Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:36]=[CH:35][C:10]([O:11][C:12]3[CH:13]=[C:14]([C:24]4[NH:28][C:27]([C:29]([NH:31][CH2:32][CH2:33]Cl)=[O:30])=[CH:26][CH:25]=4)[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=3)=[C:9]([F:37])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[N:1]1([C:5]([C:7]2[CH:36]=[CH:35][C:10]([O:11][C:12]3[CH:13]=[C:14]([C:24]4[NH:28][C:27]([C:29]5[O:30][CH2:33][CH2:32][N:31]=5)=[CH:26][CH:25]=4)[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=3)=[C:9]([F:37])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C(=O)NCCCl)[nH]2)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C3=NCCO3)[nH]2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 41.8 %

Procedure:
5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-N-(2-chloroethyl)-1H-pyrrole-2-carboxamide (85 mg, 0.16 mmol) synthesized in Example (68a) was dissolved in tetrahydrofuran (3 mL), and sodium hydride (37 mg, 0.82 mmol) was added at 0° C., followed by stirring at room temperature for 20 hours. To the reaction solution, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out with ethyl acetate (50 mL). After washing with saturated brine, drying was carried out over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate 100%-methanol/chloroform=2%) to afford the desired product (33 mg, yield 41%) as a pale yellow solid.
Reaction SMILES: [Cl-].[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:10]=1)(=[O:4])[CH3:3].[O:31]1[CH2:35][CH2:34][O:33][CH:32]1[C:36]1[S:40][C:39]([CH:41]=O)=[CH:38][C:37]=1[CH3:43]>>[O:31]1[CH2:35][CH2:34][O:33][CH:32]1[C:36]1[S:40][C:39]([CH:41]=[CH:11][C:9]2[N:10]=[C:6]([NH:5][C:2](=[O:4])[CH3:3])[S:7][CH:8]=2)=[CH:38][C:37]=1[CH3:43]
Reactant: CC(=O)Nc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Reactant: Cc1cc(C=O)sc1C1OCCO1
Agent: [Cl-]
Product: CC(=O)Nc1nc(C=Cc2cc(C)c(C3OCCO3)s2)cs1
Yield: 74.7 %

Procedure:
In a similar manner as in Production Example 16, step 1, {[2-(acetylamino)-1,3-thiazol-4-yl]methyl}(triphenyl)phosphonium chloride (12.03 g, 26.56 mmol) and 5-(1,3-dioxolan-2-yl)-4-methylthiophene-2-carbaldehyde (3.51 g, 17.7 mmol) were condensed to give N-(4-{2-[5-(1,3-dioxolan-2-yl)-4-methylthiophen-2-yl]vinyl}-1,3-thiazol-2-yl)acetamide (4.450 g, 13.23 mmol, yield 74.7%) as a yellow solid.
Reaction SMILES: C(OC(N1CCC(OC2C=C(C(C)(C)C)C=CC=2C(N[C:20]2[CH:35]=[CH:34][CH:33]=[CH:32][C:21]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=O)CC1)=O)(C)(C)C>Cl.O1CCOCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:22](=[O:23])[C:21]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:20]=2)=[N:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 219.9 %

Procedure:
The 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(tert-butyl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (1.57 g, 2.58 mmol) was dissolved in 20 mL of a 4 N HCl in dioxane solution at room temperature, resulting in a modest evolution of gas. After 1 hour stirring at room temperature, the solvent and HCl gas were evaporated in vacuo, then the resulting white solid was resuspended in 75 mL 2:1 EtOAc:dichloromethane and evaporated a second time. The pasty white solid was dissolved in a solution of K2 CO3 (11.2 g) in water (75 mL), dichloromethane was added (75 mL), and the mixture vigorously stirred overnight. The mixture was partitioned, the aqueous layer back-extracted twice with dichloromethane, then the combined organic layers washed with brine. The organic layer was dried and concentrated in vacuo to provide 2-[4-tert-butyl)-2-(piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (1.32 g, 100%) as an off-white crystalline solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=4[N:14]=[CH:13]3)[CH:8]=[CH:7][C:5]=2[N:6]=1.CCN(C(C)C)C(C)C.[NH2:34][C@@H:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[OH:41]>CC(N(C)C)=O>[CH3:22][O:21][C:19]1[C:18]([O:23][CH3:24])=[CH:17][C:16]2[N:12]([CH2:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:34][C@@H:35]5[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]5[OH:41])[S:3][C:4]=4[CH:10]=3)[CH:13]=[N:14][C:15]=2[CH:20]=1
Reactant: COc1cc2ncn(Cc3ccc4nc(Br)sc4c3)c2cc1OC
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)c2cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a suspension of 2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole (202 mg, 0.5 mmol) from Step 4 of this Example in DMA (4 mL) were added DIEA (129 mg, 1.0 mmol) and (1R,2R)-2-aminocyclohexanol (69 mg, 0.6 mmol) at rt. The mixture was stirred in a sealed tube at 120° C. overnight. After cooling to rt, the mixture was concentrated under reduced pressure. The crude product was purified by HPLC using a mixture of water (5% CH3CN, 0.05% AcOH) and CH3CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as a white solid (127 mg, 58%). 1H NMR (300 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.62 (s, 1H), 7.04-7.34 (m, 4H), 5.40 (s, 2H), 4.77 (br s, 1H), 3.76 (s, 6H), 3.51 (br s, 1H), 1.77-2.14 (m, 3H), 1.61 (br, 2H), 1.04-1.38 (m, 4H). LCMS (ESI) m/z 439 (M+H)+.
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][N:24]=1>>[CH3:34][O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][N:24]=[C:23]2[N:18]1[CH2:19][CH2:20][CH:15]([N:5]2[C:6](=[O:14])[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=3)[N:3]([CH3:2])[C:4]2=[O:21])[CH2:16][CH2:17]1
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Reactant: COc1ccc2ncnc(Cl)c2c1
Agent: Br
Product: COc1ccc2ncnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2c1
Yield: 12 %

Procedure:
The procedure similar to that described in Example 57 was repeated, except that 1.06 g (3.0 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazoline hydrobromide (Compound v) obtained in Example 41 was used and 4-chloro-6-methoxyquinazoline was used in place of 4-chloro-6,7-dimethoxy-quinazoline. As a result, 154.4 mg (yield: 12%) of Compound 84 was obtained as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#N)=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:11]CN(C(C)C)C(C)C>C(O)CCC>[NH:5]1[C:6]2[CH:7]=[CH:8][CH:11]=[N:1][C:2]=2[N:3]=[CH:4]1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: c1cnc2nc[nH]c2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 4-amino-6-chloropyrimidine-5-carbonitrile (B) (1.0 eqv.), C-5 (1.0 eqv.) and DIEA (3.0 eqv.) in n-butanol was stirred at 110° C. for overnight. The reaction was monitored by TLC, after completion of reaction the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 0 to 10% gradient of MeOH in DCM as eluent to give C-6.
Reaction SMILES: CC(C)(O)[C:3]#[N:4].[OH:7][C@:8]12[CH2:25][CH2:24][C@@:22]3([CH3:23])[C@@H:18]([CH2:19][CH2:20][C:21]3=[O:26])[C@@H:17]1[CH2:16][CH2:15][C:14]1[C@:9]2([CH3:28])[CH2:10][CH2:11][C:12](=[O:27])[CH:13]=1.[C-]#N.[K+]>CO>[CH3:23][C@@:22]12[C:21]([OH:26])([C:3]#[N:4])[CH2:20][CH2:19][C@H:18]1[C@@H:17]1[CH2:16][CH2:15][C:14]3[C@@:9]([CH3:28])([C:8]1([OH:7])[CH2:25][CH2:24]2)[CH2:10][CH2:11][C:12](=[O:27])[CH:13]=3
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Reactant: CC(C)(O)C#N
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(O)(C#N)[C@@]3(C)CCC12O
Reaction time: 2 h

Procedure:
Acetone cyanohydrin (1.37 ml) is added to a mixture of 9α-hydroxyandrost-4-ene-3,17-dione (0, U.S. Pat. No. 3,065,146, 3.024 g) in methanol (10 ml). The mixture is stirred at about 35°-39° for about 2 hr, then at about 4°-54° for 1.25 hr. 0.1 ml of a potassium cyanide solution (1 g in 2.0 ml of water) is added and the mixture stirred at about 50°-55° for 30 min and then allowed to stand at 20°-25° overnight. The solids are collected, washed well with methanol and dried under reduced pressure at about 55° for 3 hr to give the title compound, NMR (CDCl3 /DMSO-d6 ; 10/1) 5.8, 2.4, 1.3 and 1.0 δ.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:7]=[CH:8][CH:9]=1)=[O:3].[ClH:25].CCOC(C)=O>CCOC(C)=O>[ClH:25].[NH:15]1[CH2:16][CH2:17][CH:12]([CH2:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:2]([NH2:1])=[O:3])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCc2cccc(C(N)=O)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc(CCC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-butyl 4-{2-[3-(aminocarbonyl)phenyl]ethyl}-1-piperidinecarboxylate (13.8 g) was dissolved in EtOAc (200 ml), and 4 M hydrogen chloride/EtOAc solution (130 ml) was added thereto, followed by stirring at room temperature for 4 hours, and then concentrated. Acetonitrile was added to the resulting residue, followed by heating, and the precipitated crystal was collected by filtration, washed with EtOAc, and dried under reduced pressure to obtain 3-[2-(4-piperidinyl)ethyl]benzamide hydrochloride (11.2 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:21](=O)[CH2:22][CH2:23][CH2:24][CH3:25])[C:17](OC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH3:27][C:28]1[NH:29][C:30]([NH:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[N:31][N:32]=1>>[CH2:22]([C:21]1[N:31]2[N:32]=[C:28]([CH3:27])[N:29]=[C:30]2[N:33]([CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[C:17](=[O:18])[C:16]=1[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:14][CH:13]=1)[CH2:23][CH2:24][CH3:25]
Reactant: Cc1nnc(NC2CCOCC2)[nH]1
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 65.6 %

Procedure:
A mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (1.2 g) and 5-methyl-N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.3 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.52 g, 66%).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH:9]([NH2:13])[CH2:8][O:7]2)([O-:3])=[O:2].[F:14][C:15]([F:34])([F:33])[O:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][CH:22]2[CH2:25][N:24]([CH2:26][CH2:27][C:28](Cl)=[O:29])[CH2:23]2)=[CH:19][CH:18]=1>>[F:34][C:15]([F:14])([F:33])[O:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][CH:22]2[CH2:25][N:24]([CH2:26][CH2:27][C:28]([NH:13][C@@H:9]3[CH2:8][O:7][C:6]4=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]4[CH2:10]3)=[O:29])[CH2:23]2)=[CH:19][CH:18]=1
Reactant: O=C(Cl)CCN1CC(Oc2ccc(OC(F)(F)F)cc2)C1
Reactant: NC1COc2nc([N+](=O)[O-])cn2C1
Product: O=C(CCN1CC(Oc2ccc(OC(F)(F)F)cc2)C1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 32 %

Procedure:
Similar to the manipulation of example 22, with (S)-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine-6-amine (110 mg, 0.6 mmol) and 3-(3-(4-(trifluoromethoxy)phenoxy)azetidin-1-yl) propionyl chloride (242 mg, 0.72 mmol) as crude materials, title compound as 91 mg yellow powder was generated and yield was 32%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][O:12][C:3]1[C:2]([Cl:1])=[C:10]([Cl:11])[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1)[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: Oc1cc2ccsc2c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2ccsc2c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 63.8 %

Procedure:
A mixture of 3.6 g of 6,7-dichloro-5-hydroxybenzo[b]thiophene, 3.0 g of ethyl bromoacetate, 1.5 g of potassium carbonate and 40 ml of anhydrous dimethylformamide is stirred at 70°-80° for 16 hours. The cooled mixture is diluted with ice-water (200 g) and the solid collected by filtration. Recrystallization of the crude product from acetone-hexane gives 3.2 g of ethyl[(6,7-dichlorobenzo[b]thien-5-yl)oxy]acetate as yellowish needles, mp 92°-93°.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]1[N:11]([CH3:12])[N:10]=[N:9][N:8]=1)C.[ClH:16].[OH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[OH:27])[CH2:21][CH2:22][NH2:23].Cl.C>O.C(O)C>[ClH:16].[CH3:12][N:11]1[C:7]([NH:6][CH2:5][CH:4]2[C:24]3[C:20](=[CH:19][C:18]([OH:17])=[C:26]([OH:27])[CH:25]=3)[CH2:21][CH2:22][NH:23]2)=[N:8][N:9]=[N:10]1
Reactant: CCOC(CNc1nnnn1C)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cn1nnnc1NCC1NCCc2cc(O)c(O)cc21
Temperature: 60 °C

Procedure:
(1-methyl-1H-tetrazol-5-yl)aminoacetaldehyde diethyl acetal (21.5 g.) and 3,4-dihydroxyphenethylamine hydrochloride (14.6 g.) were added to a mixture of ethanol (130 ml.) and water (35 ml.), and dissolved with heating and stirring. Conc. hydrochloric acid (10.5 ml.) was added thereto and the mixture was refluxed for 8 hours. The reaction mixture was treated with activated charcoal. The charcoal was filtered and washed with ethanol, after which the filtrate and the washings were combined and concentrated under reduced pressure. The residual crystals were recrystallized from a mixture of water and isopropyl alcohol and the obtained crystals (22.5 g.) were warmed for 16 hours at 60° C under reduced pressure to remove excess hydrogen chloride. The crystals were recrystallized from a mixture of a small amount of water, methanol and ether to give 1-(1-methyl-1H-tetrazol-5-yl)aminomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride trihemihydrate (15 g.), mp 107° to 110° C. Infrared Absorption Spectrum (Nujol) 1604, 1460 cm-1.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH:4]=[O:5])[CH3:2].S(OC)([O:11][CH3:12])(=O)=O.[CH3:15][O-].[Na+]>CO>[CH3:15][O:5][CH:4]([O:11][CH3:12])[N:3]([CH2:6][CH3:7])[CH2:1][CH3:2]
Reactant: CCN(C=O)CC
Reactant: C[O-]
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Solvent: CO
Product: CCN(CC)C(OC)OC
Reaction time: 8 h
Yield: 75.1 %

Procedure:
790 G (7.8moles) of N,N-diethylformamide were treated with 985 g of dimethyl sulfate while stirring, in the course of which the temperature of the mixture rose to 40°C. After stirring overnight, the reaction mixture was allowed to run into 7.8 mols of sodium methylate in methanol (total volume approximately 2.3 liters) at 0° to 5°C, while stirring, and the batch was again stirred overnight. Thereafer the methanol was first distilled from the crystal paste, following which the desired product was distilled off at 10 mm Hg up to a bath temperature of 17°C and was fractionated through a column. 862 g (75% of theory) of N,N-diethylformamide-dimethylacetal of boiling point 70°C/50 mm Hg (with foaming) and refractive index nD24 = 1.4074 were obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2ccc(N)cn2)CC1
Reaction time: 3 h
Yield: 104.5 %

Procedure:
An amount of 1 g (4.48 mmol) of 1-Methyl-4-(5-nitro-pyridin-2-yl)-piperazine is dissolved in methanol (50 mL), followed by a catalytic amount of 10% Pd/C. The mixture is hydrogenated at 35-40 psi for 3 hours, filtrated through celite followed by evaporation to give 900 mg (100% yield) of purple solid; mp 97-98° C. MS (ESI) m/z 193.1 (M+1)+.
Reaction SMILES: C([N:20]1[C:28]2[CH:27]=[CH:26][C:25](C#N)=[C:24]3[CH2:31][CH:32]([N:34]([CH2:38][CH2:39][CH3:40])[CH2:35][CH2:36][CH3:37])[CH2:33][CH:22]([C:23]=23)[CH2:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Mg]Br.[NH4+].[Cl-].C1C[O:49][CH2:48][CH2:47]1>C(OCC)C>[C:48]([C:25]1[CH:26]=[CH:27][C:28]2[NH:20][CH2:21][C@H:22]3[CH2:33][C@@H:32]([N:34]([CH2:38][CH2:39][CH3:40])[CH2:35][CH2:36][CH3:37])[CH2:31][C:24]=1[C:23]=23)(=[O:49])[CH3:47]
Reactant: CCCN(CCC)C1Cc2c(C#N)ccc3c2C(C1)CN3C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCN(CCC)[C@H]1Cc2c(C(C)=O)ccc3c2[C@@H](CN3)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.4 g (4.6 mmol) (+)-1-trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole in 100 mL of THF was treated with 25 mL of 2.0M methylmagnesium bromide in diethyl ether. The reaction mixture was refluxed for 16 hr. The reaction mixture was cooled and excess Grignard reagent was decomposed with addition of saturated NH4Cl solution. The reaction mixture was extracted with ethyl acetate. The organic solution was evaporated to an oil. The oil was dissolved in 25 mL of 5N HCl and the solution was stirred at room temperature for 30 min. The acidic solution was made alkaline with the addition of excess concentrated NH4OH solution. The basic mixture was extracted twice with ethyl acetate. The combined organic solution was washed once with saturated NaCl solution and dried over MgSO4. The ethyl acetate solution was evaporated to yield 1.4 g of an oil. Chromatography of this oil over silicia gel with ethyl acetate as eluent gave 1.2 g (87%) of product. Recrystallization from hexanes yielded 840 mg of the product (+) ketone.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[NH:13][C:12]1=[O:25])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:33]([C:36]1[CH:46]=[CH:45][C:39]([CH2:40][O:41][CH2:42][CH2:43]Cl)=[CH:38][CH:37]=1)([O-:35])=[O:34].P([O-])([O-])([O-])=O>C(Cl)Cl>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[N:13]([CH2:43][CH2:42][O:41][CH2:40][C:39]2[CH:45]=[CH:46][C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=2)[C:12]1=[O:25])[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)Sc1ccccc1
Reactant: O=[N+]([O-])c1ccc(COCCCl)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(CCOCc2ccc([N+](=O)[O-])cc2)[C@@H]1CC(=O)Sc1ccccc1
Reaction time: 2 h
Yield: 93.8 %

Procedure:
747 mg (1.97 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-[(phenylthio)carbonylmethyl]-2-azetidinone and 398 mg (3.94mmole) of triethylamine were dissolved in 20 ml of methylene chloride. To the solution were added 960 mg (3.94 mmole) of p-nitrobenzyloxyethyl chloride, with ice cooling under a stream of nitrogen. The mixture was stirred for 2 hours and then a 0.1M phosphate buffer solution (pH 7.2) was added to the reaction mixture to complete the reaction. The organic layer was separated and washed with water, after which it was dried. The solvent was distilled off and the resulting residue was purified by column chromatography through 15 g of silica gel, to give 1,032 mg (yield 89%) of the desired product as an oil from the fractions eluted with mixtures of hexane and ethyl acetate in volume ratios from 6:1 to 3:1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C:23]([C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1)(=[O:25])[CH3:24]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:35]2[CH2:34][CH2:33][N:32]([C:29]3[CH:28]=[CH:27][C:26]([C:23](=[O:25])[CH3:24])=[CH:31][CH:30]=3)[CH2:37][CH2:36]2)=[S:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=S)Oc1ccccc1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Product: COc1nc2ccccc2nc1NC(=S)N1CCN(c2ccc(C(C)=O)cc2)CC1
Yield: 56.9 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)thiocarbamate and 1-(4-acetylphenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].P([O-])([O-])(O)=O.[Na+].[Na+].[Cl:18]CCl.ClCl>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:18])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccccn1
Reactant: ClCCl
Agent: ClCl
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(Cl)cn1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
In 300 ml of water, 13.6 g (0. lmol) of 2-acetamidopyridine (Id) was dissolved. To this solution, 35.5 g (0.25 mol) of disodium hydrogenphosphate and 100 ml of dichloromethane were added in this order. While this mixture was stirred, 8.0 g (0.11 mol) of chlorine was introduced thereto at 0° C. for 30 minutes. Then the mixture was further stirred at the same temperature for 2 hours. After the mixture was brought back to room temperature, it was separated into a water layer and an extract layer. Thereafter, the water layer was further extracted with 100 ml of dichloromethane and then washed with saturated brine. The resulting extract layer was dehydrated by sodium sulfate anhydride. When dichloromethane was evaporated off, 16.0 g (yield: 94.0%) of 2-acetamido-5-chloropyridine (IIj) was obtained as a pale brown crystal.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16].Br[C:22]1[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=1>COCCOC.O.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>[Cl:7][C:8]1[CH:9]=[C:10]([C:22]2[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16]
Reactant: Nc1ncccc1Br
Reactant: CC(C)Oc1ccc(B(O)O)cc1Cl
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: COCCOC
Product: CC(C)Oc1ccc(-c2cccnc2N)cc1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
A mixture of sodium carbonate (760 mg), tetrakis(triphenylphosphine)palladium(0) (207 mg), 3-chloro-4-isopropoxyphenylboronic acid (1.00 g) and 3-bromopyridin-2-amine (621 mg) in DME (10 mL) and water (3 mL) was stirred at 80° C. overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (770 mg) as a pale yellow solid.
Reaction SMILES: ClCCOC1C=C(C=CC=1)C#N.Cl[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].N1C=NC(S)=N1.[C:32]1([C:38]2[NH:42][N:41]=[C:40]([SH:43])[N:39]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:32]1([C:38]2[NH:42][N:41]=[C:40]([S:43][CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]#[N:22])[N:39]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: N#Cc1cccc(OCCCCl)c1
Reactant: Sc1n[nH]c(-c2ccccc2)n1
Agent: N#Cc1cccc(OCCCl)c1
Agent: Sc1nc[nH]n1
Product: N#Cc1cccc(OCCCSc2n[nH]c(-c3ccccc3)n2)c1

Procedure:
By a method similar to that in Reference Example 2, and using, instead of 3-[(2-chloroethyl)oxy]benzonitrile, 3-[(3-chloropropyl)oxy]benzonitrile obtained in Reference Example 4 and using, instead of 1H-1,2,4-triazole-3-thiol, 5-phenyl-1H-1,2,4-triazole-3-thiol, the title compound was obtained as a white powder (1.01 g, 59%).