Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[C@H:13]12[CH2:19][C@H:16]([NH:17][CH2:18]1)[CH2:15][N:14]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:17]2[CH2:18][C@@H:13]3[CH2:19][C@H:16]2[CH2:15][N:14]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:3][N:4]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Clc1nnc(Cl)c2ccccc12
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1nnc(Cl)c2ccccc12
Yield: 62 %

Procedure:
1,4-Dichlorophthalazine (Aldrich Chemical Company) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), were processed as described in Example 2A to provide the title compound (62% yield). 1H NMR (CDCl3, 300 MHz) δ 1.44 (s, 4.5H), 1.47 (s, 4.5H), 1.95-2.08 (m, 2H), 3.46-3.58 (m, 1H), 3.64 (d, J=8.47 Hz, 0.5H), 3.75 (d, J=8.81 Hz, 0.5H), 3.91 (d, J=10.51 Hz, 1H), 4.19 (dd, J=2.03, 6.78 Hz, 1H), 4.59 (br s, 0.5H), 4.69 (br s, 0.5H), 5.15 (s, 1H), 7.26-7.81 (m, 2H), 8.04-8.12 (m, 1H), 8.21 (dd, J=1.70, 7.80 Hz, 1H); MS (DCI/NH3) M/Z 361 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:23][CH3:24])=[CH:5][C:6]2[CH2:7][CH:8]3[CH2:22][NH:21][CH2:20][CH2:19][N:9]3[CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]=2[CH:12]=1.C(N(CC)CC)C.[CH2:32]([O:39][CH2:40][C:41](Cl)=[O:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([O:23][CH3:24])=[CH:5][C:6]2[CH2:7][CH:8]3[CH:22]([C:41](=[O:42])[CH2:40][O:39][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[NH:21][CH2:20][CH2:19][N:9]3[CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]=2[CH:12]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)N1CCNCC1C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C(c1ccccc1)N1CCNC(C(=O)COCc3ccccc3)C1C2
Reaction time: 0.5 h

Procedure:
8,9-Dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline (the compound obtained in Example 1-(6)) (1.6 g) is dissolved in methylene chloride (10 ml), and thereto are added triethylamine (0.8 ml) and benzyloxyacetyl chloride (0.8 ml) under ice-cooling, and the mixture is stirred for 30 minutes. The reaction solution is washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel (eluent; chloroform:ethyl acetate=9:1) to give 8,9-dimethoxy-2-benzyloxyacetyl-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline (1.1 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)(=[O:13])[CH3:12].O>CC(C)=O>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[S:21]([C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:11](=[O:13])[CH3:12])=[CH:20][CH:19]=1)(=[O:23])=[O:22]
Reactant: CNCCc1ccccn1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)N(C)CCc2ccccn2)cc1
Temperature: 0 °C
Yield: 78.5 %

Procedure:
(prepared according to an analogous procedure described in U.S. Pat. No. 5,755,873) Step A: Methyl-(2-pyridin-2-ylethyl)amine (8.9 ml, 0.0643 mol) was dissolved in acetone (13 ml) and cooled to 0° C., 4-acetylaminobenzenesulfonyl chloride (5 g, 0.0214 mol) was added over 10 min. Additional acetone (5 ml) was added and the mixture was heated at reflux for 2 h. After cooling to rt, the mixture was added to water and extracted with EtOAc. The extracts were dried (MgSO4). The mixture was concentrated under reduced pressure and purified by flash chromatography (SiO2, EtOAc-MeOH/EtOAc 1:19) to give 5.6 g of N-{4-[methyl-(2-pyridin-2-yl-ethyl)sulfamoyl]phenyl}acetamide. Step B: The compound from step A (5.6 g) was suspended in water (22.4 ml), treated with concentrated HCl (13.4 ml), and the mixture heated at reflux for 1 h. After cooling to rt, NH4OH (13.7 ml) was added with stirring. The resulting mixture was extracted with CH2Cl2; the extracts were washed with water, dried (MgSO4), and concentrated under reduced pressure to give 4.8 g of 4-amino-N-methyl-N-(2-pyridin-2-ylethyl)benzenesulfonamide. LCMS: MH+=292.0.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([OH:26])([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[OH:26][C:11]1([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=3)[CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccc2cc(C3(O)CCN(Cc4ccccc4)CC3)ccc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc2cc(C3(O)CCNCC3)ccc2c1
Yield: 85.8 %

Procedure:
A mixture of 1.0 gm (2.9 mMol) 1-benzyl-4-hydroxy-4-(6-methoxynaphth-2-yl)piperidine and 5% palladium on carbon in 20 mL methanol was stirred at room temperature under about 1 atmosphere of hydrogen for 6 hours. The reaction mixture was filtered through a bed of CELITE and the filtrate was concentrated under reduced pressure to provide 0.64 gm (86%) of the desired compound as a white foam. A portion of the material was converted to the oxalate salt for analysis.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=2[CH3:22])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]=O>O>[C:1]1([N:7]2[CH2:8][C:9](=[O:10])[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=3[CH3:22])[CH2:23]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=O
Reactant: Cc1cc(S(N)(=O)=O)ccc1NC(=O)CNc1ccccc1
Solvent: O
Product: Cc1cc(S(N)(=O)=O)ccc1N1CN(c2ccccc2)CC1=O

Procedure:
2-Phenylamino-N-(2-methyl-4-sulphamoylphenyl)-acetamide (16 g) was dissolved in ethano, (320 ml) and paraformaldehyde (1.9 g) in water (640 ml) added. The mixture was refluxed 11/2 hr, cooled and filtered. The residue was crystallised from DMF/water to yield 16 g, m.p. 206°-210°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([O:16]CC)=[O:15])[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].[OH-].[Li+].Cl>O.O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=[O:15])[CH2:11][C@@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=C[C@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 5 h
Yield: 131.5 %

Procedure:
Ethyl (1R,2S)-1-(tert-butoxycarbonylamino)-2-vinyl-cyclopropane-1-carboxylate (61 g, 0.239 mol, 1.0 eq.) and tetrahydrofuran (700 mL) were charged into a 2 L round bottom flask placed in ice/water bath. Lithium hydroxide monohydrate (30 g, 0.714 mol, 3.0 eq.) was dissolved in water (800 mL) and added slowly to the mixture. The reaction mixture was heated at 50° C. for 18 hours. Monitoring the reaction conversion by LCMS showed some residual starting material so lithium hydroxide (20 g, 0.476 mol, 2 eq.) was added. The reaction was stirred further for 5 hours and then stirred at room temperature for 2 days. Monitoring the reaction conversion by LCMS showed complete conversion. The reaction mixture was acidified to pH 3 by slow addition of 1M hydrochloric acid then extracted with ethyl acetate (4×900 mL). The organic extracts were pooled, washed with brine (600 mL), dried over sodium sulfate, filtered and concentrated to dryness. Cyclohexane (100 mL) was added to the dried crude material and concentrated to afford 71.44 g (54.0 g, 100%, corrected for residual solvent) of (1R,2R)-1-(tert-butoxycarbonylamino)-2-vinyl-cyclopropane-1-carboxylic acid as a pale yellow solid which contained residual cyclohexane (24.5% w/was calculated from 1H NMR). The compound was used in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ ppm 5.79 (dt, J=17.01, 9.65 Hz, 1 H), 5.27 (br. s, 1 H), 5.30 (d, J=17.09 Hz, 1 H), 5.14 (d, J=10.38 Hz, 1 H), 2.20 (q, J=8.85 Hz, 1 H), 1.70-1.90 (m, 1 H), 1.52-1.63 (m, 1 H), 1.45 (s, 9 H). LC-MS: purity 100% (UV), tR 1.60 min, m/z [M+Na]+ 250.00.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:14]1[C:15]([CH3:29])=[CH:16][C:17]([N+:26]([O-:28])=[O:27])=[C:18]([CH:25]=1)[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH3:29][C:15]1[C:14]([O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)=[CH:25][C:18]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[C:17]([N+:26]([O-:28])=[O:27])[CH:16]=1
Reactant: Cc1cc([N+](=O)[O-])c(C(=O)OC(C)C)cc1Cl
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc([N+](=O)[O-])c(C(=O)OC(C)C)cc1Oc1ccc(OC(F)(F)F)cc1
Temperature: 102.5 °C
Reaction time: 37 h
Yield: 97.9 %

Procedure:
Dimethylacetamide (716 ml), 170 g of 4-trifluoromethoxyphenol, 246 g of isopropyl 5-chloro-4-methyl-2-nitrobenzoate, and 263.9 g of potassium carbonate were added into a 2000-ml glass flask equipped with a stirring device, a thermometer, and a reflux condenser under a nitrogen atmosphere, and the temperature of the contents of the flask was raised to 100 to 105° C. with stirring. A reaction was allowed to proceed at the same temperature for 37 hr, and 360 ml of dimethylacetamide was then removed by evaporation under the reduced pressure. The reaction solution was poured into 2 L of ice-water, and 1.7 L of ethyl acetate was added thereto. The mixture was stirred and was allowed to stand, followed by separation. The ethyl acetate layer was washed with a 1.5% aqueous sodium hydroxide solution and brine and was concentrated under the reduced pressure to give isopropyl 4-methyl-2-nitro-5-(4-(trifluoromethoxy)phenoxy)benzoate (373.3 g, yield: 97.9%).
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:5][C:6](=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][C:18]=1[CH3:19])SC)#[N:4]>C(O)C>[C:3]([NH:5][C:6]([NH:2][CH3:1])=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][C:18]=1[CH3:19])#[N:4]
Reactant: CN
Reactant: CSC(=NCCSCc1nc[nH]c1C)NC#N
Solvent: CCO
Product: CNC(=NCCSCc1nc[nH]c1C)NC#N
Reaction time: 2.5 h

Procedure:
A solution of methylamine in ethanol (33%, 75 ml) was added to a solution of N-cyano-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-S-methylisothiourea (10.1 g) in ethanol (30 ml). The reaction mixture was set aside at room temperature for 2.5 hours. Following concentration under reduced pressure, the residue was recrystallised twice from isopropyl alcohol/petroleum ether, affording N-cyano-N'-methyl-N"-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]guanidine, m.p. 141°-143°.
Reaction SMILES: [ClH:1].O1CCOCC1.[OH:8][C@H:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:12]=2[C@H:11]([CH3:31])[CH2:10]1>O1CCOCC1>[ClH:1].[ClH:1].[CH3:31][C@H:11]1[C:12]2[C:17]([N:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)=[N:16][CH:15]=[N:14][C:13]=2[C@H:9]([OH:8])[CH2:10]1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
4M HCl/dioxane (11.2 mL, 44.9 mmol) was added to a solution of tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.600 g, 1.79 mmol) in dioxane (15 mL). The reaction mixture was stirred at room temperature under nitrogen overnight (20 hours). The mixture was concentrated to dryness and dried on high vacuum line. The crude product was suspended in ether, sonicated, and stirred for 5 minutes. The solids were isolated by filtration through a medium fit funnel under nitrogen pressure, rinsed with ether, dried under nitrogen pressure, and dried further on a high vacuum line to give (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.440 g, 79.8% yield) as a powder. LC/MS (APCI+) m/z 235. The (5R,7S)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride was prepared using an analogous method.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl.[C:22](Cl)(=[O:32])[O:23][C@@H:24]1[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1>CC#N.CCOC(C)=O.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:13]([C:22]([O:23][C@@H:24]2[CH:29]3[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]3)[CH2:25]2)=[O:32])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Reactant: COC(=O)c1cc(F)cc(CNc2ccccc2F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)cc(CN(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2F)c1
Temperature: 100 °C

Procedure:
A suspension of methyl 3-fluoro-5-(((2-fluorophenyl)amino)methyl)benzoate (133 mg, 0.48 mmol) and (R)-quinuclidin-3-yl carbonochloridate hydrochloride (163 mg, 0.72 mmol) in anhydrous CH3CN (6 mL) was heated to 100° C. for 30 minutes under microwave irradiation. After cooling to room temperature, the mixture was diluted with EtOAc (30 mL) and saturated aqueous NaHCO3 (20 mL). The layers were separated and the organic phase was dried over Na2SO4. The mixture was filtered and the solvent was removed in vacuo to yield the title compound which was used directly in the next step without any further purification.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=[O:3].[CH:13](=O)[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>C(O)C>[N+:10]([C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[CH:13][CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: O=CC=Cc1ccccc1
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=CC=Cc1ccccc1)c1cccc([N+](=O)[O-])c1
Yield: 68.6 %

Procedure:
Using a procedure similar to that described in Example D, 33 g of 3-nitroacetophenone and 26.2 g of cinnamaldehyde in 200 ml of ethanol were condensed in the presence of 10 ml of a 5% strength NaOH solution to give 38 g (71% of theory) of 1-(3-nitrophenyl)-5-phenyl-2,4-pentadien-1-one of melting point 127°-129° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH3:20])[N:13]=2)[CH:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>CN1C(=O)CCC1>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH3:20])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CCOc1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CN1CCCC1=O
Product: CCOc1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Temperature: 140 °C
Reaction time: 48 h
Yield: 45.9 %

Procedure:
6-Chloro-4-(6-ethoxypyridin-2-ylamino)pyridazine-3-carboxamide (33 mg, 112 μmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (50 mg, 233 μmol) were combined in NMP (2 mL) and stirred at 140° C. for 48 h. A second portion of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (50 mg, 233 μmol) was added and the reaction was stirred at 140° C. for 96 h, then cooled to room temperature and concentrated in vacuo. The residue obtained was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the organics were combined and washed with brine. The solvent was removed in vacuo to give an orange foam. The foam was concentrated onto silica and purified by chromatography (4 g RediSep Gold, 0 to 5% of a mixture of MeOH containing 0.5% NH4OH in dichloromethane, 20 min) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-ethoxypyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (32.3 mg, 51.4 μmol, 46%) containing some dichloromethane impurity. This was used directly without further purification. MS (EI/CI) m/z: 372.3 [M+H].
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][O:12][CH:11]([CH2:15][F:16])[CH2:10]1)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[ClH:1].[F:16][CH2:15][CH:11]1[O:12][CH2:13][CH2:14][NH:9][CH2:10]1
Reactant: [H][H]
Reactant: FCC1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: FCC1CNCCO1
Yield: 64.9 %

Procedure:
To a solution of N-benzyl-2-fluoromethylmorpholine hydrochloride (1.46 g) in ethanol (85 ml) is added 10% palladium-carbon (0.2 g), and the mixture is stirred under hydrogen atmosphere (maximum hydrogen pressure: 6 kg/cm2) at room temperature. After completion of absorption of hydrogen gas, palladium-carbon is filtered off, and the filtrate is concentrated under reduced pressure. To the residue are added ether (2 ml) and ethanol (0.5 ml), and the precipitated crystals are separated by filtration and dried under reduced pressure to give the title compound (0.6 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][CH3:11])=[O:9])[C@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:4]([C:26]([O:28][CH3:29])=[O:27])[CH2:3]1.C(N(CC)CC)C.C(Cl)Cl.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>>[CH3:40][S:41]([O:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][CH3:11])=[O:9])[C@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:4]([C:26]([O:28][CH3:29])=[O:27])[CH2:3]1)(=[O:43])=[O:42]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H](OS(C)(=O)=O)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of dimethyl(2S,3S,5R)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (1.00 g, 0.00247 mol) and triethylamine (0.412 mL, 0.00296 mol) in methylene chloride (20.00 mL, 0.3120 mol) was added methanesulfonyl chloride (0.210 mL, 0.00271 mol). The mixture was stirred at rt overnight. After quenched with MeOH, the mixture was evaporated to dry in vacuo and diluted with ethyl acetate. The organic layers were washed with water, brine and dried, concentrated to dry. The residue was purified on silica gel, eluting with 0 to 80% EtOAc in hexane, to generate the mesylate compound (0.98 g, 82%). MS (ESI): (M+H)+=484.1.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:28])[CH2:18][CH2:17][C:16]([CH2:26][NH2:27])([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[F:28][C:13]1([F:12])[CH2:14][CH2:15][C:16]([CH2:26][NH:27][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:2]=2[F:1])([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:17][CH2:18]1
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Reactant: O=C(O)c1cccc(F)c1F
Product: O=C(NCC1(c2ccc(F)nc2)CCC(F)(F)CC1)c1cccc(F)c1F

Procedure:
From 2,3-difluorobenzoic acid and C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=385.0, tR (minutes, Method D)=0.71
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[N+:13]([O-])=O)[CH3:2].[Cl-].[NH4+]>C(O)C.C1COCC1.[Fe]>[CH2:1]([O:3][C:4]([C:5]1[NH:13][C:8]2=[CH:9][N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)=[O:17])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1ccncc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc2ccncc2[nH]1

Procedure:
To a solution of 3-(3-nitropyridin-4-yl)-2-oxopropionic acid ethyl ester (Preparation 13, 500 mg, 2.1 mmol) in ethanol (20 mL) and THF (10 mL) was added saturated ammonium chloride solution (10 mL) and iron powder (700 mg, 12.6 mmol). The reaction was heated under reflux for 1 h, then filtered through celite and washed through with hot ethyl acetate (3×30 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as a brown solid. δH (CD3OD): 1.44 (3H, t), 4.43 (2H, q), 7.21 (1H, s), 7.69 (1H, d), 8.12 (1H, d), 8.80 (1H, s).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=3)=[C:19]([CH3:29])[C:18]3[C:13](=[CH:14][C:15]([O:30]COCC[Si](C)(C)C)=[CH:16][CH:17]=3)[O:12]2)=[CH:7][CH:6]=1.[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH3:28][O:27][C:24]1[N:25]=[CH:26][C:21]([C:20]2[CH:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:6][CH:7]=3)[O:12][C:13]3[C:18]([C:19]=2[CH3:29])=[CH:17][CH:16]=[C:15]([OH:30])[CH:14]=3)=[CH:22][CH:23]=1
Reactant: COc1ccc(C2=C(C)c3ccc(OCOCC[Si](C)(C)C)cc3OC2c2ccc(OCCCl)cc2)cn1
Reactant: C1CCNC1
Product: COc1ccc(C2=C(C)c3ccc(O)cc3OC2c2ccc(OCCN3CCCC3)cc2)cn1

Procedure:
The title product was prepared as a white solid according to the procedure described in Example 34 using 5-[2-[4-(2-chloro-ethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxymethoxy)-2H-chromen-3-yl]-2-methoxy-pyridine and pyrolidine as the starting material.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][NH:19][C:20]([C:22]1[S:30][C:29]2[C:24](=[N:25][CH:26]=[CH:27][C:28]=2Cl)[CH:23]=1)=[O:21]>>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][NH:19][C:20]([C:22]1[S:30][C:29]2[C:24](=[N:25][CH:26]=[CH:27][C:28]=2[NH:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2]([CH3:1])=[CH:10]3)[CH:23]=1)=[O:21]
Reactant: O=C(NCc1ccccn1)c1cc2nccc(Cl)c2s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)NCc5ccccn5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid (pyridin-2-ylmethyl)-amide by a procedure analogous to Example 1C. MS: 414 (MH+); HPLC Rf: 4.34 min.; HPLC purity: 97%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[CH3:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:2]([N:28]2[CH2:29][CH2:30][N:26]([CH3:25])[C:27]2=[O:31])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCN(C)C3=O)CC2)c(C)c1
Yield: 18.3 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 12 and using (2-bromo-4-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (960 mg) described in Preparation Example 119 and 1-methyl-2-imidazolidinone (235 mg), the title compound (184 mg) was obtained.