Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](=O)[CH3:15])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[CH:17]=[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([I:1])[CH:3]=2)[C:14]=1[CH3:15])=[O:26])[CH3:10]
Reactant: Nc1cccc(I)c1
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(I)c2)c1C

Procedure:
m-Iodoaniline (5 mmol, 1.1 g), 3-Oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The named product was recrystallized in ethanol (m.p. 111° C.-112.9° C.).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[C:7]([F:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:3].Br[C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1.CCN(C(C)C)C(C)C>C(O)C.C([O-])(O)=O.[Na+]>[Cl:10][C:8]1[C:7]([F:11])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:13]2)[C:5]([O:23][CH3:24])=[C:4]([CH:2]([NH:1][C:26]2[N:34]=[CH:33][N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][N:30]3[CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH3:3])[CH:9]=1
Reactant: COc1c(C(C)N)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Yield: 96.7 %

Procedure:
A mixture of tert-butyl 3-[3-(1-aminoethyl)-5-chloro-6-fluoro-2-methoxyphenyl]azetidine-1-carboxylate (22.5 mg, 0.0627 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (24 mg, 0.085 mmol, from Example 108, Step 1) and DIPEA (33 μL, 0.19 mmol) in ethanol (1.0 mL) was heated at 100° C. overnight. The mixture was diluted with sat. NaHCO3 solution, extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give tert-butyl 3-[3-chloro-2-fluoro-6-methoxy-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]azetidine-1-carboxylate (34 mg). LCMS calculated for C27H35ClFN6O4 (M+H)+: m/z=561.2. found: 561.2. The coupling product made above was treated with 4.0 M HCl in dioxane (0.5 mL, 2 mmol) in methylene chloride (0.2 mL) at room temperature for 1 hour. The reaction mixture was then evaporated to dryness to give N-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-9H-purin-6-amine dihydrochloride. The resultant HCl salt was dissolved in methanol (0.2 mL)/acetonitrile (0.2 mL)/THF (0.2 mL) and treated with DIPEA (0.1 mL, 0.6 mmol) until the solid dissolved. Acetone (0.05 mL, 0.6 mmol) was added and the resulting mixture was stirred at room temperature for 30 min before the addition of sodium triacetoxyborohydride (0.066 g, 0.31 mmol). The reaction mixture was stirred at room temperature for 4 h and then purified on prep-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C23H25ClFN6O (M+11)+: m/z=419.2. found: 419.1. 1H NMR (300 MHz, DMSO-d6) δ 9.96 (1H, m), 8.41 (1H, m), 8.23 (1H, s), 8.20 (1H, s), 7.53 (1H, s), 5.69 (1H, m), 4.52 (2H, m), 4.26 (1H, m), 4.12 (2H, m), 3.77 (3H, s), 2.08 (3H, m), 1.46 (3H, d, J=6.9 Hz), 1.11 (6H, m) ppm.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]3)=[C:18]([F:29])[C:17]=2[F:30])=[C:12]([F:31])[C:11]=1[F:32])[CH3:8].C(OCC)(=O)C.N>C1COCC1>[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C@H:22]3[CH2:23][CH2:24][C@H:25]([OH:28])[CH2:26][CH2:27]3)=[C:18]([F:29])[C:17]=2[F:30])=[C:12]([F:31])[C:11]=1[F:32])[CH3:8]
Reactant: CCOc1ccc(-c2ccc(C3CCC(=O)CC3)c(F)c2F)c(F)c1F
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2ccc([C@H]3CC[C@H](O)CC3)c(F)c2F)c(F)c1F
Reaction time: 2 h

Procedure:
Lithium aluminum hydride (0.31 g) was suspended in THF (100 ml). 1-(4′-Ethoxy-2,2′,3,3′-tetrafluoro-1,1′-biphenyl-4-yl)-cyclohexan-4-one (s-27) (5.0 g) dissolved in THF (20 ml) was added dropwide to the suspension in the temperature range of −20° C. to −10° C., and the stirring was continued in this temperature range for another 2 hours. After the completion of the reaction had been confirmed by means of GC analysis, ethyl acetate and then a saturated aqueous solution of ammonia were added to the reaction mixture under ice-cooling and deposits were removed by filtration through Celite. The filtrate was extracted with ethyl acetate. The combined organic phase was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by recrystallization from heptane to give trans-4-(4′-ethoxy-2,2′,3,3′-tetrafluoro-1,1′-biphenyl-4-yl)-cyclohexanol (s-28) (12.1 g). The yield based on the compound (s-27) was 89.1%.
Reaction SMILES: [OH:1][CH:2]1[S:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]1=[O:13].C(N(CC)CC)C.[CH:21]([N:24]=[C:25]=[O:26])([CH3:23])[CH3:22]>C(Cl)(Cl)Cl>[CH:21]([NH:24][C:25]([O:1][CH:2]1[S:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]1=[O:13])=[O:26])([CH3:23])[CH3:22]
Reactant: O=C1C(O)SCN1c1ccccc1
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)NC(=O)OC1SCN(c2ccccc2)C1=O
Reaction time: 4 h

Procedure:
A stirred solution of 5-hydroxy-3-phenyl-4-thiazolidinone (prepared as in Preparative Example 17 above) (0.24 g) and triethylamine (0.01 ml) in chloroform (5 ml) was treated with iso-propyl isocyanate (0.116 g). The mixture was stirred for 4 hours, then evaporated under reduced pressure. Recrystallisation of the solid residue from diethyl ether/hexane afforded the title compound as colourless needles, yield 0.14 g, mp 130°-132° C.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:13]([CH3:17])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[CH3:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:9][NH:8][CH2:16]2
Reactant: Cc1cc2c(cc1C1CCOCC1)CN(C(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C1CCOCC1)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 5-methyl-6-(tetrahydro-pyran-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. MS (m/e): 218.4 ([M+H]+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[C:9](=[O:21])[C:8]2=[O:22])=[CH:4][CH:3]=1.Br[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[N:27]1[CH:28]=[CH:29][CH:30]=[N:31][C:26]=1[NH:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:26]4[N:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:24][CH:23]=3)[C:8](=[O:22])[C:9]2=[O:21])=[CH:15][CH:16]=1
Reactant: Nc1ccc(CN2CCN(Cc3ccc(N)cc3)C(=O)C2=O)cc1
Reactant: Brc1ncccn1
Product: O=C1C(=O)N(Cc2ccc(Nc3ncccn3)cc2)CCN1Cc1ccc(Nc2ncccn2)cc1
Yield: 14.7 %

Procedure:
The 1,4-bis(4-aminobenzyl)-2,3-dioxopiperazine was reacted with 2-bromopyrimidine in the same manner as in Example 6-(1) to obtain 1,4-bis[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine (14.7% yield).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7][N:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:4].Br[CH2:18][CH2:19]Br>C(OCC)C.CS(C)=O>[CH:9](=[N:8][C:7]1([C:6]([O:5][CH2:3][CH3:4])=[O:16])[CH2:19][CH2:18]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)CN=Cc1ccccc1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)C1(N=Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
25.2 g (1.05 moles) of sodium hydride are added a little at a time under nitrogen to 100 g (0.523 mole) of N-benzylideneglycine ethyl ester and 45.1 ml (0.523 mole) of 1,2-dibromoethane in 500 ml of dry diethyl ether and 170 ml of dry dimethylsulfoxide, so that the well-stirred mixture remains at from 20° to 30° C. The mixture is stirred at room temperature overnight and filtered, and 1 l of water is added to the filtrate. The ethereal phase is separated off, washed with twice 200 ml of water, dried over sodium sulfate and evaporated under reduced pressure to give 80 g (70%) of ethyl N-benzylidene-1-aminocyclopropanecarboxylate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[NH:21]1[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[N:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:26]([C:23]3[CH:24]=[CH:25][NH:21][N:22]=3)=[O:27])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1cc[nH]n1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1cc[nH]n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 1H-pyrazole-3-carboxylic acid as starting materials, MS (LC/MS): 395.2 (M−H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[CH:17][CH:18]=2)[O:13][CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>CC#N>[OH:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[C:11]([C:4]3[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=3[OH:2])=[CH:12][O:13]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2coc3cc(O)ccc3c2=O)c(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2coc3cc(O)ccc3c2=O)c(O)c1
Yield: 49.9 %

Procedure:
Compound 3-(2,4-dimethoxy-phenyl)-7-hydroxy-chromen-4-one (2 gm, 6.7 mmol) was dissolved in CH3CN (25 ml) and AlCl3 (2.6 gm, 20 mmol) was added to the solution at 0° C. The reaction was then refluxed for 10 hours. The mixture was cooled and then poured ice-cooled water. The precipitated solid were filtered, washed with water and purified by silica gel column chromatography using chloroform-methanol as the eluent to give 7-hydroxy-3-(2-hydroxy-4-methoxy-phenyl)-chromen-4-one (0.95 gm, 50%) as white solid.
Reaction SMILES: ClC1C=CC(S(Cl)(=O)=O)=CC=1[N+]([O-])=O.COC1C=CC=CC=1N.Cl[C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][CH3:42])(=[O:33])=[O:32])=[CH:27][C:26]=1[N+:43]([O-:45])=[O:44].[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>C(Cl)Cl.N1C=CC=CC=1>[CH3:42][O:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[NH:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([N:50]2[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]2)=[C:26]([N+:43]([O-:45])=[O:44])[CH:27]=1)(=[O:33])=[O:32]
Reactant: COc1ccccc1NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN1CCNCC1
Agent: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: COc1ccccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccccc1NS(=O)(=O)c1ccc(N2CCN(C)CC2)c([N+](=O)[O-])c1

Procedure:
The compound was prepared from 4-chloro-3-nitrobenzenesulfonylchloride (1 g, 3.9 mmol), 2-methoxyaniline (0.53 mL, 4.7 mmol) and pyridine (1.6 mL) in CH2Cl2 (2 mL). 4-Chloro-N-(2-methoxyphenyl)-3nitrobenzenesulfonamide (0.345 mg) was reacted with N-methylpiperazine (0.144 mL) to afford N-(2-methoxyphenyl)-4-(4-methyl-1-piperazinyl)-3-nitrobenzenesulfonamide which was treated with Raney-Ni and hydrazine monohydrate. The final product was isolated as its HCl salt 1H NMR (DMSO-d6) δ 7.185 (dd, 1H), 7.08 (dt, 1H), 6.975 (d, 1H), 6.91–6.94 (m, 2H); 6.84 (dt, 1H), 3.56 (s, 3H), 3.42–3.47 (m, 2H), 3.22–3.24 (m, 2H), 2.95 (bt, 2H), 2.79 (bs, 3H); MS (posESI) m/z=376.2 (M+H+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[C:18](=O)[C@H:17]([OH:20])[C@@H:16]([OH:21])[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]1[CH2:18][C@H:17]([OH:20])[C@@H:16]([OH:21])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1[C@H](O)[C@@H](O)C(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O[C@H]1CN(Cc2ccccc2)C[C@@H]1O
Temperature: 25 °C

Procedure:
To a suspension of LiAlH4 (18.33 g, 219.2 mmol) in 200 mL THF, (3R,4R)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione (23.1 g, 104.4 mmol) was added and the mixture was refluxed for 12 hours. The mixture was cooled down to room temperature and carefully quenched with 3 mL EtOAc and 3 mL MeOH. Wet silica gel was added to the mixture following by addition of MeOH—CHCl3, 1:1, and the mixture was filtered. The filtrate was evaporated giving the title compound that was used for the next step without additional purification.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][C:10]([CH:17]([Cl:22])[C:18]([F:21])([F:20])[F:19])([C:13]([F:16])([F:15])[F:14])[O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.[H][H].[Pd]>[NH2:1][C:4]1[C:12]2[O:11][C:10]([CH:17]([Cl:22])[C:18]([F:21])([F:19])[F:20])([C:13]([F:14])([F:15])[F:16])[O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cccc2c1OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc2c1OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2

Procedure:
84 g of 4-nitro-2-(1-chloro-2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole from Example 7 were dissolved in 500 ml of tetrahydrofuran and hydrogenated with 15-20 bar of hydrogen for 5 hours at room temperature on 5 g of palladium-on-charcoal (5%). The mixture was then filtered and the filtrate was concentrated and distilled under vacuum. The yield was 31 g (40% of theory) and the boiling point was 70° C. at 0.1 mbar. The NMR spectra showed the following characteristic absorptions: 19F NMR: -68.6 and -81.5 ppm. 1H NMR: 4.69 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14](/[CH:16]=[CH:17]/[C:18](O)=[O:19])=[CH:15][C:8]=23)=[CH:4][CH:3]=1.O.O[N:25]1C2C=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14](/[CH:16]=[CH:17]/[C:18]([NH2:25])=[O:19])=[CH:15][C:8]=23)=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)/C=C/c1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: NC(=O)/C=C/c1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Temperature: 0 °C
Reaction time: 10 h

Procedure:
A solution of Example 91C (51.5 mg, 0.155 mmol), N-hydroxybenzotriazole monohydrate (34.5 mg, 0.225 mmol), 4-methylmorpholine (47 mg, 0.464 mmol) and NH4CN (31.6 mg, 0.591 mmol) in DMF (1 mL) at 0° C. was treated with EDC (45.0 mg, 0.235 mmol), stirred at 0° C. for 4 hours and at room temperature for 10 hours, treated with chloroform (5 mL), washed sequentially with 1M NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 5% methanol/dichloromethane to provide the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]1[C@@H:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](=O)[NH:11][CH2:10][C:9]1=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:7][N:8]1[CH2:9][CH2:10][NH:11][CH2:12][C@@H:13]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN1C(=O)CNC(=O)[C@@H]1Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN1CCNC[C@@H]1Cc1ccccc1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 87.2 %

Procedure:
Lithium aluminium hydride (1.0M in ether, 20.2 mL, 20.2 mmol) was added to a stirred, cooled (0° C.) suspension of (6S)-1-methyl-6-(phenylmethyl)-2,5-piperazinedione (Description 34, 1.1 g, 5.0 mmol) in THF (60 mL) and the mixture was heated under reflux for 1 h. The mixture was cooled to −20° C. and saturated aqueous sodium sulfate (20.2 mL) was added. The mixture was stirred at room temperature for 15 min., filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2C2/MeOH/NH3(aq.) (90:10:1), to give the title compound as a yellow oil (0.83 g, 87%). 1H NMR (250 MHz, CDCl3) δ7.31-7.15 (5H, m), 3.17 (1H, dd, J 13.3, 3.9 Hz), 2.92-2.70 (4H, m), 2.46 (2H, m), 2.43 (3H, s), 2.27 (2H, m) and 1.51 (1H, br s). m/z (ES+) 191 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:19])[CH2:17][CH:16]([CH3:18])[CH2:15][CH:14]2[CH:10]1[CH2:11][NH:12][CH2:13]2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C@H:28]([CH3:32])[C:29](O)=[O:30].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@@:9]1([OH:19])[CH2:17][C@@H:16]([CH3:18])[CH2:15][C@H:14]2[C@@H:10]1[CH2:11][N:12]([C:29](=[O:30])[C@H:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:21][CH3:20])[CH3:32])[CH2:13]2
Reactant: COc1ccccc1[C@H](C)C(=O)O
Reactant: COc1ccccc1C1(O)CC(C)CC2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@H]2C[C@H](C)C[C@](O)(c3ccccc3OC)[C@H]2C1
Temperature: 5 °C
Yield: 36.1 %

Procedure:
To a solution of 1.54 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-6-methyl-4-perhydroisoindolol in 150 cm3 of dichloromethane is added 1.0 cm3 of triethylamine. The reaction is mixture is cooled to 5° C. and 1.08 g of (S)-2(2-methoxyphenyl)propionic acid, 0.10 g of 1-hydroxybenzotriazole monohydrate and 1.26 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added. The reaction mixture is maintained for 1 hour at 5° C. and for 16 hours at 20° C. and is then washed twice with 100 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.060-0.200 mm, diameter 4 cm, height 70 cm), eluting under a pressure of 0.7 bar with a mixture of ethyl acetate and cyclohexane [by volume: 20/80 (2 dm3) then 30/70 (2 dm3) then 40/60 (2 dm3) and collecting 60 cm3 fractions. Fractions 57 to 72 are concentrated and, after drying at 40° C. at 15 Pa, 0.90 g of (3aR*,4R*,6S*,7aS*)-4-(2-methoxyphenyl)-2-[2-(S)-(2-methoxyphenyl)propionyl]-6-methyl-4-perhydroisoindolol is obtained in the form of a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.Cl.C(=O)(O)[O-].[Na+]>ClCCl>[N:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=2)=[CH:16][CH:17]=1
Reactant: COc1cccc(C2CCCN2Cc2ccncc2)c1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: Oc1cccc(C2CCCN2Cc2ccncc2)c1
Temperature: -78 °C
Yield: 29.6 %

Procedure:
2-(3-Methoxyphenyl)-1-(4-pyridinylmethyl)pyrrolidine (5.70 g) was dissolved in dry dichloromethane (66 ml) and cooled to -78° C., under nitrogen. Boron tribromide in dichloromethane (1.0M solution, 66.0 ml) was added dropwise, and the reaction mixture was allowed to warm to ambient temperature overnight. The mixture was acidified with 5% hydrochloric acid to pH of 2 and then basified with saturated sodium bicarbonate solution to pH of 8. The layers were separated, and the aqueous phase was extracted with dichloromethane (3 times) and ether (1 time). The organic extracts were washed with brine, dried over anhydrous potassium carbonate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 2% triethylamine/ether). The appropriate fractions were collected and concentrated to afford 1.60 g (30%) of product. Recrystallization from ether gave the analytical sample, mp 138° C.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]=[C:10]1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17](N(C(C)C)CC)(C)C>CO.C(#N)C.CCCCCC>[CH2:1]([O:8][C:9]1[C:10]([CH3:16])=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1=NC=CC(=O)C1OCc1ccccc1
Solvent: CC#N
Solvent: CCCCCC
Solvent: CO
Product: COc1ccnc(C)c1OCc1ccccc1
Reaction time: 8 h
Yield: 75.5 %

Procedure:
3-Benzyloxy-2-methyl-4-pyridone (21.5 g, 0.10 mol) was suspended in methanol-acetonitrile (1:9 v/v, 400 ml). Diisopropylethylamine (18.1 g, 0.14 mol) was added to the suspension. The mixture was then stirred. A 2.0 M solution (70 ml) of tetramethylsilyldiazomethane in n-hexane was added dropwise to the mixture, and a reaction was allowed to proceed at room temperature overnight. The reaction solution was concentrated under the reduced pressure. The concentrate was applied to column chromatography on silica gel (Wako Gel C-200, n-hexane-ethyl acetate) to give 17.3 g (yield 76%) of 3-benzyloxy-4-methoxy-2-methylpyridine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20]OS(C)(=O)=O)[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1.C(=O)([O-])[O-].[K+].[K+]>CCCC[N+](CCCC)(CCCC)CCCC.[I-].CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)[O:17][N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Reactant: c1c[nH]cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(-c3cc(Cn4ccnc4)on3)cc2)cc1
Reaction time: 2 h

Procedure:
Methanesulfonic acid-3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester (600 mg, 1.67 mmol), imidazole (170 mg, 2.50 mmol), potassium carbonate (460 mg, 3.34 mmol), and TBAI (200 mg, 0.54 mmol) were placed in 20 ml of DMF and stirred for 2 hours. The completion of the reaction was confirmed by LC, and then a crude solid compound obtained from distillation of the DMF under reduced pressure was extracted with ethyl acetate and water. The ethyl acetate was distilled off under reduced pressure to obtain a white solid compound. The compound was purified by silica chromatography (methylene chloride:MeOH=20:1) to obtain 3-(4-benzyloxy-phenyl)-5-imidazol-1-ylmethyl-isoxazole as a white solid compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=1)[CH:6]=[CH:5]2.[CH3:23][N:24]([CH3:34])[C:25]1[CH:33]=[CH:32][C:28]([C:29]([O-])=[O:30])=[CH:27][CH:26]=1>>[CH3:23][N:24]([CH3:34])[C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]2[CH:12]=[CH:13][C:14]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:16]=2)[CH:6]=[CH:5]3)=[O:30])=[CH:27][CH:26]=1
Reactant: Nc1ccc2c(ccn2-c2ccc(N3CCOCC3)cc2)c1
Reactant: CN(C)c1ccc(C(=O)[O-])cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc3c(ccn3-c3ccc(N4CCOCC4)cc3)c2)cc1

Procedure:
Compound 376 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-morpholinophenyl)indole and 4-dimethylaminobenzoate. [M+H]+ calcd for C27H28N4O2: 441.22; found: 441.02.