Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].C(N(CC)CC)C.[CH2:16]([OH:20])[CH2:17][CH2:18][CH3:19]>O1CCCC1>[C:4]([NH:6][C:7](=[S:8])[O:20][CH2:16][CH2:17][CH2:18][CH3:19])([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCCCO
Reactant: CCOC(=O)N=C=S
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOC(=S)NC(=O)OCC
Yield: 95.8 %

Procedure:
26 g of ethoxycarbonyl isothiocyanate were added dropwise to a mixture of 0.4 ml of triethylamine, 15 g of normal butanol and 150 ml of tetrahydrofuran and the mixture was refluxed for 2 hours and concentrated to dryness by distillation under reduced pressure to obtain 39 g of raw n-butyl N-carbethoxy-thiocarbamate. The latter product was added to a mixture of 500 ml of methanol and 14 g of potassium methylate and the mixture was stirred for an hour and then concentrated to dryness under reduced pressure. The residue was added to ether and the precipitate formed was recovered by vacuum filtration and was dried to obtain 35 g of the potassium salt of n-butyl N-carbethoxy-thiocarbamate melting at 219° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[CH3:16][O:17][C:18]([C:20]1[CH:29]=[CH:28][C:23]2[S:24][C:25]([CH3:27])=[CH:26][C:22]=2[CH:21]=1)=[O:19].C(OCC)(=O)C>C(Cl)Cl>[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([C:26]1[C:22]2[CH:21]=[C:20]([C:18]([O:17][CH3:16])=[O:19])[CH:29]=[CH:28][C:23]=2[S:24][C:25]=1[CH3:27])=[O:9]
Reactant: COC(=O)c1ccc2sc(C)cc2c1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2sc(C)c(C(=O)c3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Aluminum chloride (1.24 g, 9.3 mmol) was dispersed in methylene chloride (10 ml), and 2,4-dichlorobenzoyl chloride (0.97 g, 4.7 mmol) and then 5-(methoxycarbonyl)-2-methylbenzo[b]thiophene (0.8 g, 3.9 ml) were added thereto. The mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into ice water and ethyl acetate was added. The mixture was extracted. The organic layer was washed twice with a saturated aqueous solution of sodium hydrogencarbonate and once with brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give the objective compound (1.5 g, quantitative) as pale yellow crystals.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.I[CH2:24][CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:20])[C:11](=[O:22])[N:10]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:8]=2[N:9]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
To a suspension of NaH (60% in mineral oil, 36 mg) in 8 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (205 mg, 0.67 mmol). The mixture was heated at 60° C. for 20 minutes resulting in a clear solution. 1-Iodo-2-methylpropane (110 μL, 0.94 mmol) was added, and the solution was stirred at 50° C. for 30 minutes. An additional amount of 1-iodo-2-methylpropane (40 μL, 0.34 mmol) was added, and the solution was stirred at 50° C. for 40 minutes, then cooled to room temperature and poured onto 40 mL of ice water. The resulting precipitate was removed by filtration and washed with water. The gummy residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was purified by flash chromatography, eluting with 1:1 hexane:ethyl acetate to provide 123 mg (51%) of 2-amino-6-(2,6-dichlorophenyl)-8-isobutyl-8H-pyrido[2,3-d]pyrimidin-7-one; mp 193°-195° C.
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[CH:9]([O:12][C:13]1[N:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][N:14]=1)([CH3:11])[CH3:10]>CC(C)=O.C(OCC)C>[CH:9]([O:12][C:13]1[N:18]=[CH:17][C:16]([OH:2])=[CH:15][N:14]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(C)Oc1ncc(O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
An aqueous solution (5 mL) of potassium peroxymonosulfate (1.40 g, 2.27 mmol) was added dropwise to a solution of 2-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (Preparation 100, 500 mg, 1.89 mmol) in acetone (5 ml) under a nitrogen atmosphere at 0° C. The mixture was stirred at room temperature for 2 hours, then filtered, the filtrate diluted with water (30 mL) and extracted with EtOAc (1×20 mL). The organic layer was washed with brine (2×20 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The resulting oil was dissolved in dichloromethane and purified by silica gel chromatography eluting with 0 to 5% MeOH (with 10% aqueous ammonia) in dichloromethane to yield a solid. The solid was suspended in diethyl ether and evaporated to yield the title compound as a white solid (100 mg, 34%):
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][CH2:20][CH2:21][CH2:22]I>CCCCCCC.CCOC(C)=O>[Cl:19][CH2:20][CH2:21][CH2:22][N:8]1[C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=2[O:11][CH2:10][C:9]1=[O:12]
Reactant: Cc1cccc2c1NC(=O)CO2
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1cccc2c1N(CCCCl)C(=O)CO2
Yield: 48.1 %

Procedure:
5-Methyl-4H-benzo[1,4]oxazin-3-one (81MF941a) (1.514 g, 9.28 mmol), Cs2CO3 (4.53 g, 13.9 mmol) and 3-chloro-1-iodopropane (2.09 g, 10.21 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (81MF941b) (1.07 g, 48%). 1H NMR (CDCl3) δ 6.99-6.87 (m, 3H), 4.42 (s, 2H), 4.17 (t, J=7.2 Hz, 2H), 3.45 (t, J=6.4 Hz, 2H), 2.41 (s, 3H), 2.04-1.97 (m, 2H); 13C NMR (CDCl3) δ 168.3, 149.9, 129.1, 128.7, 126.9, 125.1, 115.0, 69.4, 42.2, 42.1, 30.6, 20.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:13]O)[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.S(Cl)([Cl:17])=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:13][Cl:17])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1
Reactant: CC1(C)Cc2cc(Br)cc(CO)c2O1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C)Cc2cc(Br)cc(CCl)c2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methanol (669) (390 mg, 1.51 mmol) in dichloromethane (15 mL) was added thionyl chloride (0.56 mL, 7.58 mmol). The reaction was stirred at room temperature for 2 hours and then concentrated to afford 5-bromo-7-(chloromethyl)-2,2-dimethyl-2,3-dihydrobenzofuran (670).
Reaction SMILES: [CH2:1]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](Cl)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:41][CH2:42][CH2:43][N:44]([CH2:48][CH2:49][OH:50])[CH2:45][CH2:46][NH2:47]>C1C=CC=CC=1>[CH2:1]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20]([NH:47][CH2:46][CH2:45][N:44]([CH2:48][CH2:49][OH:50])[CH2:43][CH2:42][OH:41])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NCCN(CCO)CCO
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)NCCN(CCO)CCO
Reaction time: 3 h
Yield: 95.5 %

Procedure:
A mixture of N,N-dioctadecylcarbamyl chloride (2.9 g.), N,N-bis-(2-hydroxyethyl)-1,2-ethanediamine (4.0 g.) and benzene (50 ml.) is refluxed and stirred for three hours. The mixture is then cooled, concentrated in vacuo and the residue taken up on chloroform (100 ml.). The chloroform solution is washed successively with water (2×50 ml.), aqueous sodium hydroxide (1×50 ml. of 1N) and water (2×50 ml.), then dried (Na2SO4). Removal of the chloroform in vacuo leaves the crude product as an oil (3.3 g.).
Reaction SMILES: [F:1][C:2]1[C:21]([I:22])=[CH:20][C:5]2[C:6]3[N:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][C:7]=3[CH:16]3[CH2:19][CH:18]([C:4]=2[CH:3]=1)[CH2:17]3.[C:23](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[F:1][C:2]1[C:21]([I:22])=[CH:20][C:5]2[C:6]3[N:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]([CH3:23])[C:7]=3[CH:16]3[CH2:19][CH:18]([C:4]=2[CH:3]=1)[CH2:17]3
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1nc2c([nH]1)C1CC(C1)c1cc(F)c(I)cc1-2
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2c(n1C)C1CC(C1)c1cc(F)c(I)cc1-2
Temperature: 40 °C
Yield: 94.1 %

Procedure:
To a pressure tube containing a solution of ethyl 8-fluoro-9-iodo-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxylate (400 mg at 69% purity) in N,N-dimethylformamide (0.5 mL) was introduced potassium carbonate (134 mg, 0.97 mmol) and methyl iodide (207 mg, 1.46 mol). The pressure tube was closed under an atmosphere of nitrogen and the reaction mixture warmed to 40° C. for 2.5 hr and room temperature for 12 hr. After concentrating the reaction mixture in vacuo, the residue was suspended in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (2×10 m), water (2×10 ml) and brine (10 mL). The organic extract was dried over sodium sulfate, filtered and evaporated in vacuo to furnish the crude title compound (389 mg of 77% purity LCMS-UV215) as an orange-brown sticky solid which was used for the next step without further purification. For characterisation purposes, some of the crude product was taken and suspended in ethyl acetate by sonnication and the product, an off-white solid, collected by filtration: 1H NMR (500 MHz, CDCl3) δ 1.48 (t, J=7.09 Hz, 3H), 1.69-1.74 (m, 2H), 2.92-3.00 (m, 2H), 3.50 (td, J=7.57, 3.78 Hz, 1H), 3.56 (td, J=8.35, 3.78 Hz, 1H), 3.94 (s, 3H), 4.46 (q, J=7.15 Hz, 2H), 6.79 (d, J=8.83 Hz, 1H), 8.83 (d, J=6.62 Hz, 1H); M+1=427.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18](N[C@H](C(O)=O)CC1C=CC(O)=CC=1)=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:17])[NH2:16])=[O:8])=[O:4].P([O-])([O-])([O-])=[O:34].C([BH3-])#N.[Na+]>>[CH2:12]([CH2:13][N:14]=[C:15]([NH2:16])[NH2:17])[CH2:11][CH:10]([NH:9][C:7]([CH2:6][NH:5][C:3]([CH2:2][NH2:1])=[O:4])=[O:8])[C:18]([OH:19])=[O:34]
Reactant: O=P([O-])([O-])[O-]
Reactant: N=C(N)NCCC[C@H](NC(=O)CNC(=O)CN)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: NCC(=O)NCC(=O)NC(CCCN=C(N)N)C(=O)O
Temperature: 25 °C

Procedure:
Gly-Gly-Arg-Tyr*, prepared by the method of Section 9.2, was coupled to normal human IgG or LL 1151 or NS 4.1 antibody oxidized by the method of Section 12.1 infra, by incubating the antibody at a 300-fold molar excess of Gly-Gly-Arg-Tyr* in the 0.1 M phosphate buffer, pH 6.0. To reduce the imine, sodium cyanoborohydride (NaCNBH3) was added to a final concentration of 10 mM, and the reaction mixture was maintained at room temperature for 2 hours. Unreacted Gly-Gly-Arg-Tyr* was separated from theantibody conjugate by gel filtration. The sample was passed through a 5 ml Sephadex® G-50 column (Pharmacia Fine Chemicals, Piscataway, N.J.), which had been pre-coated with 1 ml of 10% BSA and run in PBS, pH 7.4. Theprotein fractions were pooled.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:20]=[CH:19][C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:11][CH2:12][C:6]=2[CH:5]=1.[I-:21].[Na+]>CC(C)=O>[F:15][C:14]([F:17])([F:16])[C:13]([N:10]1[CH2:9][CH2:8][C:7]2[CH:19]=[CH:20][C:4]([CH2:3][CH2:2][I:21])=[CH:5][C:6]=2[CH2:12][CH2:11]1)=[O:18]
Reactant: O=C(N1CCc2ccc(CCCl)cc2CC1)C(F)(F)F
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(N1CCc2ccc(CCI)cc2CC1)C(F)(F)F

Procedure:
To 800 mg (2.62 mmol) 1-[7-(2-chloro-ethyl)-1,2,4,5-tetrahydro-3-benzazepin-3-yl]-2,2,2-trifluoro-ethanone (preparation 6a) in 40 mL acetone is added 471 mg (3.14 mmol) sodium iodide. The reaction mixture is refluxed overnight, excess sodium iodide is added and the reaction mixture is refluxed additional three days. The solvent is evaporated, the residue is diluted with EtOAc and washed twice with water. The organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Zorbax stable bond; C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 10:90).
Reaction SMILES: ClC1C=CC(C([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=O)=CC=1C#N.[OH:25][C:26]1[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:27]=1[C:28]([OH:30])=O>>[OH:25][C:26]1[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:27]=1[C:28]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]1)=[O:30]
Reactant: O=C(O)c1cc(I)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Cl)c(C#N)c2)CC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(I)ccc2O)CC1

Procedure:
Performed identical to tert-butyl 4-(4-chloro-3-cyanobenzoyl)piperazine-1-carboxylate in Example 1 except 2-hydroxy-5-iodobenzoic acid was used in place of 3-cyano-4-chlorobenzoic acid.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:9][C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:25][CH:26](Br)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2[O:24][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][Br:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCC(Br)Br
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Yield: 29.4 %

Procedure:
A mixture of 1,4,5-triphenylimidazol-2-one (6.25 g), dibromohexane (24.4 g) and potassium carbonate (5.53 g) in dry butanone (300 ml) was heated at reflux temperature for 24 hours. The mixture was cooled and the flitrate evaporated to an oil which was chromatographed on silica gel (hexaneyethyl acetate) to give 1,4,5-triphenyl-2-(6-bromohexyloxy)-imidazole (2.8 g, 29%) as a white solid, m.p. 87°-9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:11][CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][C:3]3[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=3[Cl:1])[CH2:6][CH2:7]2)=[O:30])=[CH:25][CH:24]=1
Reactant: OC1CCN(Cc2ccccc2Cl)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3Cl)CC2)cc1
Yield: 43.6 %

Procedure:
0.451 g (0.002 mol) of 1-(2-chloro-benzyl)-piperidin-4-ol and 1.23 ml (0.0088 mol) of triethylamine were dissolved in 4 ml of toluene, treated with 0.331 ml (0.0025 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:1→1:2). 0.3 g (44%) of 1-(2-chloro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1[CH:16]=O.[Br-].[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:21])=[O:20].CC(C)([O-])C.[K+]>CC(O)(C)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1[CH:16]=[CH:25][CH2:24][CH2:23][CH2:22][C:19]([OH:21])=[O:20]
Reactant: COc1c(C)c(C=O)c(OC)c2ccccc12
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: COc1c(C)c(C=CCCCC(=O)O)c(OC)c2ccccc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a suspension of 1 g of 1,4-dimethoxy-3-methylnaphthalene-2-carbaldehyde and 3.85 g of (4-carboxybutyl)triphenylphosphonium bromide in 2.5% t-BuOH/toluene at 60° C. was added 1.95 g of potassium t-butoxide. The mixture was stirred at 60° C. for 30 min, extracted with 1N NaOH, and washed with toluene. The aqueous layer was neutralized with iN HCl until pH 4-5, then extracted with ethyl acetate. The organic layer was washed, dried, and concentrated, then the trsidue was purified with column chromatography over silica gel using n-hexane/ethyl acetate (2/1) as an eluent to give 0.9 g of the titled compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)C(C)C)C>C(#N)C>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:6]2[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(Cl)n1

Procedure:
A solution of 2,4-dichloro-6-methyl-pyrimidine (1.25 g, 7.68 mmol, 1.0 equiv; commercially available), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.0 mmol, 1.3 equiv) and N-ethyl diisopropylamine (3.0 mL, 2.3 g, 17.7 mmol, 2.3 equiv) in acetonitrile (16 mL) was heated by microwave irradiation to 160° C. for 20 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 1.15 g (46%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.24-1.31 (m, 2H), 1.40 (s, 9H), 1.80-1.83 (br d, 2H), 2.18 (s, 3H), 2.90 (br s, 2H), 3.87 (br s, 2H), 3.96 (br s, 1H), 6.23 (br s, 1H), 7.68 (d, J=8.0 Hz, 1H). MS (ISP): 327.4 [M+H]+.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.O.[OH-].[Na+].[CH:20](O)=[O:21]>>[N:1]1([CH:6]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][CH:20]=[O:21])=[CH:14][CH:15]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)C(c1ccc(N)cc1)n1ccnc1
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(c1ccc(NC=O)cc1)n1ccnc1
Temperature: 120 °C
Yield: 86.6 %

Procedure:
A mixture of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]benzenamine (0.0185 mol) in formic acid (20 ml) was stirred and heated at 120° C. for 15 minutes. The mixture was poured into water, basified with NaOH 3N and extracted with EtOAc. The organic layer was dried, filtered off and the solvent evaporated, yielding 3.9 g (86.6%) of (±)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]formamide (compound 177).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1.Cl[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=3)[CH2:22][CH2:23]2)=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Reactant: N#Cc1cc(Cl)ccn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#Cc1cc(N2CCC(CNc3ccccc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Yield: 46.3 %

Procedure:
Using a similar procedure to that described in Example 52, N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (100 mg, 0.29 mmol), 4-chloro-2-cyanopyridine (80 mg, 0.58 mmol), triethylamine (59 mg, 0.58 mmol), and ethanol (2 mL) yielded 60 mg (46%) of the title compound.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([NH2:29])=[CH:26][CH:27]=3)[O:22][C:21]([CH3:31])([CH3:30])[CH:20]=2)=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([NH:29][S:8]([CH3:7])(=[O:10])=[O:9])=[CH:26][CH:27]=3)[O:22][C:21]([CH3:31])([CH3:30])[CH:20]=2)=[CH:15][CH:14]=1
Reactant: CC1(C)C=C(c2ccc(F)cc2)c2ccc(N)cc2O1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC1(C)C=C(c2ccc(F)cc2)c2ccc(NS(C)(=O)=O)cc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under ice-cooling, pyridine (90 μL) and methanesulfonyl chloride (60 μL) were added dropwise to a solution of [4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen-7-yl]amine (a compound of Reference Example 5(5), 100 mg) in chloroform (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by column chromatography on NH-silica gel (Chromatorex NH-silica gel, Solvent: chloroform/methanol=100/0 to 90/10) to give the titled compound (123 mg) as a colorless powder.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[CH:15]=2)[N:8]=1)=O.[C:23]1([NH:29]N)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)[CH3:21]
Reactant: CCc1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Reactant: NNc1ccccc1
Product: CCc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)c1
Yield: 87 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-ethyl-phenyl)-1H-pyridazin-4-one (A-4) and phenylhydrazine according to the method described for Example 1 in 87% yield. MS: M=343.1 (M+H)+
Reaction SMILES: C(S([NH:7][CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]([CH3:17])([CH3:16])[C:11](OCC)=[O:12])=O)(C)(C)C.Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1.C[OH:40]>>[CH3:16][C:10]1([CH3:17])[C:9](=[O:40])[CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:7][C:11]1=[O:12]
Reactant: CO
Reactant: CCOC(=O)C(C)(C)CC(NS(=O)C(C)(C)C)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1(C)C(=O)NC(c2ccccc2)C1=O
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of Ethyl 4-[(tert-butylsulfinyl)amino]-2,2-dimethyl-4-phenylbutanoate from Step B (0.19 g, 0.55 mmol) in MeOH (10 mL) was added anhydrous HCl (gas, bubbled in for about 1 minute). After 20 minutes, nitrogen was bubbled though the reaction mixture for about 20 minutes. The initial solvent was removed in vacuo, and then more MeOH was added and removed in vacuo. The residue was then dissolved in MeOH (20 mL) and treated with triethylamine (0.22 g, 2.2 mmol). The solvent was once again removed in vacuo. This residue was then treated with toluene (10 mL) and triethylamine (0.22 g, 2.2 mmol) before being heated to 100° C. for 15 hours. After cooling to ambient temperature the solvent was removed in vacuo and the residue was partitioned between diethyl ether (50 mL) and 1 M HCl (50 mL). The organics were then successively washed with another volume of 1 M HCl, water and lastly saturated brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound which was used without further purification. MS: m/z=190 (M+1).