Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:3]=1.CI.[C:20]([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:20])=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@@H]1COCCN1c1nc(Cl)nc2c1ncn2C
Reaction time: 65 h
Yield: 82.5 %

Procedure:
A mixture of 2-chloro-6-((R)-3-methylmorpholin-4-yl)-9H-purine (635 mg, 2.50 mmol), methyl iodide (187 μL, 3.00 mmol) and K2CO3 (484 mg, 3.50 mmol) in THF (15 mL) were stirred at r.t. for 18 h before further methyl iodide (187 μL, 3.00 mmol) was added. The resulting mixture was allowed to stir for 65 h then concentrated in vacuo. The resulting residue was partitioned between EtOAc and H2O, the organic phase washed with brine, then dried (Na2SO4) and concentrated in vacuo affording the title compound as an off-white solid (552 mg, 83%). LCMS (method H): RT 2.76 min [M+H]+ 268.3
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)(=O)C>[Cl:13][C:5]1[C:4]([Cl:14])=[C:3]([Cl:15])[C:2]([Cl:1])=[C:7]2[C:8](=[O:10])[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:12])[C:6]=12
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Product: O=C1c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)N1c1ccccc1
Temperature: 114 °C
Reaction time: 6.5 h
Yield: 96.6 %

Procedure:
Tetrachlorophthalic anhydride (300 g, 1.05 moles) was combined with aniline (100 g, 1.08 moles) and glacial acetic acid (3750 ml) in a 3-neck round bottom flask fitted with a cold-water condenser, overhead stirrer and a thermometer. The mixture was allowed to reflux (114° C.) with stirring for 6.5 hours. Crystallization occurred upon cooling. The crystals were filtered, washed with cold water and dried at 120° C., 0.5 mm Hg for 18 hours. 366 g tetrachloro-N-phenylphthalimide (96% yield) were recovered, mp 274°-275° C. The product was identified by gc/ms.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH2:7][OH:8])[N:6]=1.C([OH:17])(C)C>CC(C)=O.S(=O)(=O)(O)O.O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[S:3][C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([C:7]([OH:17])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1sc(Cl)nc1CO
Reactant: CC(C)O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1sc(Cl)nc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of ethyl 2-chloro-4-(hydroxymethyl)-1,3-thiazole-5-carboxylate (Intermediate 8, 2.5 g, 11 mmol) in acetone at 0° C. was slowly added a solution of chromium trioxide (2.26 g, 22 mmol) in 20% conc. Sulfuric acid in water (20 mL). After stirring at room temperature for 2 hrs, isopropanol (1 mL) was added to quench unreacted chromium trioxide. The reaction was diluted with water and the acetone was removed. Partitioning with methylene chloride (×3), drying with MgSO4 and concentrating yielded a white solid (2.3 g, 90%). MS (ES): 236 (M+H+) for C7H6ClNO4S; NMR: 1.26 (t, 3H), 4.31 (q, 2H), 13.99-14.15 (m, 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[CH:11]=[C:10]([NH:13][C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([C@:21]([OH:25])([CH3:24])[CH2:22][OH:23])=[CH:17][CH:16]=4)[N:9]=[CH:8][C:7]=3[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[Cl:27]N1C(=O)CCC1=O>CN(C)C=O>[Cl:27][C:6]1[C:7]2[CH:8]=[N:9][C:10]([NH:13][C:14](=[O:26])[C:15]3[CH:20]=[CH:19][C:18]([C@:21]([OH:25])([CH3:24])[CH2:22][OH:23])=[CH:17][CH:16]=3)=[CH:11][C:12]=2[N:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@](O)(CO)c1ccc(C(=O)Nc2cc3c(ccn3C3CC3)cn2)cc1
Solvent: CN(C)C=O
Product: C[C@](O)(CO)c1ccc(C(=O)Nc2cc3c(cn2)c(Cl)cn3C2CC2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 32.3 %

Procedure:
In a 100 mL round bottom flask was added (R)-N-(1-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide (200 mg, 0.57 mmol) in N,N-dimethylformamide (2.8 mL) to give a light yellow solution. This was followed by addition of N-chlorosuccinimide (76 mg, 0.57 mmol) at room temperature and the mixture was heated to 60° C. After 4 h, another 0.1 eq of N-chlorosuccinimide was added and the mixture was heated for another hour. The mixture was directly loaded onto a silica gel column, eluting with 20-70% EtOAc in hexanes for purification. Product-containing fractions were combined and a pinkish solid was formed upon evaporation of solvents. The solid was collected and washed with 5 ml EtOAc to give the title compound (23, 71 mg, 32%) as a light pink product. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.06 (m, 2 H) 1.10 (dd, J=7.07, 4.55 Hz, 2 H) 1.43 (s, 3 H) 3.42-3.54 (m, 3 H) 4.72 (br. s., 1 H) 5.00 (s, 1 H) 7.56-7.62 (m, 3 H) 8.02 (d, J=8.59 Hz, 2 H) 8.52 (d, J=0.76 Hz, 1 H) 8.56-8.60 (m, 1 H) 10.64 (s, 1 H); ESI-MS: m/z 386 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10]CC)=[O:9])(=[O:3])[CH3:2].[OH-].[Na+].O>C1COCC1>[C:1]([C:4]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Br)cc1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc(Br)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of ethyl 2-(2-acetyl-4-bromophenoxy)acetate (8.9 g, 29.56 mmol) in THF (60 mL) was added sodium hydroxide (1.43 g, 35.75 mmol) and water (10 mL). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (30 mL) and adjusted to pH 2 with HCl (3N). The solids were collected by filtration to afford 2-(2-acetyl-4-bromophenoxy)acetic acid as a light yellow solid (6.3 g, 78%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]#[N:13])=[CH:6][CH:5]=[CH:4][C:3]1=2.Cl.[NH2:15][OH:16].C(=O)(O)[O-].[Na+]>CCO>[OH:16][NH:15][C:12]([C:7]1[C:8]2[CH2:9][CH2:10][CH2:11][C@@H:2]([OH:1])[C:3]=2[CH:4]=[CH:5][CH:6]=1)=[NH:13]
Reactant: NO
Reactant: N#Cc1cccc2c1CCC[C@H]2O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1cccc2c1CCC[C@H]2O
Temperature: 70 °C
Yield: 29 %

Procedure:
Prepared using General Procedure 1. To a stirring solution of (R)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-1-carbonitrile INT-2 (79.1 mg, 0.46 mmol) in EtOH (2 not) was added hydroxylamine hydrochloride (34.9 mg, 0.50 mmol) and sodium bicarbonate (42.2 mg, 0.50 mmol). The mixture was heated at 70° C. for 18 h. The product was purified by chromatography (MeOH/DCM) to provide 27.3 mg (29%) (R)-N,5-dihydroxy-5,6,7,8-tetrahydronaphthalene-1-carboximidamide INT-4 as a white solid. LCMS-ESI (m/z) calculated for C11H11NO: 173.2; found 174.1 [M+H]+, 156.1 [M−NH4]+, tR=2.60 min. (S)-N,5-dihydroxy-5,6,7,8-tetrahydronaphthalene-1-carboximidamide INT-5 was prepared in an analogous fashion from (S)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-1-carbonitrile INT-3.
Reaction SMILES: Cl[C:2]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[C:5]1([CH3:16])[CH3:15])=[O:3].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>ClCCl>[CH3:15][C:5]1([CH3:16])[N:4]([C:2]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14]
Reactant: CC1(C)C(=O)Nc2ccccc2N1C(=O)Cl
Reactant: C1COCCN1
Solvent: ClCCl
Product: CC1(C)C(=O)Nc2ccccc2N1C(=O)N1CCOCC1
Reaction time: 0.5 h

Procedure:
To 2.70 g of 4-(chlorocarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoxalin-2-one (prepared from 3,3-dimethyl-1,2,3,4-tetrahydroquinoxalin-2-one (EXAMPLE 2) and phosgene) in 30 ml of dichloromethane are added 1.97 g of morpholine. After stirring for 30 min, the reaction mixture is partitioned between dichloromethane and saline. The organic layers are dried over sodium sulfate, concentrated, and crystallized from dichloromethane/hexane to give the title compound, mp 190.5°-193°; MS (m/z) at 289; IR (mineral oil) 1683, 1661, 1409, 1238, 1121, 1506 cm-1 ; NMR (CDCl3) δ 1.3-1.9, 3.0-4.1, 6.70, 6.84, 6.95-7.03, 8.31.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[O:22]=[C:23]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[C:24](O)=[O:25]>>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[C:24](=[O:25])[C@@H:23]([OH:22])[C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=C(O)C(=O)c1cccnc1
Reactant: Cc1ccc(NCCc2ccc(C(F)(F)F)nc2)cc1C
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](O)c2cccnc2)cc1C
Yield: 13.1 %

Procedure:
In analogy to example 7, (3,4-dimethyl-phenyl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (250 mg, 0.85 mmol) and oxo-pyridin-3-yl-acetic acid (343 mg, 1.27 mmol, CAS 39684-37-2) were coupled together to afford the title compound (48 mg, 27%) as a colourless solid. MS m/e: 430.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].C([O-])([O-])=O.[K+].[K+].C(C(N)CBr)(O[C:23](C)([CH3:25])[CH3:24])=O>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:23]([CH3:25])[CH3:24])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: CC(C)(C)OC(=O)C(N)CBr
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 109.5 %

Procedure:
To a solution of compound 3 (5.000 g, 17 mmol) in DMF (15 mL) was added K2CO3 (3.51 g, 26 mmol) and Boc-2-amino ethyl bromide (4.56 g, 20.35 mmol). The resulting mixture was stirred at 60° C. for three hours. The mixture was diluted with water and extracted with EtOAc (3×50 mL). The organic layers were combined, dried over Na2SO4, and concentrated. Purification with column chromatography (Hexanes/EtOAc 50:50) gave the product 4 (4.08 g, 55%) as white solid.
Reaction SMILES: C(O[C:4](=[O:18])[CH:5]=[C:6]([NH:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])[CH3:7])C>C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCC>[F:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH3:17])=[C:9]2[C:14]=1[C:4]([OH:18])=[CH:5][C:6]([CH3:7])=[N:8]2
Reactant: CCOC(=O)C=C(C)Nc1cc(F)ccc1OC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(F)c2c(O)cc(C)nc12
Temperature: 25 °C

Procedure:
A solution of 3-(5-fluoro-2-methoxy-phenylamino)-but-2-enoic acid ethyl ester (1.8 g, 6.7 mmol) in diphenyl ether (10.7 mL) was heated to 250° C. for 25 min. The reaction mixture was cooled to room temperature, diluted with hexane, and filtered to give the title compound. MS (m/z): 208.1 [M+H+].
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([C:30]([O:32][CH3:33])=[O:31])([CH3:29])[CH3:28])/[C:9]1=[O:34])=O)(C)(C)C.[F:35][C:36]1[C:41]([F:42])=[CH:40][C:39]([CH:43]=[N:44][C:45]([O:47][Si](C)(C)C)=[CH2:46])=[C:38]([CH3:52])[CH:37]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:34])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]([C:30]([O:32][CH3:33])=[O:31])([CH3:29])[CH3:28])[CH2:46][C:45](=[O:47])[NH:44][CH:43]3[C:39]3[CH:40]=[C:41]([F:42])[C:36]([F:35])=[CH:37][C:38]=3[CH3:52])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1cc(F)c(F)cc1C)O[Si](C)(C)C
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)c(F)cc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 3.4 %

Procedure:
A mixture of E/Z-6-chloro-3-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.5 g, 2.9 mmol) and 1-(4,5-difluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (13 mmol) in toluene (13 mL) was heated at 60° C. for 3 h, and concentrated in vacuo. To the residue was added DCM (30 mL) and TFA (5 mL), and the resultant solution was stirred at room temperature for 3 h, then concentrated in vacuo. The residue was partitioned between ethyl acetate and aqueous diluted NaOH solution. The organic layer was washed with water to neutral, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography to give the title compound as white solid (60 mg).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH:28]1[CH:32]=[C:31]([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[N:30]=[CH:29]1>>[NH:28]1[CH:32]=[C:31]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:38]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:39][CH:40]=2)[N:30]=[CH:29]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(Cc2c[nH]cn2)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(Cc2c[nH]cn2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(imidazol-4-yl-methyl)-aniline Rf value: 0.2 (silica gel, methylene chloride/methanol=5:1) C27H22N4O3
Reaction SMILES: [C:1]1([CH:7]([NH:14][C:15]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+].Br[CH:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:26]#[N:27]>CN(C)C=O>[CH2:28]([CH:25]([N:20]1[CH:21]=[C:17]([C:15]([NH:14][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:16])[N:18]=[CH:19]1)[C:26]#[N:27])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: O=C(NC(c1ccccc1)c1ccccc1)c1c[nH]cn1
Reactant: CCCCCCC(Br)C#N
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCC(C#N)n1cnc(C(=O)NC(c2ccccc2)c2ccccc2)c1
Yield: 49.8 %

Procedure:
To a solution of 1.67 g of 4-{[(diphenylmethyl)amino]carbonyl}-1H-imidazole in 100 ml of dimethylformamide were added 5.03 g of potassium fluoride on alumina. With stirring, 1.35 g of α-bromo-octanonitrile were added. The solution was stirred at room temperature overnight and then concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, washed with a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. NMR indicated a mixture of starting material with desired product, so the residue was dissolved in 200 ml of acetonitrile, and 1 g of α-bromooctanonitrile and 5 g of potassium fluoride on alumina was added. After stirring at room temperature for 2 days, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed over SiO2 and the appropriate fractions combined and concentrated in vacuo to provide 1.2 g of the desired titled intermediate oil. MS: M+ =400
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[CH:27][C:28]=1[CH3:29].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:33]2[CH2:34][CH2:35][N:30]([C:25]3[CH:26]=[CH:27][C:28]([CH3:29])=[C:23]([CH3:22])[CH:24]=3)[CH2:31][CH2:32]2)=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccc(C)c(C)c4)CC3)nn2C(C)(C)C)cc1

Procedure:
118 mg (80%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 1-(3,4-dimethylphenyl)piperazine (57 mg, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)3 (189 mg, 0.891 mmol).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH2:16][CH3:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:16][CH3:17])[C:19]2[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNCC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN(CC1CCN(Cc2ccccc2)CC1)c1ncccc1[N+](=O)[O-]

Procedure:
1-Benzyl-4-[N-ethylamino]methylpiperidine (EXAMPLE 175, 7.59, 32.64 mmol), 2-chloro-3-nitropyridine (5.17 g, 32.64 mmol) and potassium carbonate (5.41 g, 39.17 mmol) in acetonitrile (0.25M) are refluxed 48 hr. The mixture is diluted with water and extracted with ethyl acetate and then dichloromethane. The combined extracts are dried over sodium sulfate, concentrated and chromatographed (silica gel column, 300 g; eluting with 15-80% ethyl acetate/hexane), to give the title compound, NMR (300 MHz, CD3OD) 8.43, 8.20, 7.42, 6.90, 3.61, 3.52, 3.49, 3.00, 2.10, 1.80, 1.37 and 1.25δ.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH:7]=[O:8])[CH3:2].CO.[BH4-].[Na+]>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH2:7][OH:8])[CH3:2]
Reactant: CCOc1ccc(C=O)cc1OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOc1ccc(CO)cc1OCC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 98.4 %

Procedure:
To a mixture of 3,4-diethoxybenzaldehyde (6.68 g) and methanol (100 ml) was added sodium borohydride (1.30 g) at 0° C. The resulting mixture was stirred at 0° C. for 45 minutes. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 3,4-diethoxybenzyl alcohol (6.64 g) as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([OH:13])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[N:4]=1)[CH3:2].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:13][C:12]1[C:3]([CH2:1][CH3:2])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]=[CH:7][CH:6]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCc1nc2ccncc2cc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: CCc1nc2ccncc2cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 140 °C
Reaction time: 4 h
Yield: 6.3 %

Procedure:
2-Ethyl-[1,6]naphthyridin-3-ol (69 mg), 4-chloro-6,7-dimethoxyquinoline (265 mg), and 4-dimethylaminopyridine (145 mg) were suspended in o-dichlorobenzene (3 ml), and the mixture was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (9 mg, yield 6%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]([O:30][C:31](=[O:33])[CH3:32])[CH2:19][S:20][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[NH:23][CH:24]=[N:25]4)[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[CH3:41][O:42][C:43](=[O:46])[CH:44]=[CH2:45]>CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH:18]([O:30][C:31](=[O:33])[CH3:32])[CH2:19][S:20][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][N:25]4[CH2:45][CH2:44][C:43]([O:42][CH3:41])=[O:46])[CH2:15][CH2:16]2)=[CH:6][CH:5]=1
Reactant: CC(=O)OC(CSc1ncnc2nc[nH]c12)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: C=CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCn1cnc2c(SCC(CN3CCN(C(c4ccc(F)cc4)c4ccc(F)cc4)CC3)OC(C)=O)ncnc21
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To NaH (0.02 mmol, 0.96 mg, 50% suspension in mineral oil) in DMF (5 mL) at 0° C. was added 6-(1-[1-[bis(4-fluorophenyl)methyl]-piperazin-4-yl]-2-acetoxy-3-propanylthio]purine (1.0 g, 1.8 mmol) neat in portions. After stirring about 15 min, methylacrylate (1.8 mmol, 0.16 mL) was added neat at 0° C. The ice bath was removed and the mixture stirred at room temperature for 7 days. The mixture was then heated on a 60° C. oil bath for 24 h. The DMF was removed in vacuo (1 mmHg, 60° C.) and the crude residue was eluted through silica gel using 10% MeOH:CH2Cl2. Pure product was isolated (550 mg, 49.1%) as a glassy solid; mp 55°-58° C. (dec.). DCI/MS (M+1) 625; (300 MHz) 1H NMR (CDCl3) δ: 8.15 (s,1H), 8.05 (s,1H), 7.35 (m,4H), 6.95 (m,4H), 5.3 (m,1H), 4.5 (t,2H,J=6.2 Hz), 4.2 (s,1H), 3.4 and 4.0 (q of q 2H), 3.65 (s,3H), 2.91 (t,2H,J=6.1 Hz), 2.6 (d,2H,J=6.1 Hz), 2.55 and 2.35 (m,8H), 2.0 (s,3H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]([NH:17][C:18]3[CH:30]=[CH:29][C:21]([C:22]([CH2:24][CH2:25][C:26](O)=[O:27])=O)=[CH:20][CH:19]=3)=[O:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:32][NH2:33]>C(O)C>[C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]([NH:17][C:18]3[CH:30]=[CH:29][C:21]([C:22]4[CH2:24][CH2:25][C:26](=[O:27])[NH:32][N:33]=4)=[CH:20][CH:19]=3)=[O:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(NC(=O)CCN2CCC(c3ccccc3)CC2)cc1
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccc(NC(=O)CCN3CCC(c4ccccc4)CC3)cc2)=NN1

Procedure:
10 g (23.7 millimoles) of 3-{p-[3-(4-phenylpiperidino)-propionylamino]-benzoyl}-propionic acid were stirred with 1.2 g (23.7 millimoles) of hydrazine hydrate in 200 ml of ethanol for 5 hours at 80° C. The product was filtered off under suction and recrystallized from dimethylformamide/water. 7.6 g (78%) of 6-{p-[3-(4-phenylpiperidino)-propionylamino]-phenyl}-4,5-dihydro-3(2H)-pyridazinone.1/4H2O were obtained as colorless crystals of melting point 238°-240° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].Cl[CH2:13][C:14]([OH:16])=[O:15]>>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][O:6][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CCl
Reactant: OCCc1ccc(F)cc1F
Product: O=C(O)COCCc1ccc(F)cc1F
Temperature: 120 °C
Yield: 54.4 %

Procedure:
3.63 g of 2,4-difluorophenethyl alcohol were reacted with 2.17 g of chloroacetic acid in a manner analogous to that described in Example 1(a), except that the reaction mixture was heated at 120° C. for 1 hour, to give 2.7 g (54%) of 2-(2,4-difluorophenyl)ethoxyacetic acid in the form of an oil which was homogeneous according to chromatography.