Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=O)[C:18]2=[O:25].FC1C=C2C(=CC=1)NC(=O)C2=O>>[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]1[C:19](=[N:11][C:5]3[C:6]([C:7]1=[O:8])=[CH:13][CH:2]=[CH:3][CH:4]=3)[C:18]2=[O:25]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: O=C1Nc2ccc(F)cc2C1=O
Product: O=C1c2cc(Br)ccc2-n2c1nc1ccccc1c2=O
Yield: 9 %

Procedure:
Using the procedure in Example 12 and substituting isatoic anhydride for 5-chloroisatoic anhydride and 5-bromoisatin for 5-fluoroisatin gave the title compound in 9% yield: mp 288°-290.2° C.; 1H NMR (300 MHz, CDCl3) δ 8.56 (d, 1H) 8.44 (d, 1H) 8.06 (s, 1H) 8.04 (s, 1H) 7.82-7.96 (m, 2H) 7.66-7.76 (m, 1H); MS (M+H)+ 328.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])#[N:2].[H][H].C(Cl)(Cl)[Cl:16]>CCO.O=[Pt]=O>[NH2:2][CH2:1][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[ClH:16]
Reactant: COC(=O)c1ccccc1C#N
Reactant: ClC(Cl)Cl
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: COC(=O)c1ccccc1CN
Product: Cl

Procedure:
A mixture of methyl 2-cyanobenzoate (1.0 g, 6.2 mmol) and PtO2 (100 mg) in 20 mL EtOH and 1 ml of chloroform was hydrogenated under 50 psi of hydrogen for 2 h. The reaction mixture was filtered through Celite® in a sintered glass funnel and concentrated on a rotary evaporator to give methyl 2-(aminomethyl)benzoate as a HCl salt and this was carried to the next step crude.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7](Cl)[C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13](OCC)=[O:14].C([Cl:21])(=O)C>O1CCOCC1>[Cl:21][C:8]1[CH:7]=[C:3]2[C:4]([O:6][C:13](=[O:14])[NH:1][C:2]2=[CH:10][CH:9]=1)=[O:5]
Reactant: CCOC(=O)Cl
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: CC(=O)Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Temperature: 50 °C
Reaction time: 10 h
Yield: 97 %

Procedure:
2-Amino-6-chlorobenzoic acid (30 g) was suspended in 1,4-dioxane (225 ml) and ethyl chloroformate (75 ml) was added. The mixture was heated at reflux for 1 hour, then cooled to 50° C., and acetyl chloride (75 ml) was added. The mixture was stirred for 10 hours, after which the precipitated product was filtered off and washed with toluene. Drying in vacuum yields 5-chloroisatoic anhydride (33 g, 97% yield).
Reaction SMILES: C([O:3][C:4](=[O:40])[CH:5]([CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[S:6][C:7]1[CH:8]=[N:9][C:10]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH3:26])[N:25]=2)=[C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)C.[OH-].[Na+]>>[C:36]([O:35][C:33]([N:30]1[CH2:29][CH2:28][CH:27]([CH:5]([S:6][C:7]2[CH:8]=[N:9][C:10]([NH:20][C:21]3[S:22][CH:23]=[C:24]([CH3:26])[N:25]=3)=[C:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=2)[C:4]([OH:40])=[O:3])[CH2:32][CH2:31]1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CCOC(=O)C(Sc1cnc(Nc2nc(C)cs2)c(Oc2ccccc2)c1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Product: Cc1csc(Nc2ncc(SC(C(=O)O)C3CCN(C(=O)OC(C)(C)C)CC3)cc2Oc2ccccc2)n1
Yield: 98.6 %

Procedure:
Prepared according to the method of Example 70, Step B, using tert-butyl 4-(2-ethoxy-1-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)-2-oxoethyl)piperidine-1-carboxylate (1.51 g, 2.59 mmol) and 4N NaOH (15 mL); (1.42 g, 98.6% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][NH:15][C:16](OCC2C=CC=CC=2)=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].ClC1[N:37]=[C:36]([N:38]([CH3:40])[CH3:39])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1.C([O-])(O)=O.[Na+]>CO.CC(O)C.[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:9][CH2:10][C@@H:11]([CH2:14][NH:15][C:16]2[N:37]=[C:36]([N:38]([CH3:40])[CH3:39])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)[CH2:12][CH2:13]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CNC(=O)OCc2ccccc2)CC1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Product: CN(C)c1nc(NC[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)nc2ccccc12
Temperature: 50 °C
Reaction time: 12 h
Yield: 32.7 %

Procedure:
A mixture of cis-[4-(benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamic acid tert-butyl ester (4.00 g, 11.0 mmol) and 5% Pd/C (400 mg) in MeOH (40 mL) was stirred under hydrogen atmosphere at ambient temperature for 8.5 hr and at 50° C. for 12 hr, filtered through a pad of celite, and concentrated. The precipitate was suspended in hexane and the suspension was stirred at ambient temperature for 30 min. The solid was collected by filtration, washed with hexane, and dried (3.03 g). A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (1.00 g, 4.82 mmol) and the above solid (1.65 g, 7.23 mmol) in 2-propanol (10 mL) was stirred at reflux for 5 days, poured into saturated aqueous NaHCO3, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 20% EtOAc in hexane) to give cis-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (629 mg, 43%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:6][CH:7]=1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)c3ccccc3)cc1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxy late (100 mg, 0.32 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.64 mmol) in dichloro methane (5 mL) was added benzoyl chloride (0.04 mL, 0.35 mmol) with ice cooling. Upon completion of addition, the resultant solution was allowed to warm back to room temperature and stir overnight. LC-MS showed the reaction was complete. Solvent was removed in vacuo and the residue was purified by preparative Thin layer chromatography to afford 70 mg of methyl 2-(4-benzamidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid. Yield: 53%. MS (ESI+APCI) M+1=415.20.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(OCC)C>[OH:24]/[C:18](=[C:13]1/[CH2:12][O:11][CH2:16][CH2:15][C:14]/1=[O:17])/[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Product: CCOC(=O)/C(O)=C1\COCCC1=O
Temperature: -72 °C
Reaction time: 1 h

Procedure:
Lithium bis(trimethylsilyl)amide 1M solution (30.0 ml, 30.0 mmol) and diethyl ether (40 ml) were added into a flask under nitrogen atmosphere and cooled to −72° C. with dry ice/acetone-bath. Tetrahydro-4H-pyran-4-one (3 g, 30.0 mmol) was diluted with diethyl ether (10 ml) and added slowly to the previously cooled mixture. The resulting mixture was stirred at −70° C. for one hour. Diethyl oxalate (4.07 ml, 30.0 mmol) diluted with diethyl ether (10 ml) was added and the reaction mixture was allowed to warm to RT and stirred overnight. The formed yellow precipitate was filtered, washed with cold diethyl ether and dried with vacuum at 40° C. 1H-NMR (400 MHz; d6-DMSO): δ 1.16 (d, 3H), 1.92 (t, 2H), 3.68 (t, 2H), 3.98 (q, 2H), 4.19 (s, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.[N:10]1([CH2:15][C:16]2[CH:17]=[CH:18][C:19](Br)=[N:20][CH:21]=2)[CH:14]=[CH:13][N:12]=[CH:11]1>>[N:10]1([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[N:20][CH:21]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: OB(O)c1ccncc1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: c1cc(-c2ccc(Cn3ccnc3)cn2)ccn1

Procedure:
Synthesized using 4-pyridylboronic acid (123 mg, 1.00 mmol) and 1a (95 mg, 0.4 mmol) according to Method C. Yellow solid. Yield: 73 mg, 77%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.22 (s, 2H), 6.94 (t, J=1.3 Hz, 1H), 7.14 (brs, 1H), 7.54 (dd, J=2.5, 8.2 Hz, 1H), 7.60 (s, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.88 (dd, J=1.6, 4.1 Hz, 2H), 8.64 (dd, J=0.6, 2.5 Hz, 1H), 8.73 (dd, J=1.6, 4.4 Hz, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.3, 119.3, 121.2, 130.8, 132.3, 136.2, 137.6, 149.1, 150.8, 155.1; MS (ESI): m/z=237.02 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[OH:24].C(S(C1C=C(C2C=C[C:44]([O:47]CCO)=[C:43]3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[O:24][CH2:43][CH2:44][OH:47]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCO)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(Cl)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCO)c3[nH]c4ncc(Cl)cc4c23)c1

Procedure:
The title compound was prepared from Compound 218 by using an analogous procedure to that outlined in the preparation of Compound 215. 1H NMR (400 MHz, Methanol-d4) δ 8.39 (s, 1H) 8.14 (m, 1H) 8.06 (m, 1H) 8.00 (m, 1H) 7.87 (t, J=8.0 Hz, 1H) 7.71 (d, J=4.0 Hz, 1H) 7.21 (d, J=8.0 Hz, 1H) 7.16 (d, J=8.0 Hz, 1H) 4.36 (t, J=4 Hz, 2H) 4.07 (t, J=4 Hz, 2H) 3.30 (q, J=7.5 Hz, 2H) 1.31 (t, J=7.5 Hz, 3H). [M+H] calc'd for C21H20ClN2O4S, 431; found, 431.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[O:17]CC2C=CC=CC=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])=O.[NH4+]>CO.[Pd]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[OH:17])[C:10]([O:12][CH3:13])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1ccc(O)c(OC2CCCC2)c1

Procedure:
A solution of methyl 3-cyclopentyloxy-4-benzyloxybenzoate (2.64 g; that is prepared as described in Reference Example 39) in methanol (120 mL) is treated with palladium on charcoal (5%,0.5 g) and ammonium formate (2.0 g) and heated at reflux for 45 minutes. The catalyst is filtered off through a pad of diatomaceous earth and washed with methanol. The filtrate and washings are evaporated under reduced pressure, and the resulting residue is subjected to flash chromatography on silica gel using a mixture of diethyl ether and pentane 1:1 v/v), to give methyl 3-cyclopentyloxy-4-hydroxybenzoate (1.8 g), in the form of a cream solid, m.p. 73°-75° C.
Reaction SMILES: [CH:1]1([NH:11][C:12]([NH2:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH2:17]=O.[C:19](=[O:21])=O>CO>[CH3:17][O:21][CH2:19][NH:14][C:12]([NH:11][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:13]
Reactant: C=O
Reactant: NC(=O)NC1CCCc2ccccc21
Reactant: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCNC(=O)NC1CCCc2ccccc21

Procedure:
A solution of 7.6 grams (0.04 mole) of (1,2,3,4-tetrahydro-1-naphtyl)urea, 2.0 grams of sodium hydroxide and 2.2 grams of para-formaldehyde in 150 ml. of methanol is stirred at reflux temperature for 10 hours. The reaction mixture is cooled and neutralized with dry ice. The solvent is evaporated at reduced pressure. The residue is treated with water, the mixture filtered, and the filter cake washed with water and dried to give 8.2 grams of product, melting point 124.5° C. to 127.5° C. Recrystallization from methyl isobutyl ketone gives the analytical sample, melting point 136° to 138.5° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][C:26]([C:28]5[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH:29]=5)=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1.Cl>C(Cl)Cl.O1CCOCC1>[NH:31]1[CH2:30][CH:29]=[C:28]([C:26]2[CH:25]=[CH:24][C:23]3[N:19]([CH2:18][C:16]4[CH:15]=[CH:14][C:12]5[N:13]=[C:9]([NH:8][C@@H:3]6[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]6[OH:1])[S:10][C:11]=5[CH:17]=4)[CH:20]=[N:21][C:22]=3[CH:27]=2)[CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)ncn3Cc2ccc3nc(N[C@@H]4CCCC[C@H]4O)sc3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(C5=CCNCC5)ccc43)cc2s1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 6 %

Procedure:
To a stirred solution of tert-butyl 4-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (30 mg, 0.05 mmol) from the previous step in DCM (3 mL) at 0° C. was added 4M HCl in 1,4-dioxane (0.3 mL), and the mixture was stirred at 0° C. for 5 min. The mixture concentrated under reduced pressure and the residue was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Phenomenex Luna C-18 column as the stationary phase to afford (1R,2R)-2-((6-((5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as a solid (1.38 mg, 5%). 1H NMR (500 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.00 (d, J=7.4 Hz, 1H), 7.62 (d, J=5.9 Hz, 2H), 7.47 (d, J=8.9 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.18 (dd, J=1.2, 8.1 Hz, 1H), 6.14 (br s, 1H), 5.44 (s, 2H), 3.47-3.57 (br m, 2H), 2.94 (t, J=5.4 Hz, 2H), 2.40 (br s, 2H), 2.02 (d, J=11.8 Hz, 1H), 1.85-1.87 (m, 6H), 1.57-1.66 (m, 2H), 1.12-1.30 (m, 4H); LCMS (ESI) m/z 460 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OCC)(=O)C.[ClH:39]>C(OCC)(=O)C.CO>[ClH:39].[CH3:25][NH:24][CH2:23][C:11]1[CH:10]=[C:9]([C:8]2[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=2)[N:13]([S:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH:12]=1
Reactant: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccccc2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CNCc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
tert-Butyl {[5-(2-cyanopyridin-3-yl)-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (250 mg) was dissolved in ethyl acetate (5 mL) and methanol (3 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL) was added. The mixture was stirred at room temperature for 4 hr, and concentrated under reduced pressure. The obtained residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 127 mg, 59%).
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH:13]3[NH:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:10][O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:26][O+](C)C>>[CH3:26][O:20][C:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([CH2:12][C:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][O:9][CH:10]=2)[N:19]=1
Reactant: C[O+](C)C
Reactant: O=C1CCCCC(Cc2conc2-c2ccccc2)N1
Agent: F[B-](F)(F)F
Product: COC1=NC(Cc2conc2-c2ccccc2)CCCC1

Procedure:
The title product of Example 126 is reacted with trimethyloxonium tetrafluoroborate by the method of Example 3 to generate the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:29][CH2:30][CH2:31][OH:32])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH3:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:29][CH2:30][C:31]([NH2:33])=[O:32])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N
Reactant: C[C@@H](c1ccc(-c2cccnc2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2cccnc2)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one using a procedure analogous to that described in Example 12 Step 2, followed by a procedure analogous to that described in Example 8 Step 2 using ammonia. LC-MS Method 2 tR=1.372, min, m/z=448.3; 1H NMR (CDCl3) 1.52 (d, 3H), 1.97 (m, 2H), 2.27-2.33 (m, 4H), 2.43 (m, 1H), 2.97 (m, 1H), 5.13 (s, 1H), 5.24 (s, 1H), 5.66 (m, 1H), 6.92-7.08 (m, 4H), 7.22 (m, 2H), 7.31 (m, 2H), 7.48 (m, 1H), 7.97 (m, 1H), 8.57 (m, 1H), 8.74 (m, 1H).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([NH:22][CH3:23])=[N:19][C:18]=3[CH3:24])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([N:22]([CH3:23])[C:32](=[O:34])[CH3:33])=[N:19][C:18]=3[CH3:24])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(NC)nc3C)c(C)nc12
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N(C)C(C)=O)nc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
60 mg of N-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-methylamine (0.17 mmol) and 86 mg of triethylamine (0.85 mmol) are dissolved in 3.0 ml of CH2Cl2 and 16 mg of acetylchloride (0.2 mmol) is added. The vial is capped with a Teflon® lined cap and shaken at room temperature for 2 h. The reaction mixture is concentrated and applied onto a silica-gel chromatography column (Hexane:AcOEt=3:1 and Hexane:AcOEt=2:1) to give 33.8 mg of the title compound. Yield 50%: mass spectrum (m/e): 386 (M+1); 1H-NMR (CDCl3): 7.03 (s, 1H), 3.79 (s, 3H), 3.47 (m, 1H), 2.54 (s, 3H), 2.47 (s, 3H), 2.46 (s, 3H), 2.31 (s, 3H), 1.86 (m, 4H), 0.91 (t, 6H, J=7.4 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=C1C.[OH-].[K+]>C(O)C.O>[NH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:8][NH:4][CH2:3][CH2:2][OH:1]
Reactant: CC1=NC(c2ccccc2)CN1CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(CNCCO)c1ccccc1

Procedure:
The hydroxyethylmethylphenylimidazoline produced in Example II in the amount of 30 g and 60 g potassium hydroxide, in 150 ml ethanol and 40 ml water, are refluxed for 24 hours. The solution is then concentrated by removal of the ethanol, and the residue is taken up in 50 ml of water.
Reaction SMILES: C1C2(N(C3C=CC=CC=3)CNC2=O)CCN(CCC[C:21]([C:23]2[CH:28]=[CH:27][C:26](F)=CC=2)=[O:22])C1.C(O)[C:31](N)([CH2:34][OH:35])[CH2:32]O.Cl.[Na+].[Cl-].CC([C@]1(O)C[C@H]2[N:48](C[C@H]3C4C2=CC=CC=4CCC2C=CC=CC3=2)CC1)(C)C>>[NH2:48][CH2:26][CH2:27][C:28]1[CH:32]=[CH:31][C:34]([OH:35])=[C:21]([OH:22])[CH:23]=1
Reactant: CC(C)(C)[C@@]1(O)CCN2C[C@@H]3c4ccccc4CCc4cccc(c43)[C@H]2C1
Reactant: NC(CO)(CO)CO
Reactant: O=C(CCCN1CCC2(CC1)C(=O)NCN2c1ccccc1)c1ccc(F)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: NCCc1ccc(O)c(O)c1
Reaction time: 0.25 h

Procedure:
0.5 mL aliquots of the membrane preparation were incubated with unlabeled drugs, and 0.15 nM [3H]spiperone in a final volume of 1 mL containing 50 mM Tris HCl, 120 mM NaCl and 1 mM MgC12 (pH 7.7). Nonspecific binding was measured in the presence of 100 nM (+)-butaclamol. After 15 minutes of incubation at 37° C., samples were filtered rapidly through Whatman GF/C glass filters under negative pressure, and washed three times with ice-cold binding buffer (5 mL).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[N:10][N:11]([CH:13]([CH2:15][CH3:16])[CH3:14])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH:23]([NH2:26])([CH3:25])[CH3:24].CN(C)[CH:29]=[O:30]>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[CH:13]([N:11]1[CH:12]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:29]([NH:26][CH:23]([CH3:25])[CH3:24])=[O:30])[CH:7]=2)[C:9]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[N:10]1)([CH2:15][CH3:16])[CH3:14]
Reactant: CC(C)N
Reactant: CN(C)C=O
Reactant: CCC(C)n1cc(-c2ccnc(Cl)c2)c(-c2ccc(Cl)s2)n1
Agent: [Mo]
Agent: [C-]#[O+]
Product: CCC(C)n1cc(-c2ccnc(C(=O)NC(C)C)c2)c(-c2ccc(Cl)s2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
To a solution of 2-chloro-4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (0.28 mmol) in 2 mL of N,N-dimethylformamide was added molybdenum hexacarbonyl (0.28 mmol), tetrakistriphenylphosphine palladium (0) (0.028 mmol), isopropylamine (0.85 mmol), and 1,8-diazabicyclo(5-4-0)undece-7-ene (0.85 mmol). The mixture was stirred at 80° C. overnight. The solvent was then evaporated and the residue was purified by chromatography on silica gel (hepthane:ethyl acetate 5:1 to 2:1) to afford 30 mg of 4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]-N-isopropylpyridine-2-carboxamide (26% yield).
Reaction SMILES: [CH2:1]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:20][CH2:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[O:24].C(N(CC)CC)C>C(OCC)C>[ClH:20].[CH2:1]([C:13]1[CH:14]=[CH:15][C:16]([NH:17][CH2:21][CH2:22][C:23]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[O:24])=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1ccc(N)cc1
Reactant: O=C(CCCl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCCCCc1ccc(NCCC(=O)c2ccc(F)cc2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.9 %

Procedure:
A mixture of 4-dodecylaniline (26.2 g, 0.1 mole) and 3-chloro-4'-fluoropropiophenone (18.7 g, 0.1 mole) in diethyl ether (200 ml) was stirred for 16 hours at room temperature. The mixture was treated with triethylamine (10.1 g, 0.1 mole), stirred for an additional 72 hours, and concentrated in vacuo. The residue was partitioned between diethyl ether (200 ml) and hydrochloric acid (IN, 200 ml). The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to an impure tacky solid (41.9 g). A small portion (5 g) was recrystallized from ethanol to give the title compound (4.0 g); mp 107°-109° C.; IR(nujol) C=O @ 1674 cm-1 ; NMR(DMSO-d6, TMS): δ0.5-1.7(m,23H,C11H23), 2.50(t,2H,ArCH2), 3.30(m,4H, N--CH2 --CH2), 6.50,7.00(2d,4H,p-N-phenyl), [ 7.37(d of d,2H) and 8.07(m,2H) p-F-phenyl]; Anal. Calcd. for C27H38FNO.HCl, MW 448.05: C,73.37; H,8.77; N,3.19. Found: C,73.09; H,8.50; N,3.19. Mass spectrum m/e 411,284.