Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrBr.[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:21][CH2:22][CH3:23])[NH:10][C:9]2=[O:24].[Br:25]N1C(=O)CCC1=O>C(O)(=O)C.CN(C)C=O>[Br:25][C:18]1[CH:17]=[CH:16][C:15]([O:20][CH2:21][CH2:22][CH3:23])=[C:14]([C:11]2[NH:10][C:9](=[O:24])[C:8]3[C:13](=[C:4]([CH3:3])[CH:5]=[CH:6][CH:7]=3)[N:12]=2)[CH:19]=1
Reactant: CCCOc1ccccc1-c1nc2c(C)cccc2c(=O)[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: BrBr
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCOc1ccc(Br)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Temperature: 105 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
Bromine (3.2 g, 0.020 mol) was added dropwise to a stirred solution of 8-methyl-2-(2-n-propoxyphenyl)-quinazolin-4(3H)-one (3 g, 0.010 mol) in glacial acetic acid (45 ml) at 95° C. The resulting suspension was heated at 105° C. for 18 hours and then evaporated under vacuum. The resulting solid was dissolved in dimethylformamide (25 ml) and the stirred solution treated dropwise with a solution of N-bromosuccinimide (0.89 g, 0.0051 mol) in dimethylformamide (25 ml). After 1 hour at ambient temperature, the solvent was evaporated under vacuum and the residue dissolved in ethyl acetate (50 ml). This solution was washed with saturated aqueous sodium carbonate solution (50 ml), dried (Na2SO4) and evaporated under vacuum. The residue was chromatographed on silica gel (30 g) using a methanol in dichloromethane elution gradient (0-100%) to give the title compound as a white solid (1.67 g, 45%), m.p. 179-180° C.; Rf 0.7 (silica; dichloromethane-methanol; 99:1). This material was used without any further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][C:6]2[CH:8]=[CH:9][C:10]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])=[CH:11][C:5]=2[CH:4]2[O:21][CH:3]12.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[N+:30]([C:27]1[CH:28]=[CH:29][C:24](=[O:23])[N:25]([C@H:4]2[C@H:3]([OH:21])[C:2]([CH3:1])([CH3:22])[O:7][C:6]3[CH:8]=[CH:9][C:10]([S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)(=[O:14])=[O:13])=[CH:11][C:5]2=3)[CH:26]=1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: CC1(C)Oc2ccc(S(=O)(=O)c3ccccc3)cc2C2OC21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(S(=O)(=O)c3ccccc3)cc2[C@@H](n2cc([N+](=O)[O-])ccc2=O)[C@@H]1O

Procedure:
4.00 g (12.6 mmol) of 3,4-dihydro-2,2-dimethyl-3,4-epoxy-6-(phenylsulfonyl)-2H-benzo[b]pyran and 1.77 g (12.6 mmol) of 2-hydroxy-5-nitropyridine are suspended in a little absolute THF, and 16.7 ml (12.6 mmol) of a 1 M solution of lithium bis-trimethylsilylamide are added dropwise under argon with stirring and ice cooling. The mixture is stirred at room temperature for a further 72 hours, hydrolyzed and extracted three times with ethyl acetate. The combined organic extracts are washed with water and saturated sodium chloride solution and dried over sodium sulfate. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel (ethyl acetate/ cyclohexane 1:1). The compound can be crystallized in ethyl acetate.
Reaction SMILES: [CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9]CC(Cl)(Cl)Cl)=[O:8])[N:5]1[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C@H:4]1[S:3]2>CN(C)C=O.C(O)(=O)C.[Zn]>[CH3:1][C:2]12[CH2:15][C:6]1([C:7]([OH:9])=[O:8])[N:5]1[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C@H:4]1[S:3]2
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cc3cccs3)[C@H]1S2
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC12CC1(C(=O)O)N1C(=O)C(NC(=O)Cc3cccs3)[C@H]1S2
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-[2-(2-thienyl)acetamido]penam-3-carboxylate (1.4 g.) in a mixture of dimethylformamide (7.5 ml.) and acetic acid (1.75 ml.) was added zinc powder (1.8 g.) unde ice cooling, and the mixture was stirred for 1 hour. After the reaction, the reaction mixture was post-treated in the similar manner as described in Example 1 to give 2-methyl-2,3-methylene-6-[2-(2-thienyl)acetamido]penam-3-carboxylic acid (0.8 g.), mp 106° to 108°C (dec.) Infrared Absorption Spectrum (Nujol): 3350, 1765, 1720 cm-1
Reaction SMILES: CO.[N:3]1[CH:8]=[CH:7][C:6]([O:9][CH:10]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)[CH3:11])=[CH:5][CH:4]=1.[OH-].[Li+].Cl>O>[N:3]1[CH:4]=[CH:5][C:6]([O:9][CH:10]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=2)[CH3:11])=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(C(C)Oc2ccncc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(Oc1ccncc1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.5 %

Procedure:
To a mixed solution of methanol (10 mL) and water (2 mL), methyl 4-(1-(pyridin-4-yloxy)ethyl)benzoate (151 mg, 0.59 mmol) and lithium hydroxide were added. The mixture was stirred at room temperature for 12 hours. Then the reaction mixture was acidified by hydrogen chloride aqueous solution (1N) to adjust pH=6, and then extracted with dichloromethane (20 mL×3). And the mixture was concentrated to give 4-(1-(pyridin-4-yloxy)ethyl)benzoic acid (127 mg, 88%).
Reaction SMILES: NC1C=C(CN2C=CN=C2)C=CC=1NC(=O)C.[NH2:18][C:19]1[CH:24]=[C:23]([CH:25]([N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[CH3:26])[CH:22]=[CH:21][C:20]=1[NH:32][C:33](=[O:35])C>>[NH2:18][C:19]1[CH:24]=[C:23]([CH:25]([N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[CH3:26])[CH:22]=[CH:21][C:20]=1[NH:32][CH:33]=[O:35]
Reactant: CC(=O)Nc1ccc(C(C)n2ccnc2)cc1N
Agent: CC(=O)Nc1ccc(Cn2ccnc2)cc1N
Product: CC(c1ccc(NC=O)c(N)c1)n1ccnc1

Procedure:
N-[2-amino-4-(1H-imidazol-1-ylmethyl)phenyl]acetamide as a solid residue (int. 122); and N-[2-amino-4-[1-(1H-imidazol-1-yl)ethyl]phenyl]acetamide; mp. 211.7° C. (int. 123).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]([OH:12])[CH3:11])[C:4]=2[O:3][CH2:2]1.C(N(CC)CC)C>C1COCC1.ClCCl.[O-2].[O-2].[Mn+4]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10](=[O:12])[CH3:11])[C:4]=2[O:3][CH2:2]1
Reactant: CC(O)c1cccc2c1OCO2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)c1cccc2c1OCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
To a solution of 1-benzo[1,3]dioxol-4-ylethanol (11 g, 66.3 mmol) in 100 mL of THF was added 17.26 g of manganese dioxide (MnO2) in one portion and reaction was monitored by TLC. After several hours, TLC showed some product but significant alcohol left. More manganese dioxide was added and the solution stirred. TLC then showed mostly product but a significant amount of alcohol. The reaction mixture was then filtered through a bed of diatomaceous earth and the filtrate was concentrated in vacuo to give an oil that mostly crystallized on standing. To 9.24 mL of a solution of oxalyl chloride in 120 mL of dichloromethane at −60° C. was added a solution of 15 mL of DMSO in 20 mL of dichloromethane. After 10 minutes, a solution of above alcohol/ketone mixture (53 mmol) in 20 mL of dichloromethane was added, followed 15 minutes later by 44.3 mL of triethylamine. The reaction was allowed to slowly warm to room temperature overnight. The reaction mixture was then poured onto ice and the organic layer was washed with five 100 mL portions of water, then brine, and then dried over magnesium sulfate. The organics were concentrated in vacuo to leave tan solids and the solids were triturated with hexanes, collected by filtration, and dried to give 9.33 g (85.8% yield) of 1-benzo[1,3]dioxol-4-ylethanone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]1([CH2:16][N:17]=[C:18]=S)[CH2:15][CH2:14]1>C(OCC)(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:18]([NH:17][CH2:16][CH:13]3[CH2:15][CH2:14]3)=[N:12][S:9](=[O:11])(=[O:10])[C:3]=2[CH:4]=1
Reactant: Nc1ccc(Cl)cc1S(N)(=O)=O
Reactant: S=C=NCC1CC1
Solvent: CCOC(C)=O
Product: O=S1(=O)N=C(NCC2CC2)Nc2ccc(Cl)cc21

Procedure:
The title compound was prepared from 2-amino-5-chlorobenzenesulfonamide and cyclopropylmethyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 288-290° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 0.20-0.54 (m, 4H, CH2CH2), 1.05 (m, 1H, CH), 3.10 (distorted t, 1H, NHCH2), 7.22 (d, 1H, ArH), 7.31 (br., 1H, NH), 7.55-7.69 (m, 2H, ArH), 10.7 (br.s, 1H, NH); MS: m/e 285/287 (M+); (C11H12N3Cl1O2S1) calc. C, 46.24; H, 4.23; N, 14.71; found C, 46.48; H, 4.32; N, 14.72.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.Br[CH2:31][CH2:32][OH:33].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][N:25]([CH2:31][CH2:32][OH:33])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: OCCBr
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCNC2)c2cnccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCN(CCO)C2)c2cnccc12
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 1-({5-chloro-1-[(3R)-(pyrrolidin-3-yl)]-1H-benzo[d]imidazol-2-yl}methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (300 mg, 0.70 mmol) in 5 mL of DMF was added 2-bromoethanol (173 mg, 2.1 mmol) and Cs2CO3 (682 mg, 2.1 mmol). The mixture was heated to 70° C. and stirred overnight. The mixture was filtered and then purified by preparative-HPLC to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:17]([C:18]([OH:20])=O)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl.Cl.[NH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO.CCOC(C)=O.CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH:17]([C:18](=[O:20])[NH:25][CH2:26][C:27]([C:29]2[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=2)=[O:28])[CH2:16][C:13]2([CH2:14][CH2:15]2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CC2(CC2)CN1C(=O)OCc1ccccc1
Reactant: NCC(=O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNC(=O)C1CC2(CC2)CN1C(=O)OCc1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester (361 mg, 1.25 mmol) was dissolved in MeOH (10 mL) and LiOH (1 M in H2O, 5 mL, 5 mmol) was added. After stirring for 15 hours at room temperature, the reaction mixture was poured into 10% HCl and the aqueous phase was extracted 3× with DCM. The combined organics were dried over MgSO4, filtered and concentrated. The residue was treated with 2-Amino-1-(4-bromo-phenyl)-ethanone hydrochloride (344 mg, 1.38 mmol), HATU (525 mg, 1.38 mmol) and DMF (14 mL). The suspension was stirred at 0° C. for 21 minutes before DIPEA (0.72 mL, 4.1 mmol) was added dropwise. Immediately after addition, the reaction mixture was warmed to room temperature. 40 minutes later the mixture was diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and brine, then dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (30% to 50% EtOAc/hexane) to afford 6-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester (589 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[N:12]=[C:11]([CH3:25])[N:10]=2)=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C.C(Cl)(Cl)Cl>ClCCCl>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([C:13]2[N:12]=[C:11]([CH3:25])[N:10]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:3][CH:4]=3)[CH:14]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1ccc(-c2cc(Nc3ccc(N)cc3)nc(C)n2)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cc(Nc3ccc(NS(C)(=O)=O)cc3)nc(C)n2)cc1OC

Procedure:
To a solution of 4-(4-aminophenylamino)-6-(3,4-dimethoxyphenyl)-2-methylpyrimidine (1.0 g) in 1,2-dichloroethane (20 ml) were added methanesulfonyl chloride (0.28 ml) and triethylamine (0.83 ml) and the mixture was refluxed for 3 hours. After cooled, chloroform (50 ml) was added thereto, and washed with water. The solution was dried over magnesium sulfate, evaporated, and chromatographed on silica gel eluting with chloroform to give 6-(3,4-dimethoxyphenyl)-4-(4-mesylaminophenylamino)-2-methylpyrimidine (0.45 g).
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20]>>[F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1c(F)c(F)cc(C(=O)O)c1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 43.4 g (0.21 mol) portion of 2,4,5-trifluoro-3-methylbenzoic acid was added to 120 ml of concentrated sulfuric acid under ice cooling. Thereto was added dropwise fuming nitric acid (d 1.52) in such a manner that the reaction temperature did not exceed 30° C. After completion of the dropwise addition, this was stirred for 1 hour at room temperature. After completion of the reaction, the reaction solution was poured into 1.5 liters of ice water to collect the formed crystals by filtration. The thus obtained crystals were washed with water (100 ml×3) and dissolved in 500 ml of ethyl acetate, and the solution was dried over anhydrous sodium sulfate. The filtrate obtained above was extracted with chloroform (300 ml×4) and dried over anhydrous sodium sulfate. Thereafter, the organic layers were combined and concentrated to yield 50.3 g (quantitative) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[Mg].[CH3:13][C:14]1([CH3:26])[CH2:23][C:22](=O)[C:21]2[C:16](=[CH:17][C:18]([OH:25])=[CH:19][CH:20]=2)[O:15]1.[Cl-].[NH4+]>CCOCC>[CH3:13][C:14]1([CH3:26])[CH:23]=[C:22]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=2)[C:21]2[C:16](=[CH:17][C:18]([OH:25])=[CH:19][CH:20]=2)[O:15]1
Reactant: CC1(C)CC(=O)c2ccc(O)cc2O1
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(C)C=C(c2cccc(C(F)(F)F)c2)c2ccc(O)cc2O1
Yield: 86.2 %

Procedure:
3-Bromobenzotrifluoride (61 g) in dry ether (100 ml) was added to magnesium (6.6 g) in ether (50 ml). 2,2-Dimethylchroman-4-one-7-ol (17.4 g) suspended in ether (500 ml) was added and the mixture refluxed for 16 hours. The reaction mixture was poured into ammonium chloride solution and extracted with ether. The combined ether layers were washed with 2N HCl (2 × 100 ml) and dried (MgSO4). Removal of the solvent under reduced pressure gave the title compound (25 g), m.p. 102°-106° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:24]([NH:26][C:27](=[O:44])[C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=1)[CH3:25].C(=O)([O-])O.[Na+].C(Cl)Cl>C(O)(C)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.O>[CH2:24]([NH:26][C:27]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([N:11]4[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH2:12]4)=[N:7][NH:8]3)=[CH:4][CH:3]=2)[CH:29]=1)=[O:44])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCN(c2n[nH]c3cc(Br)ccc23)CC1
Reactant: CCNC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: CCNC(=O)c1ccc(C)c(-c2ccc3c(N4CCN(C(=O)OC(C)(C)C)CC4)n[nH]c3c2)c1
Yield: 82.2 %

Procedure:
A mixture, of 1,1-dimethylethyl 4-(6-bromo-1H-indazol-3-yl)-1-piperazinecarboxylate (Intermediate 6, 660 mg) N-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 10, 598 mg) tetrakis(triphenylphosphine)palladium (25 mg) and aqueous sodium hydrogen carbonate (1M, 1.5 ml) in isopropanol (6 ml) was stirred at 150° C. for 20 min in a microwave oven. DCM and water were added and the organic phase was separated using a hydrophobic filter tube and concentrated under vacuum. The residue was purified by chromatography on a silica column eluting with a cyclohexane/ethyl acetate gradient to give the title compound (660 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[C:16]1([C:22]2([C:28]#[N:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:25]2[CH2:24][CH2:23][C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:28]#[N:29])[CH2:27][CH2:26]2)=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Reactant: N#CC1(c2ccccc2)CCNCC1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(C#N)(c3ccccc3)CC2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added 4-phenylpiperidine-4-carbonitrile (10 mg, 0.054 mmol, 1.2 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C23H21N3O2: 371.1634, found 371.1635.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:20][NH:21][C:22](=[O:29])[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>N1C=CC=CC=1.O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:3]=[C:2]2[N:26]1[CH2:27][CH2:28][CH:23]([C:22]([NH:21][CH3:20])=[O:29])[CH2:24][CH2:25]1
Reactant: Fc1ccc(-c2cc(Cl)c3cc(Cl)ccc3n2)cc1
Reactant: CNC(=O)C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: CNC(=O)C1CCN(c2cc(-c3ccc(F)cc3)nc3ccc(Cl)cc23)CC1

Procedure:
The named compound was made in a manner analogous to that of Example 4(c) using 4,6-dichloro-2-(4-fluorophenyl)quinoline, prepared as in Example 20, and N-methylisonipecotamide as starting materials. It was obtained as off-white needles, mp 260°-265° dec on recrystallization from pyridine/water.
Reaction SMILES: C([N:8]1[CH2:14][CH:13]2[CH2:15][CH:10]([C:11](=[CH:17][N:18](C)C)[C:12]2=O)[CH2:9]1)C1C=CC=CC=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27]N>>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[N:18]=[CH:17][C:11]2[CH:10]3[CH2:15][CH:13]([CH2:14][NH:8][CH2:9]3)[C:12]1=2
Reactant: CN(C)C=C1C(=O)C2CC1CN(Cc1ccccc1)C2
Reactant: NNc1ccccn1
Product: c1ccc(-n2ncc3c2C2CNCC3C2)nc1

Procedure:
Following the method described in Example 14, 3-benzyl-7-dimethylaminomethylene-3-aza-bicyclo[3.2.1]octan-6-one and 2-pyridyl hydrazine were converted to the title compound in 7.6% overall yield. APCl MS m/z 227.2 (M+H)+.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([O:7][C:8]2[C:9](=[O:28])[N:10]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:11]=[CH:12][C:13]=2[N:14]2[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)=[CH:3][CH:2]=1.[BH4-].[Na+].ClCCl>CO>[C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9](=[O:28])[N:10]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:11]=[CH:12][C:13]=2[N:14]2[CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][CH2:19]2)=[CH:5][CH:6]=1
Reactant: O=C1CCN(c2cnn(-c3ccc(Cl)cc3)c(=O)c2Oc2ccc(-c3ccccc3)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=c1c(Oc2ccc(-c3ccccc3)cc2)c(N2CCC(O)CC2)cnn1-c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
0.2 g (0.424 mmol) of the compound from Example 14 are dissolved in 7 ml of methanol and, at room temperature, 50 mg (1.3 mmol) of sodium borohydride are added in portions. Stirring for 2 h is followed by dilution with dichloromethane, washing with saturated ammonium chloride solution, drying over sodium sulfate and concentration. The crude product is stirred with 25 ml of boiling methanol and then cooled and filtered off with suction.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[NH:14]C(=O)OC(C)(C)C)=[CH:6][CH:5]=1)[CH3:2].Cl.C(OC(C)C)(C)C>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[NH2:14])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2cccc(NC(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: CCOc1ccc2cccc(N)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
Next, to a solution of tert-butyl (7-ethoxy-1-naphthyl)carbamate (47.9 g, 167 mmol) in 100 ml of anhydrous 1,4-dioxane was added 4N HCl in 1,4-dioxane (100 ml) at 0° C. The mixture was stirred at room temperature for 2 hours. Diisopropyl ether was added to the reaction mixture and the precipitate was filtered. To the obtained solid was added saturated sodium bicarbonate and the product was extracted with ethylacetate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (7-ethoxy-1-naphthyl)amine (27.0 g, 86.3% yield).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.OS(O)(=O)=O.[CH3:17]O>>[C:1]([O:11][CH3:17])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccccc1
Temperature: 80 °C

Procedure:
A mixture of cinnamic acid (25 mmol) and concentrated H2SO4 (0.1 mL) in anhydrous MeOH (25 mL) was refluxed at 80° C. (bath temperature) for 16 h. After the excess MeOH was removed by a rotary evaporator, the residue was treated with H2O (50 mL), and the resulting mixture was extracted with EtOAc (3×50 mL). The combined extracts were washed with H2O (50 mL) and brine (50 mL), and dried (anhydrous Na2SO4). The solvent was evaporated to dryness, and the crude products were purified by flash silica gel chromatography (eluting with 10-60% hexane in EtOAc) to afford methyl cinnamate. To an ice-cold solution of methyl cinnamate described above (8 mmol) dissolved in anhydrous MeOH (10 mL) and THF (10 mL) was added hydroxylamine hydrochloride (1.67 g, 24 mmol, 3 equiv) followed by 25% sodium methoxide in methanol solution (8.4 mL, 36 mmol, 4.5 equiv). The reaction mixture was stirred under argon and at 0° C. for 2 h, then allowed to warm to ambient temperature with the stirring was continued overnight (16 h). The resulting yellow suspension was condensed to dryness with a rotary evaporator, and the residue was treated with 1N HCl aqueous solution (30 mL). The mixture was extracted with EtOAc (3×50 mL), and dried (anhydrous Na2SO4). Evaporation of the solvent afforded the crude products (480 mg), which was purified by flash silica gel chromatography (eluting with 5-15% MeOH in DCM) to afford the hydroxamate.