Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O:5]C(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11](=[O:46])[CH2:12][N:13]([CH2:42][C:43]([OH:45])=[O:44])[CH2:14][CH2:15][N:16]([CH2:38][C:39]([OH:41])=[O:40])[CH2:17][CH2:18][N:19]([CH2:34][C:35]([OH:37])=[O:36])[CH2:20][C:21](=[O:33])[NH:22][CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)(C)C.Cl.[OH-:49].[Na+]>O>[OH2:5].[OH2:49].[NH2:25][CH2:24][CH2:23][NH:22][C:21](=[O:33])[CH2:20][N:19]([CH2:34][C:35]([OH:37])=[O:36])[CH2:18][CH2:17][N:16]([CH2:38][C:39]([OH:41])=[O:40])[CH2:15][CH2:14][N:13]([CH2:12][C:11]([NH:10][CH2:9][CH2:8][NH2:7])=[O:46])[CH2:42][C:43]([OH:45])=[O:44]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)NCCNC(=O)OC(C)(C)C)CC(=O)O)CC(=O)O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NCCNC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)NCCN)CC(=O)O)CC(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The DTPA-B(tBA)EA prepared above was dissolved in 110 mL DI water, adjusted to pH 7 (5N HCl), and cooled in an ice bath. To the cool stirred solution was added concentrated HCl (39 mL) in one portion. The mixture was stirred 10 minutes in the ice bath then for 2 hours at ambient temperature. The solution was then cooled in an ice bath, titrated to pH 7 (50% NaOH), and concentrated by rotary evaporation to a dry solid (50 g). A portion of solid NaCl was removed from this material by suspending the solid in 50 mL DI water and vacuum filtering through a medium fritted glass funnel. The filtrate was adjusted to pH 2.5 (5N HCl), concentrated to a 50 mL suspension, and vacuum filtered through a coarse fritted glass funnel to remove additional solid NaCl. The filtrate was loaded onto a 9.5×2.0" (24.1×5.1 cm) column bed of Bio-Rad AG50-X8 (H+, 200-400 mesh). The column was eluted under nitrogen pressure with 0.75 L DI water followed by 1.25 L of 2N ammonium hydroxide. The product eluted with 2N ammonium hydroxide. The UV active fraction was concentrated by rotary evaporation to an oily residue. The residue was dissolved in 100 mL 1N acetic acid, concentrated by rotary evaporation, reconcentrated repeatedly from water (13×100 mL) to remove ammonium acetate, and lyophilized (10μ, 14 hours) to afford DTPA-B(AE)A.2H2O. 1H NMR (250 MHz, D2O/DCl:pH 2.3): δ 2.95 (t, 4H, J=5.7 Hz), δ 3.09-3.28 (b, 8H), δ 3.35 (t, 4H, J=5.7 Hz), δ 3.51 (s, 4H), δ 3.55 (s, 2H), δ 3.66 (s, 4H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C([OH:31])(C)C>O1CCCC1.O.OOS([O-])=O.[K+]>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:26])=[O:31])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([CH2:2][OH:1])[CH2:4][CH2:5]1)=[O:27]
Reactant: CC(C)O
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](CO)CC2)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)c1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](CO)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(cis-4-Hydroxymethyl-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (120 mg, 0.307 mmol) was dissolved in a solvent mixture of isopropyl alcohol (4 ml), tetrahydrofuran (1 ml) and water (0.5 ml) and oxone™ (132 mg, 0.215 mmol) was added. The reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with water (5 ml) and extracted with dichloromethane (3×10 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (98:2 increasing to 97:3, by volume). The resulting foam was triturated with diethylether (5 ml) to give the product (108 mg) as a white solid.
Reaction SMILES: Br[C:2]1[N:3]([CH2:10][CH:11]([CH2:14][O:15][C:16]2[CH:17]=[N:18][C:19]([Br:22])=[CH:20][CH:21]=2)[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+]>>[Br:22][C:19]1[N:18]=[CH:17][C:16]([O:15][CH2:14][CH:11]2[CH2:12][O:13][C:2]3=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]3[CH2:10]2)=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cn(CC(CO)COc2ccc(Br)nc2)c(Br)n1
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1cn2c(n1)OCC(COc1ccc(Br)nc1)C2
Yield: 71 %

Procedure:
Ring closure of alcohol 190 with NaH (1.35 equiv.) as in Example 2GGG for 200 min, followed by chromatography of the product on silica gel, eluting with 0-1% MeOH/CH2Cl2 (foreruns) and then with 1-3% MeOH/CH2Cl2, gave 6-{[(6-bromo-3-pyridinyl)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (191) (71%) as a pale yellow solid: mp (MeOH/CH2Cl2/hexane) 197-199° C.; 1H NMR [(CD3)2SO] δ 8.15 (br d, J=3.0 Hz, 1H), 8.10 (s, 1H), 7.56 (dd, J=8.7, 0.3 Hz, 1H), 7.42 (dd, J=8.8, 3.2 Hz, 1H), 4.60 (dd, J=11.0, 2.7 Hz, 1H), 4.45 (dd, J=11.0, 7.0 Hz, 1H), 4.29 (dd, J=12.5, 5.5 Hz, 1H), 4.20 (dd, J=10.0, 6.8 Hz, 1H), 4.17 (dd, J=10.0, 6.711z, 1H), 4.05 (dd, J=12.6, 6.8 Hz, 1H), 2.85 (m, 1H). Anal. (C12H11BrN4O4) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][C:33](O)=[O:34])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:33]([CH2:32][CH:29]2[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:31][CH2:30]2)=[O:34])[CH:7]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ccn2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 43.1 %

Procedure:
2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (400 mg) was dissolved in dimethylformamide (4.0 ml) under nitrogen atmosphere. To the solution were added 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]acetic acid (487 mg), triethylamine (0.335 ml) and BOP reagent (1.06 g) at room temperature, followed by stirring at 60° C. for 3 hours. The reaction mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was purified by silica gel column chromatography (eluent; ethyl acetate:heptane=1:2 to 1:1) to provide the titled compound (328 mg, 43%) as pale yellow powder.
Reaction SMILES: C([O:8][CH:9]1[CH2:13][N:12]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)(=[O:16])=[O:15])[CH:11]([CH2:27][C:28]([NH:30][CH:31]2[C:40]3[C:35](=[CH:36][C:37]([CH2:41][NH:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:38][CH:39]=3)[CH2:34][CH2:33][CH2:32]2)=[O:29])[CH2:10]1)C1C=CC=CC=1>CCO.[Pd]>[C:43]([NH:42][CH2:41][C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[CH:31]([NH:30][C:28](=[O:29])[CH2:27][CH:11]1[CH2:10][CH:9]([OH:8])[CH2:13][N:12]1[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=1)(=[O:16])=[O:15])[CH2:32][CH2:33][CH2:34]2)([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)NCc1ccc2c(c1)CCCC2NC(=O)CC1CC(OCc2ccccc2)CN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NCc1ccc2c(c1)CCCC2NC(=O)CC1CC(O)CN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Reaction time: 4 h

Procedure:
To a solution of 2-[4-benzyloxy-1-(3-trifluoromethyl-benzenesulfonyl)-pyrrolidin-2-yl]-N-[6-(tert-butylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide (Example 355) in EtOH was treated with 10% Pd/C ((10 wt %) and stirred under an H2 atmosphere for 4 h. The catalyst was removed by filtration affording the title compound as a white solid (MS, 568, M+H).
Reaction SMILES: [NH2:1][CH:2]([CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[F:17])[CH2:3][C:4]([O:6]C)=[O:5].O=C(CC1C=C(F)C(F)=CC=1F)CC(OC)=O.[OH-].[Na+]>CO.O>[NH2:1][CH:2]([CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[F:17])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)CC(N)Cc1cc(F)c(F)cc1F
Agent: COC(=O)CC(=O)Cc1cc(F)c(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(CC(=O)O)Cc1cc(F)c(F)cc1F

Procedure:
Methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate (5.8 g, 23.5 mmol), prepared from methyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate according to the process of WO 10/122578, was refluxed in the solution of NaOH (1.88 g, 46.9 mmol) in MeOH (40 mL) and water (20 mL) overnight. After the completion of the reaction, the MeOH was evaporated and 80 mL of water was added. The pH of the solution was adjusted to 8 by addition of 6M HCl and the resulting white precipitate was filtered off and dried overnight in an oven at 100° C. to afford 3.5 g of (±)-Ia.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][C:9]2[N:10]=[C:11]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[CH:23][CH:22]=3)[C:12]([C:17]([NH2:19])=[O:18])=[N:13][C:14]=2[CH2:15][CH3:16])[CH:5]=[N:6][CH:7]=1.[C:34](=[NH:47])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CN1CCCC1=O.COCCOC>[C:35]1([C:34](=[N:47][C:2]2[CH:3]=[C:4]([O:8][C:9]3[N:10]=[C:11]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[C:12]([C:17]([NH2:19])=[O:18])=[N:13][C:14]=3[CH2:15][CH3:16])[CH:5]=[N:6][CH:7]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cncc(Br)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cncc(N=C(c2ccccc2)c2ccccc2)c1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A mixture of 5-[(5-bromopyridin-3-yl)oxy]-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (370 mg), benzophenoneimine (145 μL), a tris(dibenzylideneacetone)dipalladium (0) chloroform complex (22 mg), di-tert-butyl (2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (28 mg), potassium phosphate (383 mg), and 1,2-dimethoxyethane (3 mL) was stirred at 80° C. for 10 hours under a nitrogen atmosphere. To the reactant was added N-methylpyrrolidone (3 mL), and a tris(dibenzylideneacetone)dipalladium (0) chloroform complex (22 mg) and di-tert-butyl (2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (28 mg) were added thereto, followed by stirring at 80° C. for 10 hours. Water was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1) to obtain 5-({5-[(diphenylmethylene)amino]pyridin-3-yl}oxy)-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (133 mg) as a brown amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:18])[C:16]=3[N:17]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:18][CH:22]([CH3:24])[CH3:23])[C:16]=3[N:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnc2ccc(-c3cccc(F)c3)nc12
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Nc1ncnc2ccc(-c3cccc(F)c3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(3-fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine 1 (100 mg, 0.42 mmol) in DMF was treated with sodium hydride 60% dispersion in mineral oil (25 mg, 0.63 mmol) followed by 2-iodopropane (0.04 mL, 0.42 mmol), stirred at room temperature for 2 hrs. The reaction mixture was poured on ice, and extracted with EtOAc three times. The combined organic layers were dried with sodium sulfate and concentrated to dry. The crude was purified by ISCO eluting with 100% EtOAc to give pure 6-(3-fluorophenyl)-N-isopropylpyrido[3,2-d]pyrimidin-4-amine 25. LC/MS (ESI+): m/z 283 (M+H). 1H NMR (400 MHz, DMSO) δ 8.53-8.43 (m, 2H), 8.37 (d, J=10.8 Hz, 1H), 8.21 (t, J=8.4 Hz, 2H), 8.15 (d, J=8.8 Hz, 1H), 7.60 (dd, J=14.2, 8.0 Hz, 1H), 7.34 (td, J=8.5, 2.5 Hz, 1H), 4.56 (dq, J=13.3, 6.7 Hz, 1H), 1.35 (d, J=6.6 Hz, 6H).
Reaction SMILES: [P:1]([O-:28])([O:22][CH2:23][CH:24]([OH:27])[CH2:25]Cl)([O:3][CH:4]=[CH: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][CH2:18][CH2:19][CH2:20][CH3:21])=[O:2].[Na+:29].C(O)C.[OH-].[Na+]>C(O)C>[P:1]([O-:28])([O:22][CH2:23][CH:24]1[O:27][CH2:25]1)([O:3][CH:4]=[CH: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][CH2:18][CH2:19][CH2:20][CH3:21])=[O:2].[Na+:29]
Reactant: CCCCCCCCCCCCCCCCC=COP(=O)([O-])OCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCC=COP(=O)([O-])OCC1CO1
Temperature: 70 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
50 g (0.11 mol) of sodium octadecenyl 2-hydroxy-3-chloropropyl phosphate was charged into a reactor, to which 1000 ml of ethanol was added, followed by agitation and heating to 70° C. to obtain a uniform mixture. Thereafter, the reaction system was cooled down to 30° C., to which was gradually added 60.0 g (0.11 mol) of a 0.0018 mol/g sodium hydroxide ethanol solution, followed by agitation for 4 hours while keeping the temperature. The HPLC analysis revealed the disappearance of a peak of the starting material with a peak for the resultant new product appearing. The resultant NaCl precipitate was removed by filtration and the ethanol was distilled off under reduced pressure to obtain 46 g (yield: 100%) of sodium octadecenyl glycidyl phosphate.
Reaction SMILES: [C:1]1([C:7]([CH2:33][CH3:34])=[CH:8][C:9]2[N:10]=[CH:11][N:12](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl>CO.[Pd]>[C:1]1([CH:7]([CH2:33][CH3:34])[CH2:8][C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC(=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCC(Cc1c[nH]cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 15.2 %

Procedure:
To a stirred solution of 4-(2-phenyl-but-1-enyl)-1-trityl-1H-imidazole (260 mg) at r.t. in methanol (5 ml) and dichloromethane (2 ml) under an argon atmosphere was added 10% Pd/C (26 mg). The mixture was then stirred at r.t. under a hydrogen atmosphere for 17 hours. The catalyst was filtered off and washed with methanol. The filtrate was concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 9:1 to give 4-(2-phenyl-butyl)-1H-imidazole (18 mg) as colorless gum. MS (ISP): 201.3 ([M+H]+)
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:6][C:7]1[CH:8]=[C:9]([OH:14])[CH:10]=[C:11]([CH3:13])[CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:6][C:7]1[C:8]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:9]([OH:14])[CH:10]=[C:11]([CH3:13])[CH:12]=1
Reactant: C1=CCCC1
Reactant: Cc1cc(C)cc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1cc(C)c(C2CCCC2)c(O)c1
Reaction time: 2 h
Yield: 31.6 %

Procedure:
102 g of cyclopentene are added dropwise to 244 g of 3,5-dimethylphenol and 20 g of p-toluene sulphonic acid at 120° C. The mixture is then stirred at this temperature for 2 h. After removal of the catalyst by washing with sodium hydrogen carbonate solution the mixture is fractionated. At boiling point 104° C (0.5 mm Hg) 90 g of 3,5-dimethyl-2-cyclopentylphenol are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1.Cl[C:20]1[N:30]=[C:29]2[C:23]([N:24]([CH3:35])[C:25](=[O:34])[CH2:26][CH2:27][N:28]2[CH:31]([CH3:33])[CH3:32])=[CH:22][N:21]=1.CCO.Cl>CO.O>[CH3:35][N:24]1[C:25](=[O:34])[CH2:26][CH2:27][N:28]([CH:31]([CH3:33])[CH3:32])[C:29]2[C:23]1=[CH:22][N:21]=[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)=[O:7])=[CH:17][CH:18]=1)[N:30]=2
Reactant: CC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: Nc1ccc(C(=O)NCCN2CCOCC2)cc1
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: O
Product: CC(C)N1CCC(=O)N(C)c2cnc(Nc3ccc(C(=O)NCCN4CCOCC4)cc3)nc21
Temperature: 25 °C

Procedure:
4-amino-N-(2-morpholin-4-ylethyl)benzamide (Buttpark; 188 mg, 0.75 mmol) and 10-chloro-6-methyl-2-propan-2-yl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 76; 160 mg, 0.63 mmol) were heated together in 1:3 EtOH:water (8 ml) in the presence of concentrated hydrochloric acid (126 ul) for 24 hours. The reaction was cooled to ambient temperature and then loaded onto an SCX-2 (5 g) column pre-wet with methanol. The product was eluted with 2M NH3/MeOH and the solvent evaporated to give product as a brown gum. This was purified by reverse phase HPLC to give the title compound a white solid. (125 mg, 42%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=O.[CH3:14]C([O-])(C)C.[K+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH2:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1cc(Br)cc(C(F)(F)F)c1
Agent: [K+]
Product: C=Cc1cc(Br)cc(C(F)(F)F)c1
Yield: 78.7 %

Procedure:
3-Bromo-5-trifluoromethylbenzaldehyde (1.10 g, 4.3 mmol) was reacted with CH3PPh3I (2.2 g, 5.4 mmol) and t-BuOK (710 mg, 6.3 mmol) as described above to give 1-bromo-3-trifluoromethyl-5-vinyl-benzene (850 mg, 79%) after purification by flash chromatography on silica gel
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si]([C:30]#[N:31])(C)C.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[C:1]([C:30]#[N:31])(=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: C[Si](C)(C)C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: COc1cccc(C(=O)C#N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
m-Anisoyl cyanide was prepared according to the general procedure reported by G. A. Olah et al. [supra]. Under dry conditions, 1.686 g of m-anisoyl chloride (99%, Aldrich) (9.88 mmol), 30 mL of methylene chloride, freshly distilled from phosphorus pentoxide under nitrogen, and 1.6 mL of trimethylsilyl cyanide (12 mmol) were added to a 100-mL round bottom flask. To this solution 0.25 mL of tin (IV) chloride (2.1 mmol) was added. On addition of the tin (IV) chloride, the color of the solution changed from pale bronze to dark yellow. The solution was stirred for 2 hr at room temperature. After 2 hr of stirring the color of the solution was dark brown. The reaction mixture was quenched with 75 mL of ice-cold water and then extracted with two 75-mL portions of methylene chloride. The methylene chloride extracts were combined, washed with two 75-mL portions of ice-cold water, dried with MgSO4, and filtered. The methylene chloride was evaporated to yield 1.506 g of a dark brown oil. This oil was stirred with hot pentane. The pentane solution was decanted and the pentane was removed by rotary evaporation to yield 1.238 g (78%) of m-anisoyl cyanide as a yellow oil: IR (CCl4) (partial) 2230, 1690 cm-1.
Reaction SMILES: [N+:1]([C:4](=[C:10]1[NH:15][CH2:14][CH2:13][CH2:12][S:11]1)C(OCC)=O)([O-:3])=[O:2].[OH-].[Na+]>C(O)(=O)C>[N+:1]([CH:4]=[C:10]1[NH:15][CH2:14][CH2:13][CH2:12][S:11]1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=C1NCCCS1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2.3 G OF 1A was added to 10 ml of 20% aqueous sodium hydroxide and the mixture was stirred at room temperature for 12 hours. The resulting solution was treated dropwise with 3.5 g of acetic acid. The addition was accompanied by vigorous gas evolution. The resulting mixture was extracted with methylene chloride and the extract was dried (magnesium sulfate) and concentrated under reduced pressure to give tetrahydro-2-(nitromethylene)-2H-1,3-thiazine (1B) as a pale yellow solid, m.p. 76°-78°.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:29]3[CH2:34][CH2:33][CH:32]([CH:35]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=4[F:44])[F:36])[CH2:31][CH2:30]3)=[C:20]([NH:25][CH:26]([CH3:28])[CH3:27])[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:44][C:38]1[CH:39]=[C:40]([F:43])[CH:41]=[CH:42][C:37]=1[CH:35]([F:36])[CH:32]1[CH2:33][CH2:34][N:29]([C:19]2[N:18]=[C:17]3[CH2:16][NH:15][CH2:24][CH2:23][C:22]3=[N:21][C:20]=2[NH:25][CH:26]([CH3:27])[CH3:28])[CH2:30][CH2:31]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CN(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CNCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-benzyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (108.3 mg, 0.174 mmol) and Pd(OH)2 on carbon, (20 wt %, 11 mg, 0.016 mmol) in THF (1.7 mL) was stirred under an atmosphere of hydrogen gas (balloon) at rt. After 2 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (67.5 mg, 72.9%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.24 (dd, J=6.6, 2.3 Hz, 6H), 1.41-1.48 (br m, 1H), 1.52-1.74 (m, 2H), 1.97-2.14 (m, 2H), 2.61-2.73 (m, 2H), 2.99 (t, J=6.3 Hz, 2H), 3.38-3.49 (m, 2H), 3.50-3.55 (m, 2H), 4.14 (s, 2H), 4.14-4.21 (m, 1H), 5.53 (dd, J=46.5, 7.3 Hz, 1H), 6.95-7.10 (m, 2H), 7.46-7.55 (m, 1H); ESI-MS m/z [M+H]+ 420.3.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([O:4][C:5]([NH:7][CH2:8][C:9]1[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[C:11]([O:18]CC2C=CC=CC=2)[C:10]=1[O:26]CC1C=CC=CC=1)=[O:6])[CH3:3]>CO.[Pd]>[CH3:3][C:2]([CH3:34])([O:4][C:5]([NH:7][CH2:8][C:9]1[NH:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][C:11](=[O:18])[C:10]=1[OH:26])=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)NCc1nc(C(=O)O)cc(OCc2ccccc2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1[nH]c(C(=O)O)cc(=O)c1O
Yield: 82.9 %

Procedure:
3.94 g 6-[[[(1,1-Dimethylethoxy)carbonyl]amino]methyl]-4,5-bis(phenylmethoxy)-2-pyridinecarboxylic acid and 1.3 g palladium/carbon (10%) were suspended in 70 ml methanol. Hydrogenation at normal pressure completed the reaction after one hour. The catalyst was then filtered off and washed with dimethylformamide. The combined filtrates were evaporated and the residue stirred with ether. 2 g of title compound were obtained as a white powder. M.P.=>300° C.