Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([O:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][NH2:16])[CH:6]=1)[CH3:3].[O:17]1[CH2:22][CH2:21][S:20][CH2:19][C:18]1=[O:23]>>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([O:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][NH:16][C:18](=[O:23])[CH2:19][S:20][CH2:21][CH2:22][OH:17])[CH:6]=1)[CH3:3]
Reactant: CN(C)Cc1ccnc(OC/C=C\CN)c1
Reactant: O=C1CSCCO1
Product: CN(C)Cc1ccnc(OC/C=C\CNC(=O)CSCCO)c1
Yield: 53 %

Procedure:
Following a procedure similar to that described in Example 68, but using 4-(4-dimethylaminomethyl-2-pyridyloxy)-cis-2-butenylamine and 1,4-oxathian-2-one as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a 53% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[C:5]([N+:17]([O-])=O)[CH:4]=2.[OH-].[Na+]>C(O)(=O)C.[Pd]>[NH2:17][C:5]1[CH:4]=[C:3]2[C:8]([N:9]=[C:10]3[C:15](=[C:2]2[NH2:1])[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=1
Reactant: Nc1c2c(nc3ccc([N+](=O)[O-])cc13)CCCC2=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ccc2nc3c(c(N)c2c1)C(=O)CCC3

Procedure:
In 250 ml of glacial acetic acid was dissolved 4.43 g of 9-amino-3,4-dihydro-7-nitroacridin-1(2H)-one and 0.44 g of 10% Pd/C was added. The mixture was put in a 500 ml hydrogenation vessel (Parr) and was shaken under 55 psig (initial) H2. The uptake of H2 was 3 eq before the reaction as complete. The reaction was poured into ice and made basic with 10% NaOH. The precipitate was filtered and dissolved in MeOH. The insoluble Pd/C catalyst was filtered off and the filtrate was diluted with toluene and concentrated until crystallization occurred. The yield was 2.84 g (73%) of a solid, melting point 310° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1([F:19])[CH2:13][CH2:12][CH:11]([C:14](OCC)=[O:15])[CH2:10][CH2:9]1>C(OCC)C>[F:7][C:8]1([F:19])[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1
Reactant: CCOC(=O)C1CCC(F)(F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC1CCC(F)(F)CC1

Procedure:
To a suspension of lithium aluminum hydride (2.6 g, 69 mmol) in diethyl ether (160 mL,) was added slowly a solution of commercially available ethyl 4,4-difluorocyclohexanecarboxylate (Matrix, 11.0 g, 57 mmol) in diethyl ether (20 mL). The reaction mixture was refluxed for 4 hours, then cooled in an ice bath, quenched cautiously with sequential addition of water (2.6 mL.), 15% NaOH (2.6 mL) and water (7.8 mL) and extracted with ethyl acetate (3×100 mL). The mixture was filtered and concentrated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:34])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11]C(C3C=CC(C(C)(C)C)=CC=3OCC)=[N:9]2)=[CH:4][CH:3]=1.CO[C:37](=O)[C:38]1[CH:43]=[C:42]([S:44]([N:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)(=[O:46])=[O:45])[C:41]([Cl:52])=[CH:40][C:39]=1[O:53][CH2:54][CH3:55].C[Al](C)C>>[Cl:52][C:41]1[C:42]([S:44]([N:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)(=[O:46])=[O:45])=[CH:43][C:38]([C:37]2[NH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH3:34])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]=2)=[C:39]([O:53][CH2:54][CH3:55])[CH:40]=1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: CCOc1cc(Cl)c(S(=O)(=O)N2CCCC2)cc1C(=O)OC
Agent: C[Al](C)C
Product: CCOc1cc(Cl)c(S(=O)(=O)N2CCCC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1

Procedure:
In a manner analogous to the method described in example 2, meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) was reacted with 4-chloro-2-ethoxy-5-(pyrrolidine-1-sulfonyl)benzoic acid methyl ester (prepared in an analogous manner as described in example 43) in the presence of trimethylaluminum to give the title compound. HR-MS (ES, m/z) calculated for C29H33N3O3SCl3 [(M+H)+] 608.1303, observed 608.1300.
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[CH2:8]([O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:15][CH:14]=1)=[O:12])[CH3:9].[N:39]1([CH2:44][C:45](=O)[CH2:46][CH2:47][CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[CH:43]=[CH:42][N:41]=[CH:40]1>CN(C)C=O>[N:39]1([CH2:44]/[C:45](/[CH2:46][CH2:47][CH2:48][C:49]2[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=2)=[CH:19]\[C:16]2[CH:15]=[CH:14][C:13]([C:11]([O:10][CH2:8][CH3:9])=[O:12])=[CH:18][CH:17]=2)[CH:43]=[CH:42][N:41]=[CH:40]1
Reactant: CCOC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(CCCC(=O)Cn2ccnc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(/C=C(/CCCc2ccc(OC)cc2)Cn2ccnc2)cc1
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of potassium t-butoxide (5.0 g, 0.045 mol) in dry dimethylformamide (20 ml) at room temperature under a nitrogen atmosphere was treated with [[4-(ethoxycarbonyl)phenyl]methyl]triphenylphosphonium bromide (20.0 g, 0.0396 mol) in portions over 5 minutes. The resulting red suspension was stirred for 5 minutes and then treated dropwise with a solution of 1-(1H-imidazol-1-yl)-5-(4-methoxyphenyl)-2-pentanone (Example 8d; 4.0 g, 0.0155 mol) in dry dimethylformamidie (4 ml) over 5 minutes. The mixture was then heated at 120° C. for 1 hour. On cooling the reaction mixture was poured onto ice water (200 ml) and extracted with ethyl acetate (2×50 ml). The extracts were combined, washed with water, dried over magnesium sulfate and the solvent was evaporated off under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, 5% methanol in dichloromethane) to initially yield the less polar isomer, ethyl 4-[2-(1H-imidazol-1-ylmethyl)-5-(4-methoxyphenyl)-1Z-pentenyl]benzoate as a pale yellow oil having the following structural chracteristics:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11](OB(O)O)=[C:10]([F:19])[CH:9]=1.[F:20][C:21]1[CH:28]=[C:27](Br)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:27]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:20])[CH:28]=2)=[C:10]([F:19])[CH:9]=1
Reactant: OB(O)Oc1c(F)cc(CCC2OCCO2)cc1F
Reactant: N#Cc1ccc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(-c2c(F)cc(CCC3OCCO3)cc2F)cc1F
Yield: 66 %

Procedure:
To 300 ml of DMF were added 14 g (54 mmol) of 4-(1,3-dioxolan-2-ylethyl)-2,6-difluorophenylboric acid obtained in Step 2 of Example 1, 10 g (50 mmol) of 2-floro-4-bromobenzonitrile, 20 g (198 mol) of triethyl amine, 0.50 g (2.2 mmol) of palladium acetate, and 0.50 g (3.8 mmol) of triphenylphosphine, and the mixture was refluxed for 7 hours. The solvent was distilled off under reduced pressure. To the residue were added 700 ml of methylene chloride and 300 ml of a 10% aqueous ammonia, and the mixture was stirred. The organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography on silica gel (eluting solvent: toluene/ethyl acetate=5/1). The solvent was distilled under reduced pressure and the residue was washed with ethanol and then dried under reduced pressure to afford 11 g (33 mmol) of 1-(1,3-dioxolan-2-ylethyl)-3,5-difluoro-4-(3-fluoro-4-cyanophenyl)benzene.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:16]=[CH:15][S:14][C:4]=2[S:5](=[O:13])(=[O:12])[CH2:6][C:7]=1[C:8]([O:10]C)=O.[NH2:17][C:18]1[CH:22]=[C:21]([CH3:23])[O:20][N:19]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:3]2[CH:16]=[CH:15][S:14][C:4]=2[S:5](=[O:13])(=[O:12])[CH2:6][C:7]=1[C:8]([NH:17][C:18]1[CH:22]=[C:21]([CH3:23])[O:20][N:19]=1)=[O:10]
Reactant: COC(=O)C1=C(O)c2ccsc2S(=O)(=O)C1
Reactant: Cc1cc(N)no1
Solvent: Cc1ccccc1C
Product: Cc1cc(NC(=O)C2=C(O)c3ccsc3S(=O)(=O)C2)no1
Temperature: 5 °C
Yield: 56.2 %

Procedure:
A mixture of methyl 4-hydroxy-6H-thieno[2,3-b]thiopyran-5-carboxylate 7,7-dioxide (3.1 g, 0.012 mole), 3-amino-5-methylisoxazole (1.5 g, 0.015 mole) and xylene (120 ml) is refluxed for 1.5 hrs. in a Soxhlet apparatus, the thimble of which contains 15 g of Linde type 4A molecular sieve. The mixture is cooled to 5° C. in an ice-bath, and the resulting crystalline precipitate is collected. The filtrate is refluxed for two additional hours and then cooled to give a second crop. The two fractions are combined and recrystallized from CH2Cl2 --CHCl3 mixture to give a off-white crystalline solid (2.2 g, 56%), m.p. 209-210° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:13]1[CH:18]=[CH:17][C:16]([O:19][C:20](Cl)=[S:21])=[CH:15][CH:14]=1>C(Cl)Cl>[CH3:12][C:3]1[C:2]([NH:1][C:20](=[S:21])[O:19][C:16]2[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: Cc1nc2ccccc2cc1N
Solvent: ClCCl
Product: Cc1nc2ccccc2cc1NC(=S)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
3-Amino-2-methylquinoline(4 g, 25 mmol) and phenyl chlorothionoformate(4.32 g, 25 mmol) were dissolved in methylene chloride and then was stirred at room temperature for 2 hours. The mixture solution was concentrated under reduced pressure to remove methylene chloride and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: I[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH3:7][O:8][C:9](=[O:34])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:18](=[O:27])[C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:11]=1>>[CH3:7][O:8][C:9](=[O:34])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)/[C:19](=[C:20](/[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)\[C:2]3[CH:6]=[CH:5][S:4][CH:3]=3)/[C:18]2=[O:27])[CH:11]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Reactant: Ic1ccsc1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccsc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 3-iodo-thiophene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.91 (s, 3H), 4.96 (s, 2H), 6.65 (d, 1H), 6.76-6.82 (m, 2H), 7.06-7.11 (m, 2H), 7.33-7.43 (m, 8H), 7.50 (d, 1H), 7.92 (d, 1H), 8.01 (s, 1H).
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[CH3:37][C:38]1[S:42][C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:40]([C:49](=O)[CH3:50])[CH:39]=1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:49]([C:40]2[CH:39]=[C:38]([CH3:37])[S:42][C:41]=2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:50]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1cc(C)sc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c(-c2ccccc2)s1
Yield: 6 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(5-methyl-2-phenyl-thiophen-3-yl)-ethanone (56 mg, 0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (8 mg, 6% yield). MS: 544.27 (M+H+) HPLC Procedure A, retention time=17.05 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2[S:26][CH:27]=[CH:28]N=2)=[CH:4][CH2:3]1.F[C:32](F)(F)S(OC1C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC=2C(C)(C)CC=1)(=O)=O>>[CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2[S:26][CH:27]=[CH:28][CH:32]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccs2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoate (Compound 67), 328.0 mg (0.685 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was converted into the title compound (colorless solid) using 186.8 mg (1.37 mmol) of zinc chloride 37.1 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium(0) and 2-lithiothiophene (prepared by the addition of 65.9 mg (0.69 ml, 1.03 mmol) of n-butyllithium (1.5M solution in hexane) to a cold solution (-78° C.) of 86.5 mg (1.03 mmol) of thiophene in 1.0 mL of THF).
Reaction SMILES: [CH2:1]([C:4]1([CH:19]=[CH:20][CH2:21][OH:22])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].[H][H]>C(O)C.[Pd]>[CH2:1]([C:4]1([CH2:19][CH2:20][CH2:21][OH:22])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCC1(C=CCO)c2ccccc2CCc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CCCC1(CCCO)c2ccccc2CCc2ccccc21
Yield: 90.1 %

Procedure:
Dissolved 3-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-prop-2-en-1-ol (4.85 g, 16.70 mmol) in 75 mL of absolute ethanol. Added 10% palladium on carbon catalyst (1.20 g), and hydrogenated on Paar shaker at 58 psi of hydrogen pressure for 16 hours. Filtered to remove catalyst, and evaporated filtrate to give 4.43 g (90% yield) of 3-[10,11-dihydro-5-propyl-5H-dibenzo[a,d]cyclohepten-5-yl]-propanol as a colorless oil. ##STR36##
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][C:3]1=[O:15].[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][N:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]1=[O:15]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cn1ccc(C2CCC(=O)CC2)cc1=O
Product: Cn1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1=O

Procedure:
The title compounds were prepared as white solids from the reductive amination of 1-methyl-4-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:13]1([C:22](Cl)=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>C(N(CC)CC)C>[CH:13]1([C:22]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: O=C(Cl)C1C=Cc2ccccc21
Reactant: C1CCC(CN2CCCC2)NC1
Solvent: CCN(CC)CC
Product: O=C(C1C=Cc2ccccc21)N1CCCCC1CN1CCCC1
Yield: 32.2 %

Procedure:
From 2.36 g of 2-(pyrrolidin-1-ylmethyl)piperidine, 2.5 g of indene-1-carbonyl chloride and 4.88 ml of triethylamine. 1.4 g of 1-(indene-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidine was obtained using a procedure similar to that in Example 2. In a mixed solvent of methanol, water and ethanol (2:1:1), this compound was catalytically reduced with 10% palladium on carbon. After completion of the reduction, the catalyst was filtered off. After evaporation of the solvent, the residue was treated with a 4N 1,4-dioxane solution of hydrogen chloride to obtain 1.05 g of the title compound, melting at 218°-221° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:15][N:16]2[C:24]3[CH:23]=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[C:18]3[CH2:26][N:27]([CH3:30])[CH2:28][CH2:29][C:17]2=3)=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H][H]>CCO.[Pd]>[CH3:30][N:27]1[CH2:28][CH2:29][C:17]2[N:16]([CH2:15][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:24]3[CH:23]=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[C:18]=2[CH2:26]1
Reactant: [H][H]
Reactant: CCOC(=O)C=C(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 3-(4-fluorophenyl)-4-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)but-2-enoate (112 mg, 0.275 mmol) in EtOH (5 mL) was added 20 mg of 10% Pd/C. The reaction mixture was stirred at RT under a hydrogen atmosphere at 60 psi for 24 h. The hydrogen pressure was released and the reaction mixture was filtered through Celite, the catalyst rinsed with EtOH and the filtrate evaporated under reduced pressure to obtain the product.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[S:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[CH:14]=2)[CH2:11][N:10]([CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[S:17]1[C:13]([CH:12]2[CH2:11][N:10]([CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])[CH2:9][CH:8]2[C:6]([OH:7])=[O:5])=[CH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]1=2
Reactant: CC(c1ccccc1)N1CC(C(=O)OC(C)(C)C)C(c2cc3ccccc3s2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(c1ccccc1)N1CC(C(=O)O)C(c2cc3ccccc3s2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from step b) (2.0 g, 0.0077 mol) was dissolved in 20 mL dichloromethane and was treated with 10 mL of TFA and stirred for 2 hours at room temperature. The solvent was evaporated in vacuo to give the crude subtitle compound that was used in the next step without further purification. MS calculated for C21H21NO2S +H: 352, observed: 352.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[C:9]([O:11][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12]
Reactant: O=C1NCc2c(Br)cc(O)cc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1cc(Br)c2c(c1)C(=O)NC2
Yield: 100 %

Procedure:
A mixture of Example 104B (103 mg, 0.45 mmol), Cs2CO3 (164 mg, 0.5 mmol) and t-butyl bromoacetate (0.075 mL, 0.5 mmol) in DMF (2.2 mL) was stirred overnight at room temperature, diluted with water, and filtered. The filter cake was dried to give 154 mg (45%) of the desired product. MS (ESI(+)) m/e 342,344 (M+H)+.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:30])[NH:10][C:11]([CH2:15][NH:16][CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[N:12]2)=[CH:7][CH:6]=1)=[O:4].Cl.O1CCOCC1>C(Cl)Cl>[OH:1][NH:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:30])[NH:10][C:11]([CH2:15][NH:16][CH:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)=[N:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2nc3cc(C(=O)NO)ccc3c(=O)[nH]2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(NO)c1ccc2c(=O)[nH]c(CNC3CCNCC3)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-[({7-[(hydroxyamino)carbonyl]-4-oxo-3,4-dihydroquinazolin-2-yl}methyl)amino]piperidine-1-carboxylate, 1-56 (98 mg, 0.23 mmol) in methylene chloride (3.2 mL) was added 4.0 M hydrochloric acid in 1,4-dioxane (3.2 mL, 12.8 mmol). The reaction mixture was stirred at rt for 2 h. The solid was filtered and washed with DCM to afford N-hydroxy-4-oxo-2-[(piperidin-4-ylamino)methyl]-3,4-dihydroquinazoline-7-carboxamide.2[HCl] (44 mg, 48%). LC-MS: (FA) ES+ 318; 1H NMR (300 MHz, DMSO) δ 12.80 (s, 1H), 11.63 (s, 1H), 10.04 (s, 1H), 9.48-9.28 (m, 1H), 9.07 (s, 1H), 8.18 (d, J=8.3 Hz, 1H), 8.07 (d, J=1.2 Hz, 1H), 7.88 (dd, J=8.3, 1.5 Hz, 1H), 4.28 (s, 2H), 3.45-3.26 (m, 3H), 3.02-2.84 (m, 2H), 2.34-2.20 (m, 2H), 2.11-1.88 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][C:10]1=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=[C:30]=[O:31])[CH:24]=1>C(Cl)Cl>[C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][CH2:13][NH:12][CH:11]([C:30](=[O:31])[NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH3:32])[CH:24]=2)[C:10]1=[O:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN1C(=O)CNCCCc2ccccc21
Reactant: Cc1cccc(N=C=O)c1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)C2NCCCc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)c1

Procedure:
A solution of 1-tert-butyloxycarbonylmethyl-2-oxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine (438 mg, 1.44 mmol) and m-tolylisocyanate (0.2 ml, 1.6 mmol) in DCM (4 ml) was stirred at room temperature for 90 minutes. Evaporation of the solvent gave the crude product which was purified by flash chromatography on silica gel with ethyl acetate-hexane (1:2) as eluant. (550 mg, 87%)
Reaction SMILES: N[C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([F:15])[CH:3]=1.[BrH:16].N([O-])=O.[Na+].S(=O)(=O)(O)O>>[Br:16][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([F:15])[CH:3]=1
Reactant: COC(=O)C(C)c1cc(F)c(N)cc1F
Reactant: Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)C(C)c1cc(F)c(Br)cc1F
Temperature: 2.5 °C
Yield: 77.6 %

Procedure:
To a solution of compound (29a) (3.0 g, 13.9 mmol) in 40% hydrobromic acid (8.0 mL, 54.4 mmol), an aqueous solution (17 mL) of sodium nitrite (1.1 g, 15.7 mmol) was added dropwise under stirring at 0 to 5° C. The solution was allowed to reach room temperature. To the solution, CuBr (1.1 g, 11.2 mmol) and 96% sulfuric acid (0.1 mL) were added, and the mixture was refluxed under stirring for 1 hour. After cooling and subsequent extraction with ethyl acetate, the obtained residue was dissolved in methanol (50 mL). To the obtained mixture, a catalytic amount of concentrated hydrochloric acid (0.1 mL) was added and refluxed for 3 hours. After cooling, the solvent was distilled off and the obtained product was treated with ether (50 mL). The organic layer was dried (over sodium sulfate) and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (4:1) solution to give 3.01 g (73%) of compound (30a) as pale yellow liquid matter.