Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[N:9]/[NH:10][C:11](=[O:22])[CH:12]([OH:21])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][C:3]=1[O:23][CH3:24].[H][H]>C(O)C.[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][NH:10][C:11](=[O:22])[CH:12]([OH:21])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: COc1ccc(C(O)C(=O)N/N=C/c2ccc(O)c(OC)c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(O)C(=O)NNCc2ccc(O)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of hydroxy-(4-methoxy-phenyl)-acetic acid [1-(4-hydroxy-3-methoxy-phenyl)-meth-(E)-ylidene]-hydrazide (21 g, 63 mmol) in 500 ml of ethanol is hydrogenated under atmospheric pressure with hydrogen and a mixture of 5% of palladium on charcoal (10.5 g) as catalyst. The reaction is stirred for 6 hours at room temperature. Subsequently, the mixture is filtered under argon and the solvent is evaporated to yield hydroxy-(4-methoxy-phenyl)-acetic acid N′-(4-hydroxy-3-methoxy-benzyl)-hydrazide as colourless tarr.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)=O>>[F:38][C:35]1[CH:36]=[CH:37][C:32]([C:30]2[N:26]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[S:27][CH:29]=2)=[CH:33][CH:34]=1
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccc(F)cc3)cs2)C1

Procedure:
100 mg (0.152 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 32 mg (0.182 mmol) of 2-chloro-1-(4-fluorophenyl)ethanone were reacted according to the General Method 3. Yield: 30 mg (39% of theory)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O:14][C:15](=[O:19])[C:16](=O)[CH3:17])C>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][N:11]=[C:16]([CH3:17])[C:15]([OH:19])=[O:14])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(C)=O
Solvent: O
Product: CC(=NNc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension in water (150 ml) of 4-nitrophenylhydrazine (15 g, 23 mmol) and 2-oxo-propionic acid ethyl ester (12 g, 100 mmol) was left under stirring at room temperature for 6 hours. The obtained precipitate was filtered and washed to give the ethyl ester of the 2-[(4-nitrophenyl)-hydrazono]-propionic acid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[CH:11][CH:10]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-hydoxybenzoate (6.85 g, 45 mmole) in 80 ml DMF was added potassium tert. butoxide (5.6 g, 51 mmole) and the mixture was stirred at room temperature for one hour. 4-Methoxybenzyl chloride (8.3 g, 52 mmole) was added and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and 200 ml ethyl acetate was added. The organic phase was washed four times with water, dried with sodium sulfate and evaporated under reduced pressure. Yield: 12.3 g=100%
Reaction SMILES: C(O)(=O)CC.C(C1C=CC=CC=1CC)C.C1(=O)OC(=O)CC1.[CH2:23]([C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][CH2:35][C:36]([OH:38])=O)[CH:28]=[CH:29][C:30]=1[CH2:31][CH3:32])[CH3:24]>>[CH2:23]([C:25]1[CH:26]=[C:27]2[C:28](=[CH:29][C:30]=1[CH2:31][CH3:32])[C:36](=[O:38])[CH2:35][CH2:34][CH2:33]2)[CH3:24]
Reactant: CCc1ccc(CCCC(=O)O)cc1CC
Agent: CCc1ccccc1CC
Agent: O=C1CCC(=O)O1
Solvent: CCC(=O)O
Product: CCc1cc2c(cc1CC)C(=O)CCC2
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
3-(3',4'-Diethylenzoyl) propanoic acid (m.p. 93° C, prepared by the acylation of 1,2-diethyl benzene with succinic anhydride) was catalytically reduced to 4-(3',4'-diethylphenyl) butanoic acid (b.p.0.7 143°-147° C). A mixture of this acid (59g; 0.27 mole) and 85% polyphosphoric acid (450g) was warmed to 80° C with stirring for 30 mins. and worked up as in example 8(a) to yield 48.30g (89%) of 6,7-diethyl-1-tetralone, b.p.0.7 118°-122° C. (Found; C, 82.95; H, 9.21; C14H18O requires; C, 83.12;H, 8.97%). Alternatively 4-(3', 4'-diethylphenyl )butanoic acid (23.3g; 0.106 mole) may be cyclised by stirring at 100° C with 80% sulphuric acid (115ml) for 11/2 hrs. After dilution, extraction into ether and distillation 15.53g (74%) of the tetralone was recovered.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])=[C:16]([OH:30])[CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:32]([O-])([O-])=O.[K+].[K+].CI>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].COCCOC>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=2[Cl:28])=[C:16]([O:30][CH3:32])[CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)c(O)c1)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: COCCOC
Solvent: CI
Product: COC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)c(OC)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a suspension of N-(tert-butoxycarbonyl)-4-(2,6-dichlorobenzyloxy)-3-hydroxy-L-phenylalanine methyl ester (0.45 g), K2CO3 (0.199 g), and n-Bu4NI (0.035 g) in DME (4.0 mL) was added CH3I (0.072 mL) and the mixture was stirred overnight at room temperature. DMF was removed and the residue was partitioned between water and EtOAc. The organic layer was separated and the aqueous solution was extracted with EtOAc. The combined extract was dried (MgSO4) and evaporated. The residue was purified by preparative TLC (silica gel; eluent: hexanes/CH2Cl2/EtOAc, 3:3:1) to yield 0.396 g of N-(tert-butoxycarbonyl)-4-(2,6-dichlorobenzyloxy)-3-methoxy-L-phenylalanine methyl ester. ESMS: m/z 484 (MH+).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2>>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:17]\[C:14]1[NH:13][C:9]2[CH2:10][CH2:11][CH2:12][N:6]([CH2:5][CH2:4][N:3]([CH2:20][CH3:21])[CH2:1][CH3:2])[C:7](=[O:19])[C:8]=2[C:15]=1[CH3:16]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4ccc(Br)cc43)c(C)c2C1=O
Yield: 67.8 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and 5-bromo-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-diethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 5 (59 mg, yield 67.8%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([NH:15][NH:16][C:17](=O)[C:18]([CH3:34])([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[C:19]([F:22])([F:21])[F:20])=[O:14])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl>[Br:12][C:5]1[N:4]=[C:3]([C:13]2[O:14][C:17]([C:18]([O:23][Si:24]([CH:25]([CH3:26])[CH3:27])([CH:28]([CH3:29])[CH3:30])[CH:31]([CH3:33])[CH3:32])([CH3:34])[C:19]([F:21])([F:22])[F:20])=[N:16][N:15]=2)[C:2]([NH2:1])=[CH:7][C:6]=1[C:8]([F:9])([F:10])[F:11]
Reactant: CC(C)[Si](OC(C)(C(=O)NNC(=O)c1nc(Br)c(C(F)(F)F)cc1N)C(F)(F)F)(C(C)C)C(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CC(C)[Si](OC(C)(c1nnc(-c2nc(Br)c(C(F)(F)F)cc2N)o1)C(F)(F)F)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a cooled (0° C.) solution of 3-amino-6-bromo-N′-(3,3,3-trifluoro-2-methyl-2-(triisopropylsilyloxy) propanoyl)-5-(trifluoromethyl)picolinohydrazide (5.42 g, 9.10 mmol) in DCM (50 ml) was added TEA (3.81 ml, 27.3 mmol). The resulting solution was stirred at 0° C. for 5 minutes and treated with Tosyl chloride (5.21 g, 27.3 mmol). The mixture was allowed to warm to RT and stirred for 48 h. The reaction mixture was partitioned between DCM (100 ml) and water (100 ml), phases shaken and separated. The organic portion was washed with 1M NaOH (100 ml), 1M HCl (100 ml), water (100 ml), brine (100 ml), dried (MgSO4) (˜10 g) and concentrated in vacuo to give an orange oil. Purification of the oil by chromatography on silica eluting with 0-15% EtOAc in iso-hexane afforded the title compound; LC-MS Rt=7.41 min [M+H]+ 577/579 Method 10minLC_v003.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH3:13])[CH3:12].[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:20]=1[F:21].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(COC)OC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:14][C:15]1[CH:16]=[C:17]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]3([CH3:13])[CH3:12])[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC1(C)C(=O)Nc2ccc(Br)cc21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: O
Product: CC1(C)C(=O)Nc2ccc(-c3ccc(F)c(Cl)c3)cc21
Temperature: 25 °C
Yield: 29.5 %

Procedure:
A solution of 5-bromo-3,3-dimethyl-1,3-dihydro-indol-2-one (0.35 g, 1.46 mmol) and tetrakis(triphenylphosphine) palladium (0.13 g, 0.11 mmol) in dimethoxyethane (10 cm3) was stirred under N2 for 20 min. To this mixture was then added 3-chloro-4-fluorobenzene boronic acid (0.26 g, 1.49 mmol) and potassium carbonate (0.62 g, 4.5 mmol) in water (5 cm3). The solution was brought to reflux for 16 h then cooled to RT, poured into saturated ammonium chloride and extracted with EtOAc (×3). The combined organic extracts were dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, ethyl acetate: hexane 1:3) to afford the title compound (0.124 g, 0.43 mmol, 30%) as a white solid: mp. 206.5-207.8° C., 1H NMR (DMSO-d6) δ1.3 (s, 6H), 6.93 (d, J=8.1 Hz, 1H), 7.45 (dd, J=8.9, 8.9 Hz, 1H), 7.5 (dd, J=8.1, 1.8 Hz, 1H), 7.6 (ddd, J=8.9, 7.1, 2.2 Hz, 1H), 7.7 (d, J=1.8 Hz, 1H), 7.8 (dd, J=7.1, 2.2 Hz, 1H), 10.5 (s, 1H); MS (EI) m/z 289/291 (M)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:17])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ncccc1CBr
Reaction time: 16 h
Yield: 52.1 %

Procedure:
To a solution of 3-methylpicolinonitrile (1.0 g, 8.47 mmol) in CCl4 (43 ml) was added NBS (1.81 g, 10.16 mmol) and benzoyl peroxide (32 mg, 1.27 mmol) and the mixture stirred at relux for 16 hours. The reaction was concentrated in vacuo to afford a black oil. Purification via column chromatography on silica gel (EtOAc:hexane, 1:9, v/v) afforded 3-bromomethyl-pyridine-2-carbonitrile as a white solid (0.87 g, 48%). 1H NMR (CDCl3) δ 4.64 (s, 2H), 7.53 (dd, 1H, J=4.4, 4.0 Hz), 7.94 (dd, 1H, J=6.1, 1.8 Hz), 8.66 (dd, 1H, J=2.6, 1.8 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)[CH:3]=[N:2]1.Br[CH2:31][CH:32]1[CH2:34][CH2:33]1.O.[OH-].[Cs+].[ClH:38]>CN(C=O)C>[ClH:38].[ClH:38].[CH:32]1([CH2:31][N:1]2[CH:5]=[C:4]([CH2:6][N:7]3[C:15]4[C:10](=[C:11]([NH:16][C:17]([C:19]5[N:23]6[CH:24]=[CH:25][CH:26]=[CH:27][C:22]6=[N:21][CH:20]=5)=[O:18])[CH:12]=[CH:13][CH:14]=4)[C:9]([CH2:28][CH3:29])=[N:8]3)[CH:3]=[N:2]2)[CH2:34][CH2:33]1
Reactant: CCc1nn(Cc2cn[nH]c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: BrCC1CC1
Agent: Cl
Agent: [Cs+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(Cc2cnn(CC3CC3)c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
To a solution of N-(1-((1H-pyrazol-4-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (20 mg, 0.052 mmol; prepared according to Example 21, Step A) in dry DMF (0.5 mL) was added (bromomethyl)cyclopropane (7.0 mg, 0.052 mmol) and cesium hydroxide hydrate (8.7 mg, 0.052 mmol). The mixture was stirred at ambient temperature for 60 minutes. The mixture was filtered, washed with methanol and ethyl acetate, and concentrated under reduced pressure. The residue was purified using preparative thin layer chromatography on silica, eluting with 10% methanol in dichloromethane. The product was dissolved in a mixture of dichloromethane and methanol. Hydrogen chloride (0.52 mmol; 2M solution in diethyl ether) was added and the solvent was removed under reduced pressure, followed by high vacuum to give N-(1-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride (5.6 mg). MS (APCI), positive scan, m/z=440.2 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:16][NH2:17])[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.CO.OO.[O-]Cl.[Na+]>O>[CH2:9]([N:6]1[CH2:5][CH2:4][C:3]2([CH2:2][N:1]=[N:17][CH2:16]2)[CH2:8][CH2:7]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCC1(CN)CCN(Cc2ccccc2)CC1
Agent: OO
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Solvent: O
Product: c1ccc(CN2CCC3(CC2)CN=NC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
2.48 g of C-(4-Aminomethyl-1-benzyl-piperidin-4-yl)-methylamine was suspended in 40 mL H2O and 10 mL MeOH and cooled with an ice bath. Simultaneously, 6.7 mL 30% H2O2 (6 equiv.) and 15.2 mL 10% NaClO (2.4 equiv.) were added dropwise. The mixture was stirred at room temperature for 1 hour. The mixture was extracted 2 times with DCM, the combined organic layers were dried over Na2SO4, filtrated and concentrated to yield 2.20 g of a yellow oil which was used without further purification in the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:21]=1.[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][CH:17]([O:20][C:25](=[O:26])[NH:24][CH2:22][CH3:23])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:21]=1
Reactant: CCN=C=O
Reactant: O=C(Cn1c(=O)sc2ccc(Cl)cc21)N1CCC(O)CC1
Solvent: c1ccncc1
Product: CCNC(=O)OC1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Temperature: 50 °C
Reaction time: 10 h
Yield: 77 %

Procedure:
5-Chloro-3-(4-hydroxypiperidinocarbonylmethyl)benzothiazolin-2-one (3.2 g) was dissolved in dry pyridine (15 ml) and the solution was cooled. After ethyl isocyanate (0.9 g) was dropwise added to the solution, the resultant was stirred for 10 hours at 50° C. Pyridine was evaporated off under vacuum from the reaction mixture and the residue was recrystallized from ethanol to yield the title compound as colorless crystals (3.0 g). mp 210°-211° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[S:5][C:6]=1[CH:7]([OH:9])[CH3:8]>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[S:5][C:6]=1[C:7](=[O:9])[CH3:8]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)O
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Yield: 100.7 %

Procedure:
A mixture of 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol (1.0 g, 3.48 mmol) and MnO2 (0.45 g, 5.22 mmol) in chloroform (30 mL) is heated to reflux, after 24 hrs, additional MnO2 (300 mg) is added and refluxed for another 9 hrs, the reaction mixture is filtered through celite. Concentration of filtrate yields the title compound (1.0 g).
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:26])[N:17]([CH3:25])[CH:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:4]1[CH:28]=[CH:27][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:26])[N:17]([CH3:25])[CH:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)[CH:10]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3)ccn2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Reaction time: 8 h

Procedure:
3-[4-(4-Nitrophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea was dissolved in tetrahydrofuran (4 ml)-methanol (4 ml), and then 10% palladium carbon (65 mg) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the system and stirring overnight. After replacing with nitrogen inside the system, the reaction mixture was filtered to remove the catalyst, which was washed with methanol. The filtrate was concentrated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated under a reduced pressure to provide the titled compound (113.5 mg, quantitatively) as colorless powder.
Reaction SMILES: [N+:1]([C:4]1[C:5](Cl)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].NC(N)=[S:13].[OH-].[K+]>C(O)C>[SH:13][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: NC(N)=S
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1cccnc1S
Temperature: 25 °C

Procedure:
2-mercapto-3-nitropyridine was prepared by treating 3-nitro-2-chloro-pyridine (50 g, 0.0317 mol) with thiourea (24 g, 0.0317 mol) in 200 mL of ethanol at reflux for several hours. After the reaction mixture was allowed to cool, 7.19 mL solution of KOH (42.8 g in 115 mL of water) was added and the resulting mixture was heated at reflux for 3 hours. The crude reaction mixture was cooled to room temperature and then concentrated to 50% of its volume in vacuo. After diluting with 300 mL of water, the product was isolated by vacuum filtration as an orange solid that was used without further purification. MS (DCI/NH3) m/z 157 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 5.76 (m, 1H), 7.67 (dd, J=8.46, 4.78 Hz, 1H), 8.63 (dd, J=8.46, 1.47 Hz, 1H), 8.73 (dd, J=4.60, 1.65 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]12[C:14]3[C:10]([CH2:11][CH2:12][CH2:13]1)=[CH:9][CH:8]=[CH:7][C:6]=3[C:5](=O)[CH2:4][CH2:3]2.[BH4-].[Na+].[Cl-].[Al+3].[Cl-].[Cl-]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]12[C:14]3[C:6]([CH:5]=[CH:4][CH2:3]1)=[CH:7][CH:8]=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]2
Reactant: CC12CCCc3cccc(c31)C(=O)CC2
Agent: [Al+3]
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC12CC=Cc3cccc(c31)CCC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A solution of 3a-methyl-2,3,3a,4,5,6-hexahydro-1-phenalenone (2.14 g) in anhydrous tetrahydrofuran (70 ml) was cooled to 0° C., and slowly added with sodium borohydride (1.62 g) and aluminum chloride (2.85 g). The reaction mixture was refluxed by heating for 3 hours, then cooled to 0° C., and diluted with ethyl acetate. The mixture was slowly added with ice until foaming ceased, and then the mixture was made to be at room temperature and stirred overnight. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane) to obtain the title compound (1.83 g, yield: 97%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCOC(C)=O.O>ClCCl>[CH3:21][C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[O:13][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][C:7]=1[S:9]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:11])=[O:10]
Reactant: Cc1ccc(C)c(Oc2ccc(C#N)cc2S(=O)(=O)Cl)c1
Reactant: C1CNCCN1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c(Oc2ccc(C#N)cc2S(=O)(=O)N2CCNCC2)c1
Reaction time: 16 h
Yield: 41.9 %

Procedure:
A solution of sulfonyl chloride 32 (1.0 g, 3.1 mmol) in 20 mL dichloromethane was infused into a stirring solution of piperazine (5.9 g, 62.2 mmol) in 20 mL of dichloromethane at a rate of 0.2 mL/min. The reaction mixture was stirred for 16 hrs. The completion of the reaction was confirmed by TLC (25% EtOAc in hexanes). Water was then added and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed sequentially with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to produce a brown solid. The product was chromatographed on normal-phase silica using a gradient of 0-25% MeOH in dichloromethane. Desired fractions were collected and concentrated to produce compound 51 as a pink solid (0.5 g, 1.3 mmol). HPLC purity: 99%; 1H NMR (500 MHz, DMSO-d6): δ 8.22 (d, J=2 Hz, 1H), 7.99 (dd, J1=2 Hz, J2=8 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.09 (d, J=8 Hz, 1H), 6.94 (s, 1H), 6.78 (d, J=8 Hz, 1H), 3.13 (m, 4H), 2.70 (m, 4H), 2.30 (s, 3H), 2.08 (s, 3H); MS (ESI, EI+): m/z=372 (MH+); melting point: 60-72° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22]C)=[C:5]([OH:14])[C:6](=[O:13])[NH:7]2.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[OH:22])=[C:5]([OH:14])[C:6](=[O:13])[NH:7]2
Reactant: COc1ccc(Cl)cc1-c1c(O)c(=O)[nH]c2cc(Cl)cc(Cl)c12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]c2cc(Cl)cc(Cl)c2c(-c2cc(Cl)ccc2O)c1O
Temperature: -78 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
To a suspension of 5,7-dichloro-4-(5-chloro-2-methoxyphenyl)-3-hydroxy-2(1H)-quinolinone (2.22 g, 6.0 mmol) [prepared in Example 1] in methylene chloride was added BBr3 (30 mL, 1.0M solution in methylene chloride, 5.0 equiv.) at -78° C. and the suspension became a clear solution. The solution was stirred under an argon atmosphere at -78° C. for 3 hours then at room temperature for an additional 20 hours. Distilled water (0.5 mL) was added dropwise and stirring continued for 10 minutes. The reaction mixture was evaporated under vacuum and the solid residue was suspended in water (100 mL), sonicated for 5 minutes then stirred for 10 minutes, filtered, washed with water (3×30 mL) and dried to yield 2.15 g (≈100%) of the title compound as a white solid: mp=297-299° C.;