Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:30]([O:32][CH2:33][CH2:34][CH:35]=O)[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:35][CH2:34][CH2:33][O:32][CH2:30][CH3:31])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOCCC=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CCCOCC)cc1
Reaction time: 20 h
Yield: 92.8 %

Procedure:
To a solution of methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (400 mg) and 3-ethoxypropionaldehyde (0.52 g) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (0.64 g) at room temperature, and the mixture was stirred for 20 hours. To the reaction system was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified with column chromatography (ethyl acetate:hexane=1:4→1:3) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3-ethoxypropyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (452 mg) as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccccc4)CC3)nc2c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 91.5 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate (28 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (23 mg, 0.15 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 36 mg of the titled compound (yield, 92%). 1H NMR (300 MHz, CDCl3): δ 3.27 (s, 4H), 3.73-3.86 (m, 6H), 4.08-4.11 (m, 4H), 6.88-7.03 (m, 4H), 7.15 (s, 1H), 7.26-7.33 (m, 3H), 7.57-7.62 (m, 1H).
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[Cl:17])[C:6](=O)[CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10]>CCOCC.C(Cl)(Cl)Cl>[Br:1][C:9]1[NH:10][C:6]([C:5]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:3]([Cl:2])[CH:4]=2)=[CH:7][C:8]=1[C:11]#[N:12]
Reactant: N#CC(C#N)CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: Br
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(-c2ccc(Cl)c(Cl)c2)[nH]c1Br
Temperature: 0 °C
Yield: 24 %

Procedure:
Hydrogen bromide gas is bubbled through a mixture of (3,4-dichlorophenacyl)malononitrile (10.0 g, 0.0395 mol) in ether (150 mL) and chloroform (100 mL) at a moderate rate, keeping the reaction mixture temperature below 35°-40° C. After ten minutes, TLC shows the reaction is complete by UV analysis. The reaction mixture is poured into an ice-water mixture, the layers are separated and the aqueous layer is extracted with ether. The combined organic layer and ether extracts are dried and concentrated in vacuo to give a brown solid. The brown solid is washed with methylene chloride and filtered to obtain the title compound as an off-white solid (3.0 g, 24%, mp >200° C.) which is identified by IR and NMR spectral analyses.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=2)[NH:12][C:11]=1[C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:38][N:39]([CH3:43])[C:40](Cl)=[O:41]>O1CCCC1>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:40]([N:39]([CH3:43])[CH3:38])=[O:41])[CH:17]=2)[NH:12][C:11]=1[C:20]1[CH:21]=[C:22]([CH3:27])[CH:23]=[C:24]([CH3:26])[CH:25]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCNC(=O)OC(C)(C)C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(NC(=O)N(C)C)cc3c2CCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Finely divided {2-[5-amino-2-(3,5-dimethylphenyl)-1H-indol-3-yl]-ethyl}-carbamic acid tert-butyl ester (265 mg) was suspended in dry tetrahydrofuran (5mL) and diisopropylethylamine (0.146 mL) and dimethylcarbamoyl chloride (0.077 mL) were added. The reaction mixture was stirred at room temperature for 2.5 days. The reaction mixture was concentrated on a rotary evaporator and the residues were applied to four (20×20 cm 1000μ) preparative silica gel plates and eluted with a solvent system comprising methanol and methylene chloride in the ratio (1:9 v/v). The product (299 mg) was isolated as a thick gum that solidified on prolonged standing.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[CH2:6][NH:5][C:4]1=[O:14].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]2.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([NH:2][C@@H:3]1[CH2:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH2:6][NH:5][C:4]1=[O:14])=[O:26])=[CH:19]2
Reactant: N[C@@H]1Cc2ccccc2CNC1=O
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1Cc2ccccc2CNC1=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 16 h
Yield: 44 %

Procedure:
(R)-4-amino-2,3,4,5-tetrahydro-2-benzazepin-3(1H)-one hydrochloride salt (387 mg) (amine free base prepared in U.S. Pat. No. 5,545,735) was added to a mixture of tetrahydrofuran (40 mL), 5-chloroindole-2-carboxylic acid (356 mg), 1-hydroxy-7-azabenzotriazole (272 mg), and 1-[3(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (382 mg) at room temperature. Diisopropylethylamine (202 mg) was added, and the resulting yellow suspension was stirred under argon for 16 h, during which a solution formed. The solution was evaporated under vacuum and the residue was redissolved in ethyl acetate (100 mL). This was washed sequentially with 1.0 M aqueous hydrochloric acid (50 mL), 1.0 M aqueous sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum. The resulting solid crude product was triturated with 20% methanol in diethyl ether (20 mL four times). Drying under vacuum provided pure title compound (283 mg). HPLC/MS [M+H]+, 354.
Reaction SMILES: [CH2:1]([P:3](Cl)([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])=[O:4])[CH3:2].[OH:27][N:28]=[C:29]([CH:34]([CH3:36])[CH3:35])[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl>[CH2:1]([P:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])([O:27][N:28]=[C:29]([CH:34]([CH3:36])[CH3:35])[C:30]([O:32][CH3:33])=[O:31])=[O:4])[CH3:2]
Reactant: COC(=O)C(=NO)C(C)C
Reactant: CCP(=O)(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: ClCCl
Product: CCP(=O)(ON=C(C(=O)OC)C(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate (700 mg, 1.65 mmol) and thionyl chloride (5 ml) is heated under reflux for 2 hours. The reaction mixture is concentrated to dryness to give P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic chloride. To a solution of the phosphinic chloride in methylene chloride (8 ml) is added methyl 2-hydroxyimino-3-methylbutanoate (320 mg, 2.48 mmol) in one portion. The mixture is stirred at RT for 3 hours. The reaction is then worked up in methylene chloride, washed, dried, evaporated to dryness and purified by prep. TLC to yield methyl 2-[P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinyloxyimino]-3-methylbutanoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][NH:6][CH2:7][CH2:8][C:9]([NH2:11])=[O:10].[Cl:15][C:16]1[CH:17]=[C:18]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH:25]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[C:18]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][N:6]([CH2:5][C:4]1[CH:12]=[CH:13][CH:14]=[C:2]([F:1])[CH:3]=1)[CH2:7][CH2:8][C:9]([NH2:11])=[O:10]
Reactant: O=Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Reactant: NC(=O)CCNCc1cccc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)CCN(Cc1cccc(F)c1)Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Yield: 40 %

Procedure:
To a mixture of 3-(3-Fluoro-benzylamino)-propionamide (98 mg, 0.5 mmol), 1-(3,5-dichloro-benzyl)-1H-imidazole-2-carbaldehyde, (see Example 2) (102 mg, 0.4 mmol) and CH2Cl2 (2 mL) was added NaBH(OAc)3 (119 mg, 0.56 mmol). The mixture was stirred at ambient temperature for 3 h before addition of saturated NaHCO3 (8 mL). The mixture was extracted with CH2Cl2 (2×15 mL) and the combined CH2Cl2 extracts dried over Na2SO4. Volatiles were removed in vacuo and the residue purified by column chromatography (silica gel, 20:1 CH2Cl2/MeOH) to provide the title compound (71 mg, 40%) as colorless, viscous oil: ESI MS m/z 435 [C21H21Cl2FN4O+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[CH:17]=[C:16]1[CH2:24][N:25]1[CH2:29][CH2:28][C@H:27]([NH:30][S:31]([C:34]2[S:38][C:37]([C:39]3[S:40][C:41]([Cl:44])=[CH:42][CH:43]=3)=[CH:36][CH:35]=2)(=[O:33])=[O:32])[C:26]1=[O:45])=O)(C)(C)C>C(Cl)Cl>[O:45]=[C:26]1[C@@H:27]([NH:30][S:31]([C:34]2[S:38][C:37]([C:39]3[S:40][C:41]([Cl:44])=[CH:42][CH:43]=3)=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH2:28][CH2:29][N:25]1[CH2:24][C:16]1[NH:15][C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[CH:17]=1
Reactant: CC(C)(C)OC(=O)n1c(CN2CC[C@H](NS(=O)(=O)c3ccc(-c4ccc(Cl)s4)s3)C2=O)cc2cnccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1[C@@H](NS(=O)(=O)c2ccc(-c3ccc(Cl)s3)s2)CCN1Cc1cc2cnccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (1.0 mL, 13.0 mol) is added dropwise to a slurry of 2-[3-(S)-(5′-chloro-[2,2′]bithiophenyl-5-sulfonylamino)-2-oxo-pyrrolidin-1-ylmethyl]pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.13 g, 0.22 mmol) in CH2Cl2 (2 mL) at 0° C. After 30 min. the ice bath is removed and the solution is stirred at room temperature for 4 h. The reaction mixture is concentrated to dryness and the crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 100% CH3CN. The appropriate product fractions are lyophilized to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH2:13][C:14](=[N:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]1=2.N12CCCN=C1CCCCC2.[CH3:34][N:35]=[C:36]=[O:37]>C(Cl)Cl>[CH3:34][NH:35][C:36](=[O:37])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:2]([CH3:1])[C:3]3[C:14](=[N:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:13][CH2:12][C:4]=3[C:5]=2[CH:6]=1
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=NCc1ccccc1
Reactant: CN=C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CNC(=O)Oc1ccc2c(c1)c1c(n2C)C(=NCc2ccccc2)CC1
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a stirred solution of 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol (2.0 g) in CH2Cl2 (40 n-A) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 g) followed by the dropwise addition of methyl isocyanate (0.39 g) in CH2Cl2 (10 ml). The reaction was monitored via TLC and after 3 hours the solution was concentrated and the precipitate was collected and recrystallized from acetonitrile to give 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl methylcarbamate (1.85 grams).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11]Br)=[CH:7][N:6]=1)=[O:4].[F:13][C:14]([F:24])([F:23])[O:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11][O:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:14]([F:13])([F:23])[F:24])[CH:17]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(CBr)cn1
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(COc2cccc(OC(F)(F)F)c2)cn1
Yield: 88.1 %

Procedure:
A solution of 5-bromomethyl-pyrazine-2-carboxylic acid methyl ester (0.305 g, 1.314 mmol) in DMF (6 mL) was treated with 3-trifluoromethoxyphenol (0.280 g, 1.577 mmol) and potassium carbonate (0.400 g, 2.89 mmol) by the general procedure G. The crude product was purified by flash column chromatography on silica gel to give 0.380 g of pure 5-(3-Trifluoromethoxy-phenoxymethyl)-pyrazine-2-carboxylic acid methyl ester. LCMS: 330 (M+2)+
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[C:4]([NH:6][CH:7]([CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])[CH:16]=[CH:15]2)[C:8]([OH:10])=[O:9])=[O:5].C(N(CC)CC)C.[C:42]([O:48][CH2:49]Cl)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]>CCOC(C)=O>[C:42]([O:48][CH2:49][O:9][C:8](=[O:10])[CH:7]([NH:6][C:4](=[O:5])[C:3]1[C:30]([Cl:34])=[CH:31][CH:32]=[CH:33][C:2]=1[Cl:1])[CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])[CH:16]=[CH:15]2)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(NC(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)C(=O)O)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCOC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To 2-[(2,6-dichlorobenzoyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoic acid 38 (534 mg) are added 195 μl of triethylamine and, after 15 minutes, 290 μl of chloromethyl pivalate. The solution is stirred at RT overnight and then poured in AcOEt. The organic phases are washed with water and brine, dried over MgSO4 and concentrated. The resulting residue is purified over silica gel using CH2Cl2/C2H5OH 99/1 as eluent to give ({2-[(2,6-dichlorobenzoyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoyl}oxy)methyl pivalate 129.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].[N:22]1([C:27]2[CH:28]=[C:29]([C:33]3[O:38]C(C)(C)[O:36][C:35](=O)[CH:34]=3)[CH:30]=[CH:31][CH:32]=2)[CH:26]=[CH:25][N:24]=[CH:23]1>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:20][C:35](=[O:36])[CH2:34][C:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:28]=1)=[O:38])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Yield: 99.9 %

Procedure:
Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G9) (142 mg, 0.5 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) (170 mg, 0.63 mmol) according to the general procedure K. Obtained as a light yellow foam (248 mg).
Reaction SMILES: C[O:2][C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O[CH:8]2[CH:5]([CH2:6][CH2:7]2)[O:4]1.C[Si](C)(C)[Cl:18]>C(Cl)Cl>[Cl:18][C@@H:8]1[CH2:7][CH2:6][C@H:5]1[O:4][C:3](=[O:2])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)Cl
Reactant: COC1(c2ccccc2)OC2CCC2O1
Solvent: ClCCl
Product: O=C(O[C@@H]1CC[C@H]1Cl)c1ccccc1
Yield: 97.6 %

Procedure:
26.0 g (0.126 mol) of 3-methoxy-3-phenyl-2,4-dioxa-bicyclo[3,2,0]heptane (stereoisomer mixture) and 17.1 g (0.16 mol) of trimethylchlorosilane in 70 ml of methylene chloride are heated to the reflux for 14 hours. Evaporation and fractional distillation in vacuo gives 25.9 g (98%) of trans-1-chloro-2-benzoyloxy-cyclobutane. Boiling point0.35 94°-95°, melting point 20°.
Reaction SMILES: O=[C:2]1[CH:10]2[CH2:11][C:6]3([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:7][CH:8]([CH2:12][CH:4]([CH2:5]3)[NH:3]1)[CH2:9]2.CO>C1COCC1>[C:6]12([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:11][CH:10]3[CH2:9][CH:8]([CH2:12][CH:4]([NH:3][CH2:2]3)[CH2:5]1)[CH2:7]2
Reactant: CC(C)(C)OC(=O)NC12CC3CC(C1)NC(=O)C(C3)C2
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC12CC3CNC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
A 1.0 M solution of BH3-Me2S in THF (1 5 mmol) was added dropwise to a solution of amide 14B (0.125 mmol) in THF (5 mL). The reaction mixture was heated at reflux for 2 h and was allowed to cool to rt. MeOH (2 mL) was cautiously added and the reaction mixture was concentrated. The residue was triturated with DCM (3×10 mL) and the combined organic layers were dried (Na2SO4) and concentrated to provide amine 15A. The amine was used in the next step without further purification. Data: LC/MS (ESR) m/z 167 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4](=[O:14])[CH2:3]1>C(OCC)(=O)C.CO.[Pt]=O>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:15])([CH3:1])[CH2:3][C:4]2=[O:14])=[CH:9][CH:8]=1
Reactant: CC1(C)CC(=O)c2cc([N+](=O)[O-])ccc21
Agent: O=[Pt]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)CC(=O)c2cc(N)ccc21
Yield: 194.1 %

Procedure:
3,3-Dimethyl-6-nitro-indan-1-one (22.2 g, 54.1 mmol) and platinum oxide (0.44 g, 1.94 mmol) in 30 mL of ethyl acetate and 60 mL of methanol was hydrogenated on a Parr Shaker for 40 min. The mixture was filtered through a pad of celite. The filtrate was evaporated and the residue was triturated with hexane to give 18.4 g (97% yield) of the title product as yellow solids; 1H-NMR (CDCl3) δ1.38 (s, 6H), 2.56 (s, 2H), 6.98 (d, J=2.3 Hz, 1H), 7.02 (dd, J=2.3, 8.2 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H); MS m/e 176 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]3[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH3:35])[C:19](Cl)=[N:18][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.O.C([O-])=O.[NH4+]>CN(C=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:22]3[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH3:35])[CH:19]=[N:18][C:17]=3[N:16]=2)=[CH:13][CH:14]=1
Reactant: CCCn1c(Cl)nc2nc(-c3ccc(OCc4ccccc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1cnc2nc(-c3ccc(O)cc3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 80 °C
Yield: 79.6 %

Procedure:
To a solution of 8-(4-benzyloxy-phenyl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.25 g, 0.00048 mol) in DMF:water nil), 10% Pd/C (0.130 g) and ammonium formate (0.66 g, 0.010 mol) were added and refluxed at 80° C. for 2 hours. The mixture was cooled and filtered through celite bed, solvent was removed and the residue was diluted with water (10 ml), acidified with citric acid and extracted with ethyl acetate (3×10 ml). The organic layer was washed with brine (2×15 ml). It was dried over Na2SO4 and the solvent was removed to obtain pale yellow solid of 8-(4-hydroxy-phenyl)-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.153 g, 80%).
Reaction SMILES: CS(O[CH:6]([CH3:15])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[O:8]([CH2:7][CH:6]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1CNCCN1
Reactant: CC(COc1ccccc1)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(COc1ccccc1)N1CCNCC1

Procedure:
1-Phenoxy-2-propyl methane sulfonate (1 mole), anhydrous piperazine (4 moles) and potassium carbonate (2 moles) are added to 1000 ml methyl ethyl ketone. The mixture is refluxed during 45 hours, with stirring. The solvent is removed in vacuo and the residue is taken up into water and ether. The ethereal phase is again treated with a dilute aqueous hydrochloric acid solution and the aqueous phase is evaporated off. The resulting oil is taken up into a minimum amount of water. Sodium hydroxide (30 g) is added thereto, after which the material is extracted twice with ether. The ether is removed and the residual oil is distilled. B.p. = 104°-105° C./0.1 mm Hg. N.M.R.: consistent.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([CH2:27][C:28]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)Cc1ccccc1
Product: CCOC(=NC(=O)Cc1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and phenylacetyl chloride, there is obtained ethyl N-(phenylacetyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e:M+ 384 (2), 355 (1), 293 (100), 265 (15), 194 (11), 179 (26), 167 (67), 91 (20);
Reaction SMILES: Cl.[C:2](=[NH:10])([O:7][CH2:8][CH3:9])[C:3]([CH3:6])([CH3:5])[CH3:4].N1C(C)=CC(C)=CC=1C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[CH2:24]([O:23][C:21]([N:10]=[C:2]([O:7][CH2:8][CH3:9])[C:3]([CH3:6])([CH3:5])[CH3:4])=[O:22])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=N)C(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)N=C(OCC)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.4 %

Procedure:
Ethyl pivalimidate hydrochloride (Example B3) (0.75 g, 4.5 mmol) was suspended in hexanes (11.3 mL) and DCM (11.3 mL) and cooled to 0° C. 2,4,6-Collidine (2.1 mL, 15.9 mmol) and ethyl chloroformate (0.98 g, 9.1 mmol) were sequentially added and the reaction mixture was allowed to warm to RT and stirred for 12 h. The solvent was removed in vacuo and the residue was slurried with EtOAc (50 mL). The solids were removed by filtration through a pad of diatomaceous earth. The filter cake was washed with EtOAc (3×10 mL) and the combined filtrates were concentrated in vacuo to afford ethyl N-ethoxycarbonylpivalimidate (0.81 g, 89%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 4.05 (q, J=7.1 Hz, 2H), 3.95 (q, J=7.0 Hz, 2H), 1.18 (t, J=7.1 Hz, 3H), 1.18 (t, 7.1 Hz, 3H), 1.15 (s, 9H).