Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:36]=[CH:35][CH:34]=[CH:33][C:9]=1[CH2:10][CH2:11][N:12]([CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[C:37]1([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>O1CCCC1>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][N:12]([CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH2:11][CH2:10][C:9]1[CH:33]=[CH:34][CH:35]=[CH:36][C:8]=1[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:46]1[CH2:47][CH2:48][N:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:44][CH2:45]1)[CH3:21]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)CCCCN(CCc1ccccc1OCCCCCBr)Cc1ccc(C(=O)OC)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCCCN(CCc1ccccc1OCCCCCN1CCN(c2ccccc2)CC1)Cc1ccc(C(=O)OC)cc1

Procedure:
200.0 mg (0.355 mmol) of methyl 4-{[{2-[(5-bromopentyl)oxy]phenethyl}(5-ethoxy-5-oxopentyl)amino]methyl}benzoate from Ex. 107, 69.21 mg of N-phenylpiperazine and 71.95 mg (0.711 mmol) of triethylamine in 2 ml of tetrahydrofuran are heated at reflux for 18 hours. The reaction solution is washed with water, concentrated and chromatographed over silica gel using the mobile phase ethyl acetate/methanol 10/1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1F
Reactant: COc1cccc(O)c1
Product: COC(=O)c1cc(Cl)ccc1Oc1cccc(OC)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 5-chloro-2-fluorobenzoate and 3-methoxyphenol: 1H-NMR (CDCl3) δ 7.89 (1H, d, J=2.8 Hz), 7.41 (1H, dd, J=8.4, 2.8 Hz), 7.24–7.19 (1H, m), 6.95 (1H, d, J=8.4 Hz), 6.67–6.64 (1H, m), 6.53–6.49 (2H, m), 3.83 (3H, s), 3.78 (3H, s).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11]([O:18][C@@H:19]2[O:45][C@H:44]([CH2:46][O:47][C:48](=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50])[C@@H:36]([O:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[C@H:28]([O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C@H:20]2[O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[N:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1.[C].[Pd]>[C:1]1([CH2:7][CH2:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11]([O:18][C@@H:19]2[O:45][C@H:44]([CH2:46][O:47][C:48](=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50])[C@@H:36]([O:37][C:38](=[O:43])[C:39]([CH3:40])([CH3:41])[CH3:42])[C@H:28]([O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:32])[CH3:33])[C@H:20]2[O:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:25])[CH3:26])=[N:12][NH:13]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(/C=C/c4ccccc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(CCc4ccccc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
To a solution of 4-[ (E)-2-phenylvinyl]-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (50 mg) in tetrahydrofuran (4 mL) was added 10% palladium-carbon powder (25 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 4-(2-phenylethyl)-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (50 mg) This material was dissolved in methanol (4 mL). To the solution was added sodium methoxide (28% methanol solution, 0.065 mL), and the mixture was stirred at 50° C. overnight. To the reaction mixture was added acetic acid (0.04 mL), and the resulting mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=5/1) to give the title compound (21 mg).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([NH2:6])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].O>C(O)(=O)C.S(=O)(=O)(O)O>[Br:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([NH:6][C:20](=[O:22])[CH3:21])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: Nc1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
To a solution of 4-bromo-2-nitro-6-[(phenylmethyl)oxy]aniline (33.0 g, 102 mmol, WO 2004054984) and acetic anhydride (14.5 mL, 153 mmol) in acetic acid (90 mL) was added concentrated sulfuric acid (2 drops) at 70° C. The mixture was stirred at 70° C. for 20 minutes. After cooling to room temperature, water (800 mL) was added, and the formed precipitate was collected by filtration, and washed with diisopropyl ether to give the title compound as a brown solid (30.9 g, 83%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1ccc(C2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1ccc(C(F)(F)F)cc1

Procedure:
The title compound, white solid, m.p. 107° C. and MS: m/e=369 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-trifluoromethyl-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [Br:1][C:2]([Br:5])=[N:3][OH:4].[C:6](Cl)(=[O:9])[CH2:7][CH3:8].N1C=CC=CC=1>C(Cl)Cl>[C:6]([O:4][N:3]=[C:2]([Br:5])[Br:1])(=[O:9])[CH2:7][CH3:8]
Reactant: CCC(=O)Cl
Reactant: ON=C(Br)Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)ON=C(Br)Br
Yield: 0.1 %

Procedure:
To the mixture of dibromoformaldoxime (5 g, 24.63 mole) and propionyl chloride (2.31 g, 25 mole) in dry methylene chloride (30 ml) is slowly added dry pyridine (2 g, 25.5 mole) over 10 min at 0° to 5° C. with stirring. After addition the reaction mixture is stirred at 5° C. for 30 min and at 25° C. for another 30 min. The resultant suspension is diluted with methylene chloride and washed with water and brine. The organic layer is dried over MgSO4. Evaporation of solvent affords 5.44 g (85% of theory) of O-propionyldibromoformaldoxime as a light yellow liquid. NMR spectrum shows this to be the desired compound.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:18][CH3:19])=[C:6]([C:10]2[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.C([O-])=O.[NH4+]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[C:5]([O:18][CH3:19])=[C:6]([C:10]2[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1c(-c2csc(C(=O)O)c2)cccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1c(N)cccc1-c1csc(C(=O)O)c1
Yield: 113.4 %

Procedure:
4-(3-Nitro-2-methoxy-phenyl)-thiophene-2-carboxylic acid 19a (400 mg, 1.45 mmol) was dissolved in 30 mL of ethyl acetate followed by addition of 100 mg of palladium on carbon (10%) and ammonium formate (360 mg, 5.8 mmol). The mixture was heated to reflux for 3 hours. The mixture was filtered and concentrated under reduced pressure to obtain the title compound 4-(3-amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid 19b (410 mg) as a brown oil, which was directly used in the next step.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][CH:13]=[CH:14][N:4]2[N:3]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CC(C)=O>C(Cl)Cl>[N:15]1([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]3=[N:12][CH:13]=[CH:14][N:4]3[N:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Clc1nn2ccnc2c2c1CCCC2
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: CC(C)=O
Product: c1cn2nc(N3CCCCC3)c3c(c2n1)CCCC3

Procedure:
A mixture was prepared by adding 15 g of 6-chloro-7,8,9,10-tetrahydroimidazo[2,1-a]phthalazine to 30.5 g of piperidine and the mixture was heated at reflux for 72 hours. The mixture was subjected to preparative liquid chromatography using 15% acetone in methylene chloride to separate the desired product from the impurities. The appropriate fractions from the chromatography were combined and the solvent was evaporated under reduced pressure. The resulting solid was collected by filtration and dried to give 6-(1-piperidinyl)-7,8,9,10-tetrahydroimidazo[2,1-a]phthalazine melting at about 95° C. This compound has the following structural formula ##STR2##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16].O>CN(C)C=O>[C:15]([Si:19]([O:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Dissolve 3,5 dichlorophenol (1 kg, 6.13 mol) in 3 L dimethylformamide (DMF) and cool to 0° C. Add imidazole (918.74 g, 6.75 mol), followed by tertbutyldimethylsilyl chloride (1017.13 g, 6.75 mol). Warm the mixture to room temperature and stir for 15 minutes. Pour into water (6 L) and extract with ether (4 L). Wash the organic layer with water 2 times, 10% aqueous lithium chloride solution then brine before drying over sodium sulfate. Filter and concentrate under vacuum to obtain tert-butyl-(3,5-dichloro-phenoxy)-dimethyl-silane (1700 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]2)=[CH:3][C:4]=1[C:9]([F:12])([F:11])[F:10]
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Reactant: CCOC(=O)CCC1CCNC1
Product: CCOC(=O)CCC1CCN(c2ccc(Cl)c(C(F)(F)F)c2)C1
Yield: 61 %

Procedure:
The title compound (5.0 g, yield 61%) was obtained from 4-bromo-1-chloro-2-(trifluoromethyl)benzene and ethyl 3-(pyrrolidin-3-yl)propanoate obtained in Reference Example 12 by a method similar to that in Reference Example 1.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:35][C:36]1[CH:37]=[CH:38][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:40][CH:41]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:35][C:36]1[CH:37]=[CH:38][C:39]([S:42]([NH:45][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([O:13][CH2:12][C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[S:8][CH:9]=3)[CH:15]=2)(=[O:44])=[O:43])=[CH:40][CH:41]=1
Reactant: O=C(O)c1cccc(OCc2csc(-c3ccccc3)n2)c1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)c2cccc(OCc3csc(-c4ccccc4)n3)c2)cc1
Reaction time: 1 h
Yield: 18.3 %

Procedure:
To a solution of 5.48 g (0.0176 mol) of 3-[(2-phenyl-4-thiazolyl)methoxy]benzoic acid in 100 ml of toluene are added 3.24 g (0.0200 mol) of 1,1'-carbonyldiimidazole and the solution is stirred for 1 hour. To this solution, 3.01 g (0.0176 mol) p-toluenesulfonamide are added and the solution is refluxed for 16 hours. After cooling, the bottom layer is isolated and concentrated in vacuo to obtain a clear oil. The clear oil is dissolved in methylene chloride and is washed twice with pH 4 buffer solution, twice with water and is concentrated in vacuo to obtain a residue. Recrystallization from toluene/ethyl acetate gives 1.5 g (18%) of crystals, m.p. 170°-172° C.
Reaction SMILES: C1C=C[NH+]=CC=1.[Br:7][Br-]Br.[Na].[O:11]=[C:12]1[CH:17]([CH2:18][CH2:19][N:20]2[CH:24]=[CH:23][CH:22]=[C:21]2[C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16](=[O:33])[O:15][C:14]([CH3:35])([CH3:34])[O:13]1.O>O1CCCC1>[Br:7][C:17]1([CH2:18][CH2:19][N:20]2[CH:24]=[CH:23][CH:22]=[C:21]2[C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12](=[O:11])[O:13][C:14]([CH3:35])([CH3:34])[O:15][C:16]1=[O:33]
Reactant: CC1(C)OC(=O)C(CCn2cccc2C(=O)c2ccccc2)C(=O)O1
Agent: [Na]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C(Br)(CCn2cccc2C(=O)c2ccccc2)C(=O)O1
Reaction time: 1 h

Procedure:
Pyridinium bromide perbromide (11.51 g, 36 mmoles) in tetrahydrofuran (25 ml) was added dropwise at 0°-5° C. to a vigorously stirred suspension of the sodium salt of 1-[2-(4,6-dioxo-2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-2-benzoylpyrrole (VI, prepared as described above, 13.5 g, 37.2 mole). The mixture was stirred for 1 hour at 0°-5° C. The mixture was then poured into water (600 ml) and extracted three times with diethyl ether (100 ml, then 2×50 ml). The organic phase was separated and washed with two 200 ml portions of water, dried over magnesium sulfate and evaporated to afford crystalline 1-[2-(5-bromo-4,6-dioxo-2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-2-(benzoyl)pyrrole (VIIa). The product could be recrystallized from ethyl acetate/hexane to give material with the following properties: m.p. 89°-91° C. 1H NMR (CDCl3): delta 1.81 (s, 3H); 2.00 (s, 3H); 3.19 (t, 2H); 4.58 (t, 2H); 6.19 (dd, 1H); 6.71 (dd, 1H); 6.89 (dd, 1H); 7.4-7.55 (m, 3H); 7.78 (dd, 2H). 13C NMR (CDCl3): delta 26.8, 28.9, 39.7, 43.5, 45.8, 107.3, 123.5, 127.9, 129.2, 130.3, 131.4, 139.1, 163.0, 186.9.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH2:6][CH2:7][OH:8])[CH3:4].[CH:9]1([N:14]2[C:19]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:18]=3[CH:17]=[C:16](F)[C:15]2=[O:27])[CH2:13][CH2:12][CH2:11][CH2:10]1>C1COCC1>[CH:9]1([N:14]2[C:19]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:18]=3[CH:17]=[C:16]([O:8][CH2:7][CH2:6][O:5][CH2:3][CH3:4])[C:15]2=[O:27])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOCCO
Reactant: CSc1ncc2cc(F)c(=O)n(C3CCCC3)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCCOc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (45 mg, 1.1 mmol, 60% oil dispersion) in THF (10 mL), under nitrogen, was added 2-ethoxyethanol (113 mg, 1.25 mmol). The reaction mixture was stirred at RT for 30 min. To this mixture, 8-cyclopentyl-6-fluoro-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one was added. The reaction mixture was then heated to reflux and stirred overnight. The cooled solution was quenched with water (25 mL) and extracted with ethyl acetate (50 mL). The organic layer was subsequently washed twice with aq. NH4Cl (20 mL each) and brine (20 mL). The organic layer was dried over magnesium sulfate. Removal of the drying agents and evaporation of the solvent gave a yellow oil, which was chromatographed on silica gel eluted with an ethyl acetate/hexane gradient to give 8-cyclopentyl-6-(2-ethoxy-ethoxy)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as a clear oil (289 mg, 0.83 mmol). 1H NMR δ(400 MHz, CDCl3) 8.52 (s, 1H), 6.77 (s, 1H), 6.04-5.95 (m, 1H), 4.16 (t, J=4.0 Hz, 2H), 3.86 (t, J=4.0 Hz, 2H), 3.58 (q, J=8.0 Hz, 2H), 2.59 (s, 3H), 2.34-2.25 (m, 2H), 2.13-2.03 (m, 2H), 1.91-1.82 (m, 2H), 1.71-1.60 (m, 2H), 1.20 (t, J=8.0 Hz, 3H); MS (APCI +) 350 (M+1).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([NH:10][NH2:11])[CH:6]=[CH:7][C:8]=1[CH3:9].[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:2][C:3]1[CH:4]=[C:5]([N:10]2[C:12](=[O:17])[CH:13]=[C:14]([CH3:16])[NH:11]2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccc(NN)cc1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(=O)n(-c2ccc(C)c(C)c2)[nH]1

Procedure:
A solution of 3,4-dimethylphenylhydrazine hydrochloride (17.7 g; 0.1 mol.), ethyl acetoacetate (13.0 g; 0.1 mol.) and sodium acetate (8.2 g; 0.1 mol.) in glacial acetic acid; (250 mL) was stirred and heated under reflux for 24 h.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7]1.[NH3:16].CO>[Ni]>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:16])=[CH:7]1
Reactant: N
Reactant: O=Cc1ccn(Cc2cccc(F)c2)c1
Agent: [Ni]
Solvent: CO
Product: NCc1ccn(Cc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
7N Ammonia/methanol (40 mL) and Raney nickel (2 g) were added to 1-(3-fluoro-benzyl)-1H-pyrrole-3-carbaldehyde described in Preparation Example 58 (1.0 g, 4.9 mmol), and the solution was stirred for 18 hours under hydrogen atmosphere at room temperature. The catalyst was removed by filtering through Celite pad, then, NH silica gel was added to the filtrate, the solvent was evaporated in vacuo for adsorption, purification by NH silica gel column chromatography (hexane:ethyl acetate=2:1, then 1:1, then ethyl acetate) was carried out, and the title compound (530 mg, 2.5 mmol, 53.0%) was obtained as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1.[C:31](N1C=CN=C1)(N1C=CN=C1)=[O:32]>C1COCC1>[CH2:24]([N:21]1[CH2:22][CH2:23][CH:18]([N:17]2[CH:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[NH:1][C:31]2=[O:32])[CH2:19][CH2:20]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc(C(NC2CCN(Cc3ccccc3)CC2)c2ccccc2N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cccc(C2c3ccccc3NC(=O)N2C2CCN(Cc3ccccc3)CC2)c1
Yield: 98.5 %

Procedure:
To a solution of 2.65 g (6.60 mmol) of α-(2-aminophenyl)-N-(benzylpiperidin-4-yl)-3-methoxybenzylamine in 53 ml of THF, 1.50 g (9.24 mmol) of carbonyldiimidazole were added and stirred under reflux-heating for 3 hours. After allowed to stand cool, the reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (1% methanol/chloroform) to give 2.8 g (6.5 mmol) of the title compound as colorless amorphous.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:11][C@H:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C1(C)C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[N:19][C@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:11])=[CH:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: C[C@H](N)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C=N[C@@H](C)c2ccccc2)cc1
Temperature: 25 °C
Yield: 102.1 %

Procedure:
A mixture of p-anisaldehyde (11.24 g, 82.5 mmol) and (S)-α methyl benzyl amine (10.0 g, 82.5 mmol) in toluene (100 mL) was heated to reflux with removal of water by a Dean-Stark apparatus. After cooling to ambient temperature, the mixture was concentrated to provide 20.15 g (100%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 7.75-7.68 (m, 2H), 7.45-7.15 (m, 5H), 4.50 (q, 1H, J=6.6 Hz), 3.82 (s, 3H), 1.58 (d, 3H, J=6.6 Hz).
Reaction SMILES: [C:1](=[S:9])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16]C)=[O:14]>C1COCC1>[C:2]1([C:1]2[S:9][CH:11]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccccc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: C1CCOC1
Product: COC(=O)c1csc(-c2ccccc2)n1

Procedure:
A solution of benzothioamide (4.0 g, 29.2 mmol) in THF (80 mL) was treated dropwise with ethyl bromopyruvate (7.6 g, 39 mmol) and heated at reflux for 18 hours. The reaction was then concentrated under vacuum, diluted with ethyl acetate, washed with water (1×), brine (1×) and dried over anhydrous magnesium sulfate. The residue obtained after concentration was purified by silica gel chromatography (4.5×11 cm, 20% AcOEt/toluene), followed by a second purification with 20% AcOEt/hexane. The title material was obtained after concentration as a yellow oil (5.25, 77%). 1H NMR (CDCl3, 400 MHz): 8.14 (s, 1H) 8.00 (m, 2H) 7.46-7.42 (m, 3H) 4.43 (q, J=7.0 Hz, 2H) 1.42 (t, J=7.3 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:18]O>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([O:7][CH3:18])=[O:6]
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(N)cc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of 3-amino-5-nitrobenzoic acid 10.3 g (56.6 mmol) in methanol (100 mL) was added thionyl chloride 6.5 mL (89 mmol) dropwise under ice-cooing, and the mixture was stirred at 70° C. for 4 hours. The solvent was evaporated and thereto was added water and the mixture was extracted three times with ethyl acetate (100 mL). The organic layer was washed with an aqueous saturated sodium bicarbonate solution and dried on magnesium sulfate, filtered and concentrated to give 11.0 g (56.1 mmol) of methyl 3-amino-5-nitrobenzoate as a brown solid (yield: 99%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][CH2:29]O)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:31])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][CH2:29][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[O:18][C:17]3=[O:31])[CH3:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCO)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCN2CCOCC2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one and morpholine following procedures analogous to those described in Example 178. LC-MS Method 2 tR=1.19 min, m/z=511.2; 1H NMR (CDCl3) 1.49 (t, 3H), 2.05-2.11 (m, 3H), 2.16 (m, 1H), 2.23-2.41 (m, 5H), 2.51 (m, 1H), 2.71 (m, 1H), 3.61 (m, 4H), 5.61 (m, 1H), 6.83 (d, 2H), 7.20-7.32 (m, 4H), 7.31 (m, 5H), 7.43 (m, 2H).
Reaction SMILES: B(Cl)(Cl)Cl.[CH3:5][C:6]([C:10]1[CH:11]=[CH:12][C:13]([O:18]C)=[C:14]([CH:17]=1)[CH:15]=[O:16])([CH3:9])[CH:7]=[CH2:8].O>C(Cl)Cl>[CH3:9][C:6]([C:10]1[CH:11]=[CH:12][C:13]([OH:18])=[C:14]([CH:17]=1)[CH:15]=[O:16])([CH3:5])[CH:7]=[CH2:8]
Reactant: C=CC(C)(C)c1ccc(OC)c(C=O)c1
Agent: ClB(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: C=CC(C)(C)c1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
A solution of boron trichloride (1M in CH2Cl2, 39.7 mmol) was added dropwise under argon at −78° C. to a stirred solution of 5-(1,1-Dimethyl-allyl)-2-methoxy-benzaldehyde (13.2 mmol) in dry CH2Cl2 (120 ml). The dry ice—acetone bath was removed and reaction allowed warming to RT. Stirred at RT for 18 hours, before the reaction mixture was cooled to 0° C. and iced water (125 ml) slowly added. Extracted with CH2Cl2 (2×100 ml). The organic phases were washed with brine, dried (Na2SO4), filtered, and evaporated to black oil. Purified by flash chromatography (heptane:EtOAc) to give the title product as yellow oil in 56% yield. 1H-NMR (CDCl3) δ 10.82 (s, 1H), 9.81 (s, 1H), 7.43 (d, 1H), 7.41 (s, 1H), 6.86 (d, 1H), 5.92 (dd, 1H), 5.02-4.96 (m, 2H), 1.34 (s, 6H).