Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.[C:13](OC(=O)C)(=[O:15])[CH3:14].C(N(CC)CC)C>ClCl.O>[C:13]([NH:1][C:2]1([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1)(=[O:15])[CH3:14]
Reactant: COc1ccc(C2(N)CC2)cc1
Reactant: CC(=O)OC(C)=O
Agent: ClCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C2(NC(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 80.1 %

Procedure:
To a stirred suspension of Compound 7 (1.25 g, 7.66 mmol) in CH2 Cl2 (40 ml) was added acetic anhydride (860 mg, 8.42 mmol) and triethylamine (2.32 g, 22.98 mmol) at room temperature. The reaction mixture was stirred at room temperature for 22 h. The mixture was diluted with H2O (50 ml) and stirred for 10 min. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with 10% HCl aq., sat. NaHCO3 aq. and brine, dried (MgSO4) and concentrated in vacuo to give crude product (1.58 g, quant.), which was recrystallized from hexane-ethyl acetate to give Compound 8 (1.26 g, 80%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:32])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]([O:29]C)=[O:28])[C:21](=[O:31])[CH2:20]2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-:33].[Li+].Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:32])[CH2:18][CH:19]([CH2:24][C:23]([NH:22][CH2:26][C:27]([OH:29])=[O:28])=[O:25])[CH2:20][C:21]([OH:33])=[O:31])[CH2:15][CH2:16]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: [OH-]
Reactant: COC(=O)CN1C(=O)CC(CC(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1=O
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)CC(CC(=O)O)CC(=O)NCC(=O)O)CC1
Yield: 108.5 %

Procedure:
To a stirred solution of methyl (4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}-2,6-dioxopiperidin-1-yl)acetate (Example 72, 0.463 g, 1.04 mmol) in THF (5 mL) stirring at 0° C. was added 1 M lithium hydroxide solution (5 mL, 5 mmol). After 3 h the reaction mixture was acidified with 1 M hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to provide 5-[4-(2-tert-butylphenyl)piperazin-1-yl]-3-{2-[(carboxymethyl)amino]-2-oxoethyl}-5-oxopentanoic acid (0.505 g, quant) as a pale brown solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[N:5]=[CH:4][C:3]=1[C:15]([O:17]CC)=[O:16].[OH-].[Na+]>CO.O>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[N:5]=[CH:4][C:3]=1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1cnn(-c2ccccc2OC)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccccc1-n1ncc(C(=O)O)c1C
Yield: 85 %

Procedure:
To a solution of ethyl 5-methyl-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxylate in 15 ml methanol and 17 ml water was added 20 ml of 1 N sodium hydroxide and the resulting mixture was refluxed overnight under nitrogen. The methanol was removed in vacuo and the aqueous phase was acidified with dilute aqueous hydrochloric acid solution and extracted with 2×70 ml ethyl acetate. The combined ethyl acetate extracts were washed with 70 ml water and 70 ml brine, dried over sodium sulfate and concentrated in vacuo to a white solid (2.14 g, 85% yield).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([SH:30])[C@@H:28]([C@H:31]([O:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH3:32])[C:27]1=[O:40])=[P:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3].N1C=CC=CC=1.[F:48][C:49]1[CH:59]=[CH:58][C:52]([O:53][CH2:54][C:55](Cl)=[O:56])=[CH:51][CH:50]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1.[Ag]>[CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([S:30][C:55](=[O:56])[CH2:54][O:53][C:52]2[CH:58]=[CH:59][C:49]([F:48])=[CH:50][CH:51]=2)[C@@H:28]([C@H:31]([O:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH3:32])[C:27]1=[O:40])=[P:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1S
Reactant: O=C(Cl)COc1ccc(F)cc1
Agent: [Ag]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SC(=O)COc1ccc(F)cc1

Procedure:
1.74 g of the silver salt of 2-[(3S,4R)-3-[(1R)-1allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester are reacted in 30 ml of methylene chloride with 0.41 ml of pyridine, 20 mg of 4-dimethylaminopyridine and 0.7 g of 4-fluorophenoxyacetyl chloride. After working up analogously to Example 1, 2-[(3S,4R)-3-[(1R)-1-allyloxycarbonyloxyethyl]-4-(4-fluorophenoxyacetylthio)-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][O:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: O=Cc1ccccc1O
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccccc1OCCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.3 %

Procedure:
To a solution of 2-hydroxybenzaldehyde (226 mg) and 1-(2-bromoethoxy)-4-nitrobenzene (500 mg) in N,N-dimethylformaldehyde (5 mL) was added potassium carbonate (281 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water (20 mL), and the mixture was extracted with ethyl acetate (20 ml). The extract was washed successively with 0.5M aqueous hydrochloric acid solution, 1M aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2-(2-(4-nitrophenoxy)ethoxy)benzaldehyde (560 mg).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[CH:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(O)C.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>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:28]3[CH:29]=[CH:30][C:25]([CH:23]=[O:24])=[CH:26][CH:27]=3)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: O=Cc1ccc(B(O)O)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: [K+]
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccc(C=O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 4) (1 g, 2.71 mmol), (4-formylphenyl)boronic acid (0.487 g, 3.25 mmol, available from Aldrich), Pd(Ph3P)4, (0.156 g, 0.135 mmol) and potassium carbonate (0.487 g, 3.52 mmol) were combined in dry Ethanol (7 ml) and dry toluene (7.00 ml) and the reaction mixture was de-gassed for 10 mins. The reaction mixture was heated at 85° C. overnight. The reaction mixture was allowed to cool to r.t. and concentrated. The crude reaction mixture was partitioned between water (15 ml) and ethyl acetate (5 ml) and stirred at r.t. for 30 mins. A light grey solid precipitated out and was filtered off, washed with water (5 ml) and dried in a vacuum oven to give 854 mg of grey solid. LCMS (Method B): Rt=1.00, MH+=395
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)c1
Reactant: c1nc[nH]n1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3cncn3)nc3sc([N+](=O)[O-])cc23)c1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-nitro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-nitro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])[CH2:10]2)=[C:4]([F:25])[CH:3]=1.[Cu][C:27]#[N:28].CN(C)C=O.[OH-].[NH4+]>O>[O:23]=[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:24])[N:14]1[CH:11]1[CH2:12][CH2:13][CH:9]([C:5]2[C:4]([F:25])=[CH:3][C:2]([C:27]#[N:28])=[C:7]([F:8])[CH:6]=2)[CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(c2cc(F)c(Br)cc2F)C1
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(F)c(C2CCC(N3C(=O)c4ccccc4C3=O)C2)cc1F
Yield: 89.8 %

Procedure:
A suspension of 91.35 g (0.225 mol) of 2-[3-(4-bromo-2,5-difluorophenyl)cyclopentyl]-1H-isoindole-1,3-(2H)-dione, 22.4 g (0.25 mol) of copper (I) cyanide and 250 ml of N,N-dimethylformamide was stirred and heated in a nitrogen atmosphere at 170° for 18 hours. The cooled mixture was poured into a solution of 100 ml of concentrated ammonium hydroxide in 1 L of water. The aqueous mixture was extracted with ether (4×350 ml) and the combined ether layers were washed with water (3×300 ml), dried (MgSO4), and evaporated in vacuo to give 71.2 g of the title compound which was used as is for the next step.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[CH3:15][N:16](C)C(=O)C>CO.C(OCC)(=O)C.[Zn].[C-]#N.[Zn+2].[C-]#N>[C:15]([C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[NH:4][N:3]=1)#[N:16]
Reactant: CC(=O)N(C)C
Reactant: COC(=O)c1cnc2[nH]nc(Br)c2c1
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc2[nH]nc(C#N)c2c1
Temperature: 120 °C
Yield: 39 %

Procedure:
Methyl 3-bromo-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1.28 g, 5.01 mmol) was combined with N,N-dimethylacetamide (34 mL). To this mixture was added zinc dust (195 mg, 2.90 mmol) and zinc cyanide (1.20 g, 10.2 mmol). Nitrogen was bubbled through the mixture for 30 minutes. Then 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (611 mg, 0.749 mmol) was added and the reaction vessel was sealed. The reaction was heated to 120° C. for 65 hours. The reaction was diluted with 20% methanol/ethyl acetate and filtered through Celite. The filtrate was diluted with water and transferred to a separatory funnel. The phases were separated, and the organics were washed again with water and brine. The organics were then dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-75% ethyl acetate/heptanes) gave the title compound (390 mg, 39%). +ESI (M+H) 203.1.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:17])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[NH:10][C:9](=[O:15])[C:8]([CH3:16])=[CH:7]2)[CH:2]=[CH2:3].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:18][CH2:3][CH:2]1[O:17][C:5]2=[C:6]3[C:11](=[C:12]([CH3:14])[CH:13]=[C:4]2[CH2:1]1)[NH:10][C:9](=[O:15])[C:8]([CH3:16])=[CH:7]3
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCc1cc(C)c2[nH]c(=O)c(C)cc2c1O
Solvent: ClC(Cl)Cl
Product: Cc1cc2c3c(cc(C)c2[nH]c1=O)CC(CBr)O3
Temperature: 75 °C
Reaction time: 0.42 h
Yield: 65.4 %

Procedure:
To 6-allyl-5-hydroxy-3,8-dimethylcarbostyril (3.86 g, 16.68 mmol), N-bromsuccinimide (3.0 g, 16.68 mmol) and chloroform (140 ml) were added, and stirred for 25 minutes in a bath at 75° C. After cooling, the mixture was washed with water, dried, and condensed. The resultant residue was subjected to recrystallization (chloroform-methanol-ether) to obtain 3.36 g of the title compound as pale yellow prisms (64.7%).
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.C1(C2C3C=CC=CC=3N(CC(C3CCCC3)=O)C(=O)N(CC(O)=O)N=2)CCCCC1.[C:70]([O:74][C:75](=[O:85])[N:76](C1C=CC=C(N)C=1)[CH3:77])([CH3:73])([CH3:72])[CH3:71].C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[C:70]([O:74][C:75](=[O:85])[N:76]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:77])([CH3:73])([CH3:72])[CH3:71]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: COC(=O)c1cccc(N)c1
Agent: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 22, step a) and (3-amino-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step c) were used in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. 1H NMR (CDCl3) 8.07 (1H, s), 7.47 (2H, m), 7.27 (1H, m), 7.04 (2H, m), 6.92 (1H, t), 6.44 (1H, dd), 6.31 (1H, dd), 4.64 (1H, d), 4.48 (1H, d), 4.36 (1H, d), 4.13 (1H, d), 3.71 (1H, br s), 2.95 (1H, m), 2.80 (4H, m), 2.05-1.56 (13H, m), 1.27 (5H, m). The compound was further characterised as the hydrochloride salt. Found: C, 64.90; H, 7.02; N, 12.57%; C30H37N4O3.HCl requires: C, 65.26; H, 6.94; N, 12.68%.
Reaction SMILES: [CH3:1][C:2]([CH3:48])([CH3:47])[Si:3]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[O:4][CH2:5][CH:6]([C:31]([F:34])([F:33])[F:32])[NH:7]/[C:8](=[N:20]/C(=O)OCC1C=CC=CC=1)/[NH:9]C(=O)OCC1C=CC=CC=1.[H][H]>CCO.C1COCC1.[OH-].[OH-].[Pd+2]>[Si:3]([O:4][CH2:5][CH:6]([NH:7][C:8]([NH2:20])=[NH:9])[C:31]([F:34])([F:33])[F:32])([C:2]([CH3:1])([CH3:47])[CH3:48])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: [H][H]
Reactant: CC(C)(C)[Si](OCC(N/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(F)(F)F)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)[Si](OCC(NC(=N)N)C(F)(F)F)(c1ccccc1)c1ccccc1
Yield: 100 %

Procedure:
To a stirred solution of 346 (210 mg, 0.310 mmol) in 95% EtOH/THF (5 mL, 1:1) was added Pearlman's Catalyst (21.8 mg, 0.0310 mmol). The suspension was put through a vacuum/purge cycle three times with hydrogen gas and then maintained under 1 atmosphere of hydrogen pressure overnight. The mixture was then filtered through GF/F filter paper with 95% ethanol and the filtrate was concentrated to afford 127 mg (100%) of 1-(3-(tert-butyldiphenylsilyloxy)-1,1,1-trifluoropropan-2-yl)guanidine (348) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH3:13])[CH:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].[CH3:22]I.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:22])[C:7](=[O:12])[N:6]([CH3:13])[CH:5]2[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN1C(=O)Nc2ccc(Br)cc2C1c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)N(C)C(c2ccccc2)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-Bromo-3-methyl-4-phenyl-3,4-dihydro-1H-quinazolin-2-one (0.2 g, 0.6 mmol) in DMF (10 mL) is cooled to 0° C., then NaH (16.7 mg, 0.7 mmol) is added. After the addition the mixture is stirred at 0° C. for 0.5 h. Then CH3I (107 mg, 0.76 mmol) is added and the mixture is stirred at r.t. for 2 h. Then H2O is added and is extracted with EtOAc, dried over Na2SO4 and concentrated to give product. This is used in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].C([NH:28][C@H:29]([C:31](O)=[O:32])[CH3:30])(OC(C)(C)C)=O>>[NH2:28][C@H:29]([C:31]([C:2]1([NH2:1])[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20])=[O:32])[CH3:30]
Reactant: CN1C(=O)C(N)N=C(N2CCCCC2)c2ccccc21
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: C[C@H](N)C(=O)C1(N)N=C(N2CCCCC2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3-amino-1,3-dihydro-1-methyl-5-(1-piperidinyl)-2H-1,4-benzodiazepin-2-one (Example 4-A) and N-Boc Alanine (Novabiochem), the title compound was prepared as a white foam.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C.[NH2:38][C@@H:39]([CH3:58])[C:40]([N:42]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:43][CH:44]([O:48][CH2:49][CH3:50])[O:45][CH2:46][CH3:47])=[O:41]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:51]([N:42]([CH2:43][CH:44]([O:45][CH2:46][CH3:47])[O:48][CH2:49][CH3:50])[C:40](=[O:41])[C@@H:39]([NH:38][C:13](=[O:15])[CH2:12][O:11][NH:10][C:9]([NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:16])[CH3:58])[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: O=C(O)CONC(=O)NCc1ccccc1
Reactant: CCOC(CN(Cc1ccccc1)C(=O)[C@H](C)N)OCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: CCOC(CN(Cc1ccccc1)C(=O)[C@H](C)NC(=O)CONC(=O)NCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a solution of 2-(3-benzylureidooxy)acetic acid (Compound VI-6) (53.8 mg, 0.24 mmol) and hydroxybenzotriazol (40.5 mg, 0.3 mmol) in dichloromethane (1 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (57.5 mg, 0.3 mmol) and 4-dimethylaminopyridine (2.4 mg, 0.02 mmol) and the mixture was stirred at room temperature for 0.5 hr. A solution of (S)-2-amino-N-benzyl-N-(2,2-diethoxyethyl)propanamide (Compound IV-19) (58.9 mg, 0.2 mmol) in dichloromethane (1 ml) was added to the reaction mixture and the mixture was stirred at room temperature for 18 hr. The reaction mixture was washed with sat. NaHCO3 aq. (1 ml), water (1 ml) and brine (1 ml). The organic layer was filtered on Celite (1 g) and magnesium sulfate (150 mg). The filtrate was concentrated in vacuo and the residue was purified with PTLC (development solvent: chloroform:methanol=98:2) to obtain the titled compound (60 mg, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[C:3]=1[F:10].CC(C)([O-])C.[K+].[O:17]1[CH2:21][CH2:20][O:19][CH:18]1[C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:36][C:35]3[C:30](=[N:31][CH:32]=[CH:33][C:34]=3Cl)[CH:29]=2)=[N:26][CH:27]=1.O>CS(C)=O>[O:17]1[CH2:21][CH2:20][O:19][CH:18]1[C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:36][C:35]3[C:30](=[N:31][CH:32]=[CH:33][C:34]=3[O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([F:10])[C:4]=3[F:9])[CH:29]=2)=[N:26][CH:27]=1
Reactant: Nc1ccc(O)c(F)c1F
Reactant: Clc1ccnc2cc(-c3ccc(C4OCCO4)cn3)sc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To a solution of 4-amino-2,3-difluorophenol (1.59 g, 7.49 mmol) in DMSO (10 mL) was added potassium tert-butoxide (1.1 g, 8.98 mmol), and the reaction mixture was stirred for 2 hours. Chloride 301 (1.6 g, 4.99 mmol) was added and the reaction mixture was heated at 100° C. for 2 hours. The mixture was cooled down then poured into water (150 mL) at 40-45° C. and stirred for 30 min. The precipitate was collected by filtration, washed with water and dried overnight. The crude product was triturated with EtOAc/Hexane (2/1, 100 mL) for 1 h, to afford title compound 302 (1.7 g, 79% yield) as a pale violet solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.70 (d, J=2.1 Hz, 1H), 8.53 (d, J=5.4 Hz, 1H), 8.39 (s, 1H), 8.31 (d, J=8.1 Hz, 1H), 7.98 (dd, J=8.1, 2.1 Hz, 1H), 7.10-7.00 (m, 1H), 6.71 (d, J=5.1 Hz, 1H), 6.72-6.61 (m, 1H), 5.90 (s, 1H), 5.64 (s, 2H), 4.16-3.96 (m, 4H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13].CC(C)([O-])C.[K+]>CN(C=O)C.CCOCC>[N+:12]([C:11]1[CH:10]=[CH:9][S:8][C:7]=1[N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)([O-:14])=[O:13]
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1ccsc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccsc1-n1cncn1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
1H-1,2,4-triazole (582 mg, 8.43 mmol), 2-chloro-3-nitrothiophene (1.15 g, 7.03 mmol) and potassium t-butoxide (944 mg, 8.43 mmol) were dissolved in DMF (30 mL). The resulting solution was stirred at 90° C. for 2 h, after which the reaction mixture was cooled to room temperature and diluted with Et2O. The solution was washed with brine and the organic phase was separated, dried (Na2SO4), filtered, concentrated under vacuum to give 1-(3-nitrothiophen-2-yl)-1H-1,2,4-triazole. Retention time (min)=1.073, method [1], MS(ESI) 197.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][CH2:13][C:14](=O)[CH2:15][CH3:16].N1CCCC1>CO>[CH2:13]([C:14]1([CH2:15][CH3:16])[CH2:9][C:8](=[O:10])[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:7]=2)[O:11]1)[CH3:12]
Reactant: CCC(=O)CC
Reactant: CC(=O)c1cc(F)ccc1O
Solvent: CO
Solvent: C1CCNC1
Product: CCC1(CC)CC(=O)c2cc(F)ccc2O1
Temperature: 60 °C
Yield: 89.3 %

Procedure:
1-(5-Fluoro-2-hydroxyphenyl)ethanone (30.2 g, 196 mmol) and MeOH (300 mL) were stirred at ambient temperature and 3-pentanone (41.6 mL, 392 mmol) and pyrrolidine (17.8 mL, 216 mmol) were added. The mixture was heated to 60° C. for 62 h at which point LCMS analysis showed clean conversion to product. The reaction was cooled, concentrated to a minimal volume of MeOH, and MTBE (300 mL) was added. The organics were washed with 2N HCl (150 mL), brine (60 mL), 2N NaOH (150 mL), and brine (60 mL). The solution was passed through a plug of silica gel (30 g), washing with MTBE (150 mL). The filtrate was concentrated, giving the title compound (38.8 g, 175 mmol, 89%) as a light brown oil. MS (DCI/NH3) m/z 240 (M+NH4)+.