Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([N:15]=[C:16]=[S:17])[CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([N:15]2[C:5](=[O:7])[CH2:4][N:3]([CH2:1][CH3:2])[C:16]2=[S:17])[CH:14]=1
Reactant: CCNCC(=O)O
Reactant: COc1ccc(Cl)cc1N=C=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2cc(Cl)ccc2OC)C1=S
Yield: 53.3 %

Procedure:
A mixture N-ethyl glycine (9.2 g), 5-chloro-2-methoxyphenyl-isothiocyanate (10 g), triethylamine (10.1 g), methylene chloride (150 mL) was heated at reflux for 3.5 hours. The mixture was evaporated to dryness. The residue collected, washed with hot ethanol and dried. Title compound (7.6 g) was obtained as a creamy solid, m.p. 171°-174° C. Anal. Calcd. for. C12H13Cl N2O2S: C, 50.61; H, 4.60; N, 9.84. Found: C, 50.33; H, 4.50; N, 9.69. Mass spectrum (El, M.+) m/z 284/286.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[C:6]([CH3:12])=[C:5]([N+:13]([O-])=O)[CH:4]=1)#[N:2]>CO.[Pd]>[NH2:13][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[C:6]=1[CH3:12]
Reactant: Cc1c([N+](=O)[O-])cc(C#N)c2nc[nH]c12
Agent: [Pd]
Solvent: CO
Product: Cc1c(N)cc(C#N)c2nc[nH]c12
Yield: 516.2 %

Procedure:
5-Amino-7-cyano4-methylbenzimidazole (4 g) is prepared treating a heterogeneous solution of 7-cyano-4-methyl-5-nitrobenzimidazole (0.91 g, 0.0045 mol) and 10% Pd/C (100 mg) in methanol (200 mL) with an atmosphere of H2 (1 atm, balloon) for 14 hr. The resulting mixture is filtered through celite and concentrated via rotary evaporation to give rise to a yellow residue. This residue is chromatographed (silica gel, 95:5 ethyl acetate:methanol) to give rise to 5-amino-7-cyano4-methylbenzimidazole. 5-amino-7-cyano-4-methylbenzinidazole N-methoxycarbonyl-2-thiomethyl-2-imidazoline (4.45 g, 1.1 eq.) (prepared as described in Example 2) are dissolved in acetonitrile (100 mL) and glacial acetic acid (10 mL), and the reaction mixture is stirred at 70° C. until the coupling step is complete. The reaction mixture is diluted with methanol (50 mL) and refluxed until deprotection is complete, and then the acetonitrile is evaporated under reduced pressure. The acetic acid solution obtained is dissolved in water (9.25 mL) and the resulting mixture is cooled to 0° C. A 5 molar aqueous solution of H2SO4 (5.1 mL) is added dropwise to the cold mixture. The solution is then heated to 65° C. and absolute ethanol is added until cloudiness is observed. The mixture is allowed to come to room temperature and is then cooled to 5° C. The solid obtained is filtered, washed with ethanol and dried to provide N-(4,5-dihydro-1H-imidazol-2-yl)-7-cyano-4-methyl-1H-benzimidazol-5-amine as its sulfuric acid salt.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][N:3]=[C:2]1[NH2:7].[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([NH:17][C@H:18]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:19][NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](OC)=[O:31])=[CH:24][CH:23]=3)=[N:14][C:13]=2[CH:42]=1>C1COCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([NH:17][C@H:18]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:19][NH:20][C:21](=[O:34])[C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][C:30](=[O:31])[NH:7][C:2]4[NH:3][CH2:4][CH2:5][CH2:6][N:1]=4)=[CH:26][CH:27]=3)=[N:14][C:13]=2[CH:42]=1
Reactant: NC1=NCCCN1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](Nc2nc3cc(Br)ccc3o2)C(=O)OC(C)(C)C)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)Nc1nc2cc(Br)ccc2o1
Reaction time: 4 h
Yield: 45.2 %

Procedure:
1,4,5,6-tetrahydro-2-pyrimidinamine (94 mg) is added to the ester 10-6 (140 mg) in 3 ml of THF, and agitation is carried out at ambient temperature for 4 hours. After evaporating under reduced pressure, the dry extract obtained is purified by chromatography eluting with a CH2Cl2/AcOEt 80/20 then CH2Cl2/MeOH 85/15 mixture. 71 mg of expected product 10-7 is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[CH:7]=[O:8])[CH3:2]
Reactant: OCCCCCCCCCCCBr
Reactant: CCOc1cc(C=O)ccc1O
Product: CCOc1cc(C=O)ccc1OCCCCCCCCCCCO
Yield: 95 %

Procedure:
3-ethoxy-4-[(11-hydroxyundecyl)oxy]benzaldehyde is prepared starting from 3-ethoxy-4-hydroxybenzaldehyde and 11-bromoundecan-1-ol according the same procedure following for example 7 in 95% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: Br.[NH2:2][CH:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][CH:4]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+].Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CN(C)C=O>[NH2:2][CH:3]1[C:9](=[O:10])[N:8]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][CH:4]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC1C(=O)Nc2ccccc2SC1c1ccccc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)C(N)C(c2ccccc2)Sc2ccccc21
Temperature: 50 °C
Yield: 76.1 %

Procedure:
4.8 g of 3-amino-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrobromide was dissolved in 80 ml of N,N-dimethylformamide. After the addition of 1.2 g of sodium hydride (in the form of a 60% suspension in oil), the resulting mixture was stirred at 50° C. for an hour. Then, a solution of 2.7 g of t-butyl bromoacetate in 10 ml of N,N-dimethylformamide was added and the mixture was stirred at 50° C. for an additional hour. After the solvent was distilled off under reduced pressure, hexane was added to the residue so as to cause crystallization. The product was separated by filtration and washed with ether, with water and then with ether to obtain 4.0 g of the desired compound. This compound had a melting point of 178°-180° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:34]3[CH2:35][CH2:36][N:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)[CH2:32][CH2:33]3)=[O:16])[N:12]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Product: O=C(C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1)N1CCN(c2ccccn2)CC1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was coupled with 1-(2-pyridyl)piperazine to give the title compound as an off-white solid. MS: 498.3 ([M+H]+)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([NH2:18])=[N:13][CH:12]=[CH:11]3)[CH2:2]1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(#N)C>[CH2:19]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([NH2:18])=[N:13][CH:12]=[CH:11]3)[CH2:2]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1nccc2cc(OC3CCCNC3)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: Nc1nccc2cc(OC3CCCN(Cc4ccccc4)C3)ccc12
Reaction time: 0.33 h
Yield: 102.3 %

Procedure:
A couple of drops of glacial acetic acid was added to a solution of racemic 6-(piperidin-3-yloxy)-isoquinolin-1-ylamine (52 mg, 0.214 mmol) and benzaldehyde (26 mL, 0.256 mmol) in acetonitrile (2 ml). The mixture was stirred for 20 minutes and then sodium triacetoxyborohydride (68 mg, 0.321 mmol) was added in portions. The mixture was stirred at ambient temperature for 20 h then concentrated in vacuo. The mixture was then partitioned between dichloromethane and saturated aqueous sodium hydrogencarbonate. The organic layer was separated then concentrated in vacuo to give a residue. The residue was purified by prep-HPLC to give 6-(1-benzylpiperidine-3-yloxy)isoquinolin-1-yl amine (73 mg) El-MS: m/z=334.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:14][CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:31]=1[NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:14][CH2:13]3)[N:9]=[C:10]([C:34]3[CH:33]=[CH:32][C:31]([NH:45][C:46]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:52])=[C:30]([O:29][CH3:28])[CH:35]=3)[C:3]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Reactant: Nc1ncnc2c1c(I)nn2C1CCN(C(=O)OCc2ccccc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn(C3CCN(C(=O)OCc4ccccc4)CC3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Temperature: 75 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
A mixture of benzyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (7.0 g, 0.0146 mol), tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (6.15 g, 0.0176 mol), tetrakis(triphenylphosphine)palladium (1.0 g, 0.000876 mol) and sodium carbonate (3.9 g, 0.0365 mol) in ethylene glycol dimethyl ether (170 mL) and water (70 mL) was heated at 75° C. for 16 hours under an atmosphere of nitrogen. After addition of tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (6.15 g, 0.0176 mol, 1.2 eq.) and tetrakis(triphenylphosphine)palladium (1.0 g, 0.000876 mol) the mixture was stirred at 85° C. for additional 16 hours. The mixture was allowed to cool to ambient temperature and ethylene glycol dimethyl ether was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a brownish solid which was purified by flash column chromatography on silica using 20%-40% ethyl acetate/dichloromethane followed by 2%-5% methanol/dichloromethane as a mobile phase to give benzyl 4-(4-amino-3-{4-[(tert-butoxycarbonyl)amino]-3-methoxyphenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (8.0 g, 0.014 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 12.6 min. MS: MH+ 574.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]2[CH2:12][O:11][CH2:10]2)[CH:8]=1)([O-])=O>[Pd].CO>[O:11]1[CH2:12][CH:9]([N:7]2[CH:8]=[C:4]([NH2:1])[N:5]=[CH:6]2)[CH2:10]1
Reactant: O=[N+]([O-])c1cn(C2COC2)cn1
Agent: [Pd]
Solvent: CO
Product: Nc1cn(C2COC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A 25-mL single-neck round-bottomed flask was purged with nitrogen and charged with 285a (100 mg, 0.6 mmol), 10% palladium on carbon (10% wet, 10 mg) and methanol (10 mL). The flask was evacuated, charged with hydrogen gas (via balloon), and stirred for 1 h at room temperature. The hydrogen was then evacuated and nitrogen was charged to the flask. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 285b (70 mg, 85%). MS-ESI: [M+H]+ 140.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[CH:24][C:25]([C:27](O)=[O:28])=[CH:26][C:17]=4[C:16]=3[N:30]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH2:39])=[CH:33][CH:32]=1>>[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH:39][C:27]([C:25]2[CH:24]=[CH:23][C:18]3[NH:19][C:20](=[O:22])[CH2:21][C:15]4[CH:14]=[N:13][C:12]([NH:11][C:5]5[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)=[N:30][C:16]=4[C:17]=3[CH:26]=2)=[O:28])=[CH:33][CH:32]=1
Reactant: NCCc1ccncc1
Reactant: COc1ccc(Nc2ncc3c(n2)-c2cc(C(=O)O)ccc2NC(=O)C3)cc1OC
Product: COc1ccc(Nc2ncc3c(n2)-c2cc(C(=O)NCCc4ccncc4)ccc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described for Method N, 2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylic acid (I-43) and 2-(pyridin-4-yl)ethanamine were converted I-48 (6%): HRMS Calcd. for C28H26N6O4: 551.2093, Found 511.2098.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.S(Cl)([Cl:17])=O>CN(C)C=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([Cl:17])=[O:14]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2ccccc2c1O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Dry 1-hydroxy-2-naphthoic acid (50 gms., 0.266 mole) was suspended in 350 ml. dry benzene in a flame-dried 1 liter 1-neck round bottom flask under an air condenser and drying tube. Thionyl chloride (31.7 gms., 0.266 mole) was added in one portion followed by 1.5 ml. dry N,N-dimethylformamide. The reaction mixture was stirred magnetically 2-3 days at room temperature. Insoluble material (6.5 gms.) was removed by filtration, and the yellow-tan filtrate was evaporated to dryness to give pale yellow 1-hydroxy-2-naphthoyl chloride, m.p. 87°-88° C. Chilled anhydrous methanol (100 ml.) was added quickly to the solid chloride in an exothermic reaction. The partial solution was heated about 5 minutes on the steam bath under a drying tube then allowed to cool. The suspension was chilled and the solid was collected to give 43 gms. (92% by weight) of 1-hydroxy-2-methyl naphthoate.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:47][O:48][C:49]1[C:50]2[N:63]=[C:62]([NH2:64])[S:61][C:51]=2[C:52]([CH:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)=[N:53][CH:54]=1>C1COCC1>[CH3:47][O:48][C:49]1[C:50]2[N:63]=[C:62]([NH:64][C:13](=[O:15])[C:11]3[CH:10]=[CH:9][N:8]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:12]=3)[S:61][C:51]=2[C:52]([CH:55]2[CH2:56][CH2:57][O:58][CH2:59][CH2:60]2)=[N:53][CH:54]=1
Reactant: O=C(O)c1ccnc(N2CCOCC2)c1
Reactant: COc1cnc(C2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(C2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12

Procedure:
From 2-(4-morpholinyl)-4-pyridinecarboxylic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-(tetrahydro-pyran-4-yl)thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 456 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[N:6]([C@@H:9]3[CH2:13][C@H:12]([CH2:14][OH:15])[CH:11]=[CH:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C(OC(=O)C)(=O)C.[Br:26]N1C(=O)CCC1=O>N1C=CC=CC=1>[Br:26][C:7]1[N:6]([C@@H:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[CH:11]=[CH:10]2)[C:5]2[CH:16]=[C:17]([Cl:18])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: OC[C@@H]1C=C[C@H](n2cnc3cc(Cl)c(Cl)cc32)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: OC[C@@H]1C=C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)C1
Yield: 14.8 %

Procedure:
(±)-cis-[4-(5,6-Dichloro-1H-benzimidazol-1-yl)-2-cyclopenten-1-yl]methanol (1.55 g, 5.47 mmol) was acetylated in pyridine (17 mL) with acetic anhydride (0.6 mL) at ambient temperature for 2 days. Volatiles were removed in vacuo and the residual oil partitioned between chloroform and aqueous sodium bicarbonate. The chloroform solution was dried (sodium sulfate) and concentrated to dryness. The residue was dissolved in dry dioxane (10 mL) and the solution brought to reflux. N-bromosuccinimide (930 mg, 5.23 mmol) was added all at once. The dark solution was cooled after 4 minutes of reflux. Volatiles were evaporated in vacuo and the residue was chromatographed on silica gel. Elution with 2-5% methanol-chloroform gave fractions containing starting material (1.05 g) followed by fractions containing title compound as a dark oil (0.28 g). The recovered starting material was again treated with N-bromosuccinimide and the crude product chromatographed. All product-containing fractions were combined and rechromatographed on silica gel with elution by hexanes-ethyl acetate to give the acetate of title compound as a yellow oil (0.62 g). Deacetylation was carried out as in Example 4. Volatiles were evaporated in vacuo from the neutralized solution and the residue was chromatograped on silica gel. Elution with 2% methanol-chloroform gave (±)-cis-[4-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-2-cyclopenten-1-yl]methanol as off-white powder (293 mg, 15%), after resolidification from hexanes-ethyl acetate, m.p. 126°-128.5° C.; 1H-NMR(DMSO-d6) δ: 8.09 and 7.95 (both s, 1 each, aromatic CH), 6.24-6.20 and 5.98-5.94 (both m, 2, CH=CH), 5.81-5.76 (2 m, 1 each, CH2O), 4.96 (t, J=4.9 Hz, 1, OH), 3.02-2.95 (m, 1, CH), 2.67-2.51 (m overlapping solvent, 1/2CH2), 2.0-1.8 (m, 1, 1/2CH2); mass spectrum (CI) consistent with structure.
Reaction SMILES: Br[C:2]1[C:20]([C:21]([N:23]([CH:37]([CH3:39])[CH3:38])[C@@H:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]2)=[O:22])=[CH:19][C:5]2[N:6]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.C[O-].[Na+].CN([CH:46]=[O:47])C>O>[CH:37]([N:23]([C:21]([C:20]1[C:2]([O:47][CH3:46])=[CH:3][C:4]2[O:9][C:8]([CH3:11])([CH3:10])[C:7](=[O:12])[N:6]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[C:5]=2[CH:19]=1)=[O:22])[C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)([CH3:39])[CH3:38]
Reactant: COCCCCN1C(=O)C(C)(C)Oc2cc(Br)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COCCCCN1C(=O)C(C)(C)Oc2cc(OC)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To tert-Butyl (3R)-3-[{[7-bromo-4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (500 mg) were added CuBr (59 mg), NaOMe (1M methanol solution) (16.4 ml) and DMF (5.5 ml), and the mixture was stirred at 100° C. for 15 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound (240 mg) as a colorless liquid.
Reaction SMILES: B.O1CCCC1.O1CCCC1.[CH2:12]([N:19]1[C:26](=O)[C:23]2([CH2:25][CH2:24]2)[NH:22][C:21](=O)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([N:19]1[CH2:26][C:23]2([CH2:25][CH2:24]2)[NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CN(Cc2ccccc2)C(=O)C2(CC2)N1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc(CN2CCNC3(CC3)C2)cc1
Reaction time: 1 h
Yield: 59.2 %

Procedure:
A borane-tetrahydrofuran complex (0.93 M tetrahydrofuran solution) (375 ml, 0.35 mol) was added to a tetrahydrofuran (200 ml) solution of the compound (20 g, 86.8 mmol) obtained in Step 2 above with ice cooling and then the resulting mixture was heated to reflux for 19 hours. Methanol (130 ml) was added to the reaction mixture with ice cooling, the resulting mixture was stirred for 60 minutes, and the solvent was concentrated under reduced pressure. Ethanol (450 ml), water (150 ml), and triethylamine (150 ml) were added to the resulting residue, the resulting mixture was heated to reflux for 2 hours, and then the solvent was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give the title compound (10.4 g, 59%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([NH2:16])=[N:12][NH:13][C:14]=2[NH2:15])=[CH:6][CH:5]=1.CN(C)[CH:21]=[CH:22][CH:23]=O>C(O)C.C(O)(=O)C>[F:18][C:2]([F:1])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([NH2:15])=[N:13][N:12]3[CH:23]=[CH:22][CH:21]=[N:16][C:11]=23)=[CH:6][CH:5]=1
Reactant: Nc1n[nH]c(N)c1-c1ccc(OC(F)(F)F)cc1
Reactant: CN(C)C=CC=O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1nn2cccnc2c1-c1ccc(OC(F)(F)F)cc1
Yield: 107.5 %

Procedure:
In a microwave vessel containing the product from Example 1B (0.4 g, 1.549 mmol) and 3-(dimethylamino)acrylaldehyde (0.155 g, 1.549 mmol) in ethanol (5 mL) was added two drops of acetic acid. The mixture was irradiated with microwave at 140° C. for 15 minutes and concentrated. The resulting solid was purified by flash chromatography on silica gel, eluting with EtOAc/Hexanes (40-70% gradient), to yield the title compound (0.49 g, 59%). MS ESI+ m/z 295.5 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([CH2:9][P:10](=[O:15])([O:13]C)[O:11]C)(O)=[O:7].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[C:6]([CH2:9][P:10](=[O:15])([OH:13])[OH:11])=[O:7])[CH3:2]
Reactant: COP(=O)(CC(=O)O)OC
Reactant: CCNCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCN(CC)C(=O)CP(=O)(O)O

Procedure:
Diethylamine (0.045 mole) and dimethyl (carboxymethyl)phosphonate (0.04 mole) were dissolved in 100 ml. of methylene chloride. As the solution was stirred, dicyclohexylcarbodiimide was added portionwise. The solution was stirred overnight and the mixture was filtered. The filtrate was concentrated to a solid. It was recrystallized from an appropriate solvent such as methanol.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].Br[CH:15]([CH3:28])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1)=O.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:4][O:3][C:1](=[O:2])[C:5]1[CH:13]=[CH:12][C:8]([C:9]2[O:10][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=3)=[C:15]([CH3:28])[N:11]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(C(N)=O)cc1
Reactant: COC(=O)c1ccc(C(=O)C(C)Br)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2nc(C)c(-c3ccc(C(=O)OC)cc3)o2)cc1

Procedure:
α-(p-Carbomethylbenzamido)-p-carbomethoxypropiophenone, obtained by reacting p-carbomethoxybenzamide with α-bromo-p-carbomethoxypropiophenone, was refluxed with phosphorus oxychloride in toluene to yield dimethyl-4,4'-(4-methyloxazol-2,5-diyl)dibenzoate, G. The VIII was obtained in a similar manner as in Example 1.