Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:8][CH2:7]1)([O:3]CC)=[O:2].O.[OH-].[Li+]>C(O)C.O.O1CCCC1>[C:1]([C:6]1([S:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH2:8][CH2:7]1)([OH:3])=[O:2]
Reactant: CCOC(=O)C1(SCc2ccc(OC)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CSC2(C(=O)O)CC2)cc1
Yield: 96.2 %

Procedure:
Dissolve 1-(carboethoxy)-1-(4-methoxybenzylthio)cyclopropane (0.310 g, 1.16 mmol) in 95% ethanol (6 mL), water (3 mL), and tetrahydrofuran (6 mL). Treat with lithium hydroxide monohydrate (420 mg, 10 mmol). Stir at a gentle reflux for 6 hours and evaporate the solvent in vacuo. Add water (50 mL) and wash with ether (50 mL). Acidify the aqueous phase and extract into methylene chloride (50 mL). Dry (Na2SO4) and evaporate the solvent in vacuo to give 1-(carboxy)-1-(4-methoxybenzylthio)cyclopropane as a pale yellow solid (266 mg).
Reaction SMILES: [Si:1]([CH:8]([OH:24])[C@H:9]1[O:13][C@@H:12]([N:14]2[CH2:19][N:18]([CH3:20])[C:17](=[O:21])[NH:16][C:15]2=[O:22])[CH2:11][C@@H:10]1[OH:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:31](Cl)(=[O:43])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O>[Si:1]([CH:8]([OH:24])[C@H:9]1[O:13][C@@H:12]([N:14]2[CH2:19][N:18]([CH3:20])[C:17](=[O:21])[NH:16][C:15]2=[O:22])[CH2:11][C@@H:10]1[O:23][C:31](=[O:43])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CN1CN([C@H]2C[C@H](O)[C@@H](C(O)[Si](C)(C)C(C)(C)C)O2)C(=O)NC1=O
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)O[C@H]1C[C@H](N2CN(C)C(=O)NC2=O)O[C@@H]1C(O)[Si](C)(C)C(C)(C)C
Temperature: 10 °C
Yield: 88.7 %

Procedure:
To a solution consisting of 3.59 gm. (0.010 mole) of 1-(5-tert-butyldimethylsilyl-2-deoxy-β-D-ribofuranosyl)-5-methyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione and 30 ml. A. R. pyridine that had been cooled to 5° C. was added, with stirring, 2.55 gm. (0.0116 mole) of freshly distilled lauroyl chloride. This reaction mixture was stirred for 18 hours at 25° C. Then it was cooled to 10° C. and 3 ml. water was added. This mixture was stirred at 25° C. while the solvents were removed by evaporation under reduced pressure. The residue thus obtained was dispersed in a solvent mixture consisting of 100 ml. chloroform and 50 ml. saturated aqueous sodium bicarbonate. The aqueous and organic phases were allowed to stabilize and the organic phase was saved. It was washed two times with 50 ml. portions of saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The dried chloroform solution was filtered and the filter was washed with chloroform. The filtrate and washings were combined and the chloroform was removed by evaporation under reduced pressure. There was thus obtained 4.8 gm. (88.7% yield) of 1-(5-tert-butyldimethylsilyl-3-O lauroyl-2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:5]/[OH:6].[CH3:21]N(C)C=O.[OH-].[K+].COS(OC)(=O)=O>CCOCC.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:5]/[O:6][CH3:21]
Reactant: COC(=O)/C(=N/O)c1ccccc1Oc1ccccc1
Reactant: CN(C)C=O
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Product: CO/N=C(/C(=O)OC)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
To E-α-hydroxyimino-2-phenoxyphenylacetic acid methyl ester (1.09 g, 0.004 mole) were added dried dimethylformamide (6 ml) and potassium hydroxide (0.29 g, 0.0044 mole) and the mixture was stirred at room temperature for 15 minutes. Then, dried toluene (6 ml) was added to the mixture, to this was further added dropwise dimethylsulfate (0.61 g, 0.0044 mole) under ice cooling. After completion of the addition, the mixture was stirred at room temperature for 2 hours. Then, ether (100 ml) was added, followed by washing with water three times. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain E-α-methoxyimino-2-phenoxyphenyl acetic acid methyl ester (1.20 g, yield: 80.6%) as colorless crystals (melting point: 109 °-110° C.).
Reaction SMILES: [ClH:1].CN(C)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:17]=[C:18]([C:23]([NH2:25])=[NH:24])[S:19][C:20]=3[S:21][CH3:22])[N:15]=2)=[CH:6][CH:5]=1.Br.CN(C)C1C=CC(NC2SC=C(C3([C:48]([OH:50])=S)CC=C(C)S3)N=2)=CC=1>>[ClH:1].[CH3:48][O:50][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:17]=[C:18]([C:23]([NH2:25])=[NH:24])[S:19][C:20]=3[S:21][CH3:22])[N:15]=2)=[CH:6][CH:5]=1
Reactant: CSc1sc(C(=N)N)cc1-c1csc(Nc2ccc(N(C)C)cc2)n1
Reactant: CC1=CCC(C(O)=S)(c2csc(Nc3ccc(N(C)C)cc3)n2)S1
Agent: Br
Agent: Cl
Product: COc1ccc(Nc2nc(-c3cc(C(=N)N)sc3SC)cs2)cc1
Yield: 22 %

Procedure:
4-(2-{[4-(Dimethylamino)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine hydrochloride: Methyl 4-(2-{([4-(dimethylamino)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate hydrobromide (50 mg, 0.10 mmol) was treated as described in Example 154, step (b) to give 9.4 mg (22% yield) of 4-{2-[(4-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine hydrochloride. 1H NMR (DMSO-d6, 300 MHz) 2.70 (s, 3H), 2.84 (s, 6H), 6.75 (d, 2H, J=9.2 Hz), 7.00 (s, 1H), 7.56 (d, 2H, J=9.1 Hz), 8.31 (s, 1H), 8.68 (bs, 3H), 9.92 (bs, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[CH3:22])=[O:4].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH3:22])[CH:10]=1)[N:7]=[C:6]([N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCNCC
Reactant: COC(=O)c1c(Cl)nc2c(C)cc(Cl)cc2c1-c1ccccc1
Product: CCN(CC)c1nc2c(C)cc(Cl)cc2c(-c2ccccc2)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 40 step D from 2,6-dichloro-8-methyl-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 40 step C) and diethylamine. Brown solid. MS (ESI): 369.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[CH:3]=[N:2]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(Cl)(Cl)Cl>[NH:1]1[CH:5]=[C:4]([C:6]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:8])[CH:3]=[N:2]1
Reactant: O=C(O)c1cn[nH]c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(c1cn[nH]c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A suspension of 1H-pyrazole-4-carboxylic acid (1.05 g), 1-{3-(dimethylamino)propyl}-3-ethylcarbodiimide hydrochloride (2.5 g), 1-hydroxybenzotriazole hydrate (1.6 g) and morpholine (1.2 g) in chloroform (18 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: chloroform:methanol=100:0 to 95:5) and silica gel column chromatography (eluting solvent: chloroform:methanol=100:0 to 90:10). The resulting colorless solid was washed with ethyl acetate to give the titled compound (1.00 g) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(=O)([O-])O.[Na+].[C:20](Cl)(=[O:24])[O:21][CH2:22][CH3:23].O>ClCCl>[CH2:22]([O:21][C:20]([NH:1][C:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:4])=[O:24])[CH3:23]
Reactant: COC(=O)c1ccc(C(C)(C)N)cc1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)NC(C)(C)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-(1-amino-1-methylethyl)benzoate (410 mg) in dichloromethane (15 mL) was added saturated aqueous sodium hydrogen carbonate solution (3 mL), a solution of ethyl chlorocarbonate (0.24 mL) in dichloromethane (5 mL) was added dropwise under ice-cooling, and the mixture was stirred at the same temperature for 1 hr and at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (551 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH2:21]Br.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:21][C:20]2[C:19]([F:18])=[CH:26][CH:25]=[CH:24][C:23]=2[F:27])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: Fc1cccc(F)c1CBr
Reactant: O=[N+]([O-])c1ncc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ncc(Cl)cc1OCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
33 g of 5-chloro-2-nitropyridin-3-ol (Example 12A; 189 mmol, 1 equivalent) and 61.6 g of caesium carbonate (189 mmol, 1 equivalent) were initially charged in 528 ml of DMF, 40.4 g of 2,6-difluorobenzyl bromide (189 mmol, 1 equivalent) were added and the mixture was stirred at RT overnight. The reaction mixture was stirred into a water/1N aqueous hydrochloric acid mixture. The solid obtained was filtered off, washed with water and air-dried. This gave 54.9 g (97% of theory) of the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16](=[O:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C(OCC)C>[CH2:7]([N:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([OH:21])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CCCCN(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OC1CCCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.9 %

Procedure:
Under a nitrogen atmosphere, lithium aluminum hydride (1.4 mg, 0.0369 mmol) was added to a solution of 1-benzylazepan-3-one (15 mg, 0.0738 mmol) in diethyl ether (1 ml) at 0° C., and the resulting mixture was heated to room temperature. After 30 minutes, water, a 2M-aqueous sodium hydroxide solution and water were added in that order to the reaction solution. The resulting mixture was filtered by the use of Celite, and the filtrate was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol) to obtain 1-benzylazepan-3-ol (16.2 mg, 100%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.[CH2:32]([S:35](Cl)(=[O:37])=[O:36])[CH2:33][CH3:34]>>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([S:35]([CH2:32][CH2:33][CH3:34])(=[O:37])=[O:36])[CH2:28][CH2:27]2)[N:10]=1
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CCCS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 28 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 11, and propanesulfonyl chloride (Aldrich), to give [4-amino-2-[1-(propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone. HRMS, observed: 434.1860; Calcd for (M+H)+: 434.1857.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:20])[NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH:16]1([NH:15][C:14]([C@@H:9]2[CH2:10][C@H:11]([OH:13])[CH2:12][NH:8]2)=[O:20])[CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)NC1CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CCC1)[C@@H]1C[C@H](O)CN1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 463 mg (2S,4S)-2-Cyclobutylcarbamoyl-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester in 8 ml dichloromethane were added 1.2 ml TFA. After 5 h stirring at RT the solvents were removed and the residue was codistilled twice with toluene. Yield: 463 mg.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:14]([NH:18][NH2:19])(=O)[CH2:15][CH3:16]>C(O)CCC>[CH2:15]([C:14]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:19][N:18]=1)[CH3:16]
Reactant: CCC(=O)NN
Reactant: Clc1ccc(-c2ccccc2)nn1
Solvent: CCCCO
Product: CCc1nnc2ccc(-c3ccccc3)nn12

Procedure:
A mixture of 7.6 g. of 3-chloro-6-phenylpyridazine, 7.4 g. of propionic acid hydrazide and 60 ml of n-butanol is stirred at reflux temperature for 48 hours. The solution is cooled in a chilled room, concentrated to remove the solvent and triturated with water giving crystals. The mixture is filtered, washed with petroleum ether and water and dried. The product is recrystallized from 20 ml. of ethanol giving 3-ethyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine, m.p. 133°-135° C.
Reaction SMILES: [F:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].C(C1C=C(N)[O:15][N:14]=1)(C)C>>[F:1][C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[O:15][N:14]=1)([CH3:9])[CH3:8]
Reactant: CC(C)c1cc(N)on1
Reactant: CC(C)(F)C(=O)CC#N
Product: CC(C)(F)c1cc(N)on1
Yield: 71 %

Procedure:
Prepared from 4-fluoro-4-methyl-3-oxopentanenitrile (6 g, 47 mmol) according to the method described for 3-isopropylisoxazol-5-amine in Example 122A Step 2, to afford 3-(2-fluoropropan-2-yl)isoxazol-5-amine as a light yellow solid (4.83 g, 71%) which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 5.19 (s, 1H), 4.48 (brs, 2H), 1.68 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 145 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[N:12]1([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
Benzyl chloroformate (Aldrich, cat #:119938) (191 mL, 1.34 mol) was slowly added to a cooled (at 0° C.) mixture of ethyl piperidine-3-carboxylate (Aldrich, cat #:194360) (200 g, 1.27 mol) and triethylamine (266 mL, 1.91 mol) in methylene chloride (1000 mL). The reaction mixture was allowed to gradually warm to ambient temperature and stirred for 3 h. The reaction was quenched by the addition of 1N HCl aq. solution and the product was extracted several times with methylene chloride. The combined extracts were washed with water, saturated aq. NaHCO3, water, brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product as oil (359.8 g, 97%). LC/MS 292.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:33][CH3:34])=[CH:4][C:5](OC)=[C:6]([CH:30]=1)[C:7]([C:9](=[CH:15][NH:16][C@H:17]([C:21]([CH3:29])([CH3:28])[O:22][SiH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]([CH3:20])[CH3:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+].O>[Br:1][C:2]1[CH:30]=[C:6]2[C:5](=[CH:4][C:3]=1[O:33][CH3:34])[N:16]([C@H:17]([C:21]([CH3:28])([CH3:29])[O:22][SiH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:18]([CH3:19])[CH3:20])[CH:15]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7]2=[O:8]
Reactant: CCOC(=O)C(=CN[C@@H](C(C)C)C(C)(C)O[SiH2]C(C)(C)C)C(=O)c1cc(Br)c(OC)cc1OC
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn([C@@H](C(C)C)C(C)(C)O[SiH2]C(C)(C)C)c2cc(OC)c(Br)cc2c1=O
Temperature: 110 °C
Reaction time: 11 h

Procedure:
Under a nitrogen atmosphere, ethyl 2-(5-bromo-2,4-dimethoxybenzoyl)-3-((S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropylamino)acrylate (5.0 g) was added to toluene (30 mL), and potassium carbonate (1.24 g) and tetra-n-butylphosphoniumbromide (1.52 g) were added. After stirring at 110° C. for 11 hr, the completion of the reaction was confirmed by HPLC. After cooling the reaction mixture, tetrahydrofuran (40 mL) and 10% brine (40 mL) were added, and the toluene layer was separated. The toluene layer was washed twice with 10% brine (40 mL). After washing, toluene was evaporated under reduced pressure to give crude ethyl 6-bromo-1-((S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate.
Reaction SMILES: [C:1]1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.Cl.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]([NH2:33])[CH3:32])=[CH:25][CH:24]=1.CN1CCOCC1>C(Cl)Cl.CN(C)C=O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:31]([NH:33][C:12]([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][CH2:10][CH2:11]2)=[O:14])[CH3:32])=[CH:27][CH:28]=1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: CC(N)C(Cc1ccc(Cl)cc1)c1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(NC(=O)C1(c2ccccc2)CCCC1)C(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of phenylcyclopentanecarboxylic acid (Aldrich, 23 mg, 0.12 mmol) in methylene chloride (1 mL) at 0° C. was added a drop of dimethylformamide and oxalyl chloride (0.025 mL, 0.29 mmol). After stirring at room temperature for 1 h, the reaction mixture was concentrated on a rotary evaporator and dried under vacuum, and the resulting crude acyl chloride was used without further purification. The crude acyl chloride was dissolved in 1 mL of methylene chloride and was added to a suspension of N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-amine hydrochloride (Reference Example 2) (diastereomer α, 30 mg, 0.10 mmol) and N-methylmorpholine (0.053 mL, 0.48 mmol) in 1 mL of methylene chloride. After stirring at room temperature overnight, the reaction mixture was loaded onto a silica gel column, which was eluted with 10% ethyl acetate to give the title compound. 1H NMR (400 MHz, CD3OD): δ 7.45 (d, 2H), 7.35-7.08 (m, 6 H), 6.97 (d, 2H) 6.90 (d, 2H), 6.59 (d, 2H), 4.19 (m, 1H), 2.74-2.45 (m, 5), 2.12-1.65 (m, 6H), 0.79 (d, 3H). LC-MS: m/e 432 (M+H)+ (4.4 min).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:18]([CH3:21])[CH:19]=O)[CH2:5][CH2:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH3:1][O:2][CH2:3][CH:4]([N:18]([CH3:21])[CH3:19])[CH2:5][CH2:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: COCC(CCOc1cccc2ccccc12)N(C)C=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COCC(CCOc1cccc2ccccc12)N(C)C

Procedure:
N-[1-(Methoxymethyl)-3-(1-naphthyloxy)propyl]-N-methylformamide, described in Example 8, is reduced with LiAlH4 in the manner described in Example 4 to give the title compound, nmr (CDCl3) δ 2.05 (m, 2H), 2.35 (s, 6H), 3.0 (s, 1H), 3.35 (s, 3H), 3.5 (m, 2H), 4.25 (t, J = 5.5Hz, 2H) and 6.75-8.4 (7H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][N:8]2[C:16]([C:19]([OH:21])=O)=[CH:17][CH:18]=[C:7]2[CH2:6]1)=[O:4].[NH:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25]>>[OH:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][OH:28])[C:19]([C:16]1[N:8]2[C:7]([CH2:6][N:5]([C:3]([O:2][CH3:1])=[O:4])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9]2)=[CH:18][CH:17]=1)=[O:21]
Reactant: OCCNCCO
Reactant: COC(=O)N1Cc2ccc(C(=O)O)n2Cc2ccccc21
Product: COC(=O)N1Cc2ccc(C(=O)N(CCO)CCO)n2Cc2ccccc21

Procedure:
The title compound was prepared by coupling the 10-(methoxycarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of step A with diethanolamine (1.2 equiv.), in the manner of Example 1, Step G,
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:15]C1C=CC=CC=1CBr.COP(OC)OC>>[CH3:15][C:13]1[CH:14]=[CH:2][CH:3]=[CH:4][C:5]=1[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: Cc1ccccc1CBr
Reactant: COP(=O)(Cc1ccc(F)cc1)OC
Agent: COP(OC)OC
Product: COP(=O)(Cc1ccccc1C)OC

Procedure:
Following the procedure of Compound 11, 2-methylbenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[N:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:21](Cl)(=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].Cl>N1C=CC=CC=1>[C:17]([C:14]1[S:13][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:21](=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[N:16][N:15]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1nnc(NS(=O)(=O)c2ccc(N)cc2)s1
Reactant: CCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(C(C)(C)C)s2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
Compound 113 (250 mg, 0.80 mmol) was suspended in pyridine (1.5 mL). Decanoyl chloride (122 mg, 0.64 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred for 1 h. The reaction mixture was then added to aqueous 3 N HCl solution (4 mL) and the mixture extracted with ethyl acetate (3×10 mL). The organic extracts were washed with water (3×20 mL), brine (3×20 mL), dried over anhydrous Na2SO4, and filtered. Evaporation of the solvent left a residue which was crystallized from hexanes and ethyl acetate (1:2) to give the product (294 mg, 0.63 mmol, 98%) as a solid, mp 156-157° C.; 1H NMR (500 MHz, DMSO) δ 0.80 (3, t, J=7.0 Hz), 1.15-1.33 (21, m), 1.56 (2, t, J=7.0 Hz), 2.32 (3, t, J=7.0 Hz), 7.74 (2, d, J=8.0 Hz), 7.77 (2, d, J=8.0 Hz), 10.21 (1, s), 13.90 (1, s); 13C NMR (125 MHz, DMSO): δ 13.9, 22.1, 25.0, 28.6, 28.7, 28.8, 28.9, 29.3, 31.1, 36.0, 36.5, 118.6, 126.9, 135.7, 142.9, 167.0, 167.2, 171.9; MS (LCQ, ESI+) Calculated for C22H35N4O3S2 467.2. found 467.2 (M+H)+. HRMS (FAB+, m/z) Calculated for C22H35N4O3S2 467.2151. found 467.2131 (M+H)+.
Reaction SMILES: C([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[C:15]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=3[S:17][CH:18]=2)[C:5]1=[O:24])(C)=C.CO.Cl>O>[CH3:23][C:22]1[C:15]2[C:14]([CH2:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[NH:4][C:5]3=[O:24])=[CH:18][S:17][C:16]=2[CH:19]=[CH:20][CH:21]=1
Reactant: C=C(C)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cccc2scc(Cn3c(=O)[nH]c4ccccc43)c12
Temperature: 65 °C
Yield: 113.2 %

Procedure:
1-Isopropenyl-3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (0.70 g, 2.1 mmol) was treated with MeOH (10 mL) followed by water (10 mL). To this heterogeneous reaction mixture was added 37% hydrochloric acid (5 mL). This reaction mixture was heated to 65° C. for 3 h. The reaction mixture maintained as a heterogeneous mixture with white precipitates. The reaction mixture was extracted with CH2Cl2 (×2). The combined organic phase was washed with water. The organic phase was dried over Na2SO4 and concentrated to afford 0.7 g of the desired product as a white scaly solid.