amino pyridine (20.42 , 217.0 mmol) in dichloromethane 500 mL was cooled to 0° C. and treated with triethyl amine (36.29 mL, 260.4 mmol) and pivaloyl chloride (28.06 mL, 227.8 mmol). After 15 minutes, the reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was poured onto ice, and the organic layer was washed with saturated NaHCO3 (aq), and dried over Na2SO4. The volatile components were removed, and a brown oil was isolated. Crystallization with hexanes afforded 31 g of N-(pyrid-2-yl)-2,2-dimethylacetamide (EX-5A) as white crystals in 80% yield. Reference: Turner, J. A. J. Org. Chem, 1983, 48, 3401.
Reaction SMILES: Br[CH:2]1[C:8](=O)[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]([C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:4][CH2:3]1.[C:25]([NH2:28])(=[S:27])[CH3:26]>C(O)C>[CH3:26][C:25]1[S:27][C:2]2[CH2:3][CH2:4][N:5]([C:14](=[O:24])[C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)[C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=3[C:8]=2[N:28]=1
Reactant: O=C1c2ccccc2N(C(=O)c2ccc([N+](=O)[O-])cc2)CCC1Br
Reactant: CC(N)=S
Solvent: CCO
Product: Cc1nc2c(s1)CCN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1-2
Yield: 96.7 %

Procedure:
A mixture of 1.19 g of 4-bromo-1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one and 0.230 g of thioacetamide in 4 ml of ethyl alcohol is refluxed under argon for 18 hours. The volatiles are evaporated in vacuo to a residue which is partitioned between CHCl3 and 10% NaHCO3. The organic layer is separated and washed twice with water. The organic layer is separated, dried (MgSO4) and evaporated in vacuo to give 1.08 g of yellow foam which is purified by flash chromatography on silica by elution with 4% ethyl acetate in methylene chloride to give 560 mg of the desired product as pale yellow foam.