Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH:13]([CH3:16])[CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Na].[CH3:24]I.O>O1CCOCC1>[CH3:24][O:15][CH2:14][CH:13]([O:12][C:11]1[CH:17]=[CH:18][C:8]([O:7][C:6]2[CH:19]=[CH:20][C:3]([C:2]([F:21])([F:22])[F:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[CH3:16]
Reactant: CC(CO)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CI
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: COCC(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 67 %

Procedure:
6 g of β-[4-(4-trifluoromethylphenoxy)phenoxy]propanol was dissolved in 30 ml of dioxane and 0.46 g of sodium was added to the solution. The mixture was then heated for 3 hours while refluxing. 3.1 g of methyl iodide was added thereto and the resulting mixture was heated for 6 hours while refluxing. The reaction mixture was then poured into an appropriate amount of water and extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulfate. The ether was removed by distillation and the residue was distilled under reduced pressure to obtain 4.2 g of the desired product having a boiling point of 160° to 165° C/2 mmHg.
Reaction SMILES: [CH2:1]([OH:11])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12](OC)(=[O:16])[C:13]([CH3:15])=[CH2:14].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:12]([O:11][CH2:1]/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: CCCCCC=C/C=C/CO
Reactant: C=C(C)C(=O)OC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=C(C)C(=O)OC/C=C/C=CCCCCC
Yield: 65 %

Procedure:
The method of Example 1 was substantially repeated with trans, trans-2,4-decadien-1-ol (50.0 g, 0.32 mol), methyl methacrylate (140 mL, 1.3 mol), phenothiazine (1 g), and tetraisopropyl titanate (2 mL). After a 2-h period the excess methyl methacrylate was removed and the product was distilled to give 46.4 g (65% yield) of clear, colorless liquid trans, trans-2,4-decadienyl methacrylate, bp 96°-97° C./0.2 mm. IR (film): ν 2932, 1712, 1629, 1449, 1309, 1285, 1149, 984, 962, 933, 810 cm-1. UV (isooctane): λmax 230 nm, ε=29,000. 90 MHz 1H NMR: δ 6.4-5.4 (6H, m, vinyl), 4.63 (2H, d, J=7, OCH2), 2.10 (2H, q, J=7, allylic CH2), 1.97 (3H, m allylic CH3), 1.3 (6H, m, 3CH2), and 0.90 (3H, t, J=6, CH3CH2). 22.63 MHz 13C NMR: δ 166.9, 136.5, 134.8, 129.4, 125.2, 124.3, 65.1, 32.7, 31.5, 29.0, 22.6, 18.3, 14.0.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#N)([F:10])[CH3:9].[OH2:19].[OH-].[Na+]>CCOCC>[F:7][C:8]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][OH:19])([F:10])[CH3:9]
Reactant: CC(F)(F)c1cccc(C#N)c1
Reactant: O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(F)(F)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To a suspension (100 ml) of lithium aluminum hydride (2.24 g, 54.4 mmol) in ether was added dropwise a solution of 3-(1,1-difluoroethyl)benzonitrile (5.48 g, 29.4 mmol) in ether (50 ml) under ice-cooling, and the mixture was stirred at room temperature for 4 hrs. After completion of the reaction, water (2.24 ml), 15% aqueous sodium hydroxide solution (2.24 ml) and water (6.72 ml) were successively added dropwise under ice-cooling. The obtained solid was filtered with celite and washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1, 1:1) to give 3-(1,1-difluoroethyl)benzyl alcohol (3.82 g, 75%) to give a colorless transparent oil.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH2:3][CH2:4][CH3:5].C1CCC(NC2CCCCC2)CC1.[NH2:29][C@H:30]([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH2:32][S:33][CH3:34].Cl.C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)(Cl)Cl>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([NH:29][C@H:30]([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)CCSC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCSC)C(=O)OC
Reaction time: 8 h
Yield: 71 %

Procedure:
BOC-Nva-OH, liberated from 4.78 g (12 mmoles) of the DCHA salt as described in Step 1 of Example 4, and 2.6 g (13 mmoles) of H-Met-OMe.HCl are dissolved in 40 ml of chloroform, and 1.82 ml (13 mmoles) of triethylamine are added. The mixture is cooled with ice, and a solution of 2.58 g (12.5 mmoles) of DCC in 20 ml of chloroform is added under stirring. The reaction mixture is allowed to stand at 5° C. overnight, thereafter the separated DCU is filtered off. The filtrate is washed thrice with 20 ml of n hydrochloric acid, each, thrice with 20 ml of n sodium hydrocarbonate solution, each, and then with 20 ml of water, dried over anhydrous sodium sulfate, and evaporated. The oily residue is crystallized from petroleum ether, and the resulting 3.42 g of crude product is recrystallized from a mixture of ethyl acetate and petroleum ether. 3.08 g (71%) of BOC-Nva-Met-OMe are obtained; m.p.: 69°- 70° C., Rf2 =0.81, [α]D25 =-42.7° (c=1%, in methanol).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11]C2C#N)=[O:7].S(=O)(=O)(O)O.[C:24]([OH:27])(=[O:26])[CH3:25]>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11][CH:25]2[C:24]([OH:27])=[O:26])=[O:7]
Reactant: N#CC1CCc2c(C(=O)c3cccs3)cccc21
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(c1cccs1)c1cccc2c1CCC2C(=O)O

Procedure:
To 2.5 g of 4-(2-thienylcarbonyl)-1-indancarbonitrile is added 20 ml of 60% sulfuric acid together with 10 ml of acetic acid. The mixture is refluxed in argon gas for 2.5 hours. After cooling, water is added to the reaction mixture which is then extracted with benzene. The benzene layer is washed with water and extracted with a 5% aqueous solution of potassium carbonate. The extract is made acidic with hydrochloric acid and the precipitate is extracted with benzene. The benzene layer is washed with water, dried and decolorized with activated carbon. The solvent is then distilled off under reduced pressure and the residue is crystallized from benzene-cyclohexane (1:2). By the above procedure is obtained 4-(2-thienylcarbonyl)-1-indancarboxylic acid as crystals melting at 121.5°-123.5° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:16]([CH3:17])=[C:15]([O:18][CH3:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[O:20][CH3:21].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1>[CH3:19][O:18][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:20][CH3:21])=[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:16]=1[CH3:17]
Reactant: COc1c(C)c(Br)c(OC)c2ccccc12
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)c(OC)c2ccccc2c1OC
Temperature: 0 °C
Yield: 88.6 %

Procedure:
n-Butyl lithium (1.6M in hexanes, 4.1 ml, 6.56 mmol) was added dropwise to 2-bromo-1,4-dimethoxy-3-methylnaphthalene (1.537 g, 5.47 mmol) in tetrahydrofuran (30 ml) at −50° C. The reaction was stirred for 30 min at −50° C. before dropwise addition of ethyl chloroformate (1 ml, 10.46 mmol). The reaction was allowed to warm to 0° C. over 18 h quenched by addition of hydrochloric acid (2N) and extracted with ethyl acetate. The extract was dried (Na2SO4) and the solvent evaporated under vacuum. The residue was purified by SPE (silica, 10 g) eluting with 10% ethyl acetate in cyclohexane to give ethyl 1,4-dimethoxy-2-methylnaphthalene-3-carboxylate (1.33 g, 89%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)(=O)[CH3:15]>C(Cl)Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CC(=O)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(NCCCCNC(=O)OC(C)(C)C)c1ccccn1

Procedure:
Using General Procedure B, (4-aminobutyl)-carbamic acid tert-butyl ester and 2-acetylpyridine in CH2Cl2 and NaBH(OAc)3 were reacted to obtain [4-(1-pyridin-2-ylethylamino)-butyl]-carbamic acid tert-butyl ester as a light brown oil.
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17]O.[OH-].[K+]>>[CH3:17][C:16]1([CH3:20])[CH2:19][O:14][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N:15]1
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CC(C)(N)CO
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCC1=NC(C)(C)CO1
Reaction time: 4 h
Yield: 86.9 %

Procedure:
64 g (320 mmoles) of dodecanoic acid and 61.1 ml (640 mmoles) of 2-amino-2-methylpropanol was placed in a two neck flask equipped with a vigreux column, distillation condenser and a thermometer. The temperature of the reaction mixture was slowly brought to 180° C. and maintained there for 9 hours. After cooling, a 10% alcoholic KOH solution (2 g, 3.6 mmoles) was added and the reflux was continued at 180° C. for 4 hours. The excess 2-amino-2-methylpropanol was distilled at aspirator pressure (86° C./18 mm). When the vapor temperature reached 103° C., the distillation was discontinued and the residue was taken in petroleum ether and filtered. The filtrate was washed with dilute KOH, water, dried and concentrated. The oil was distilled at 120° C./1.2 mm Hg to give 70.5 g (87%) of product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([O:13][CH3:14])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+:19]>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([O:13][CH3:14])[C:10]([O-:12])=[O:11])=[CH:6][CH:7]=1.[Na+:19]
Reactant: CO[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CO[C@@H](Cc1ccc(O)cc1)C(=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.8 %

Procedure:
420 ml of the (S)-3-(4-hydroxyphenyl)-2-methoxypropionic acid solution from above are treated with stirring with a solution of 16.32 g of sodium acetate in 136 ml of methanol. After addition of seed crystals, the mixture is stirred for 12 h at room temperature. The precipitated product is filtered off and the filter cake is washed twice with 20 ml each of MIBK. The product is dried in vacuo at 50° C. in the course of 12 h. 30.2 g (34.8%) of sodium (S)-3-(4-hydroxyphenyl)-2-methoxypropionate are obtained. Optical purity ee=95-97%. Chemical purity >99%.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:11])/[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[O:12]=[C:13]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][CH2:15][N:14]1[CH2:31][C:32](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]2[N:11]=[C:32]([CH2:31][N:14]3[CH2:15][CH2:16][CH2:17][C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:13]3=[O:12])[O:1][N:2]=2)=[CH:5][CH:6]=1
Reactant: N/C(=N\O)c1ccc(O)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C1N(Cc2nc(-c3ccc(O)cc3)no2)CCCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C

Procedure:
(Z)—N′,4-Dihydroxybenzimidamide (0.251 g, 1.649 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.510 g, 1.649 mmol; Example 68E) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.474 g, 2.473 mmol) were stirred together in dichloroethane at room temperature for 2 hours, then heated to 85° C. for 16 hours. The reaction was cooled and concentrated. The residue was dissolved in dichloromethane (5 mL) and washed with water (3 mL). The organic layer was concentrated and the residue was loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 35% ethyl acetate/hexanes (Flow=35 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.95-7.78 (m, 2H), 7.40-7.16 (m, 10H), 6.85-6.71 (m, 2H), 5.93 (s, 1H), 4.88 (s, 2H), 3.64 (t, J=6.5, 2H), 2.78-2.66 (m, 2H), 1.99-1.80 (m, 2H); MS (ESI+) m/z 426.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[CH3:25][C:26]1[CH:27]=[C:28]([CH3:51])[C:29]2[O:33][C:32]([NH:34][C:35]3[CH:40]=[CH:39][C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][CH:36]=3)=[N:31][C:30]=2[CH:50]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:32]4[O:33][C:29]5[C:28]([CH3:51])=[CH:27][C:26]([CH3:25])=[CH:50][C:30]=5[N:31]=4)=[CH:40][CH:39]=3)[C:3]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCCC(n2nc(I)c3c(N)ncnc32)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCCN(C(=O)OC(C)(C)C)C5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 37.8 %

Procedure:
The mixture of tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (0.6 g, 0.00135 mol), N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.59 g, 0.00162 mol), tetrakis(triphenylphosphine)palladium (0.078 g, 0.000068 mol) and sodium carbonate (0.36 g, 0.00338 mol) in ethylene glycol dimethyl ether (50 mL) and water (10 mL) was heated at 80° C. for 16 hours under an atmosphere of nitrogen. After cooled the mixture to the room temperature, more N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.24 g, 0.00066 mol), tetrakis(triphenylphosphine)palladium (0.078 g, 0.000068 mol) were added, and the mixture was stirred at 80° C. for 5 hours. The mixture was allowed to cool to ambient temperature, and the solvent was removed under the reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a brownish oil which was purified by flash column chromatography on silica using 5%-25% isopropanol/dichloromethane as a mobile phase, and the product was triturated with N,N-dimethylformamide to give tert-butyl 3-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (0.28 g, 0.00051 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-95% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 11.9 min.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[OH:27][C:28]1([C:32](O)=[O:33])[CH2:31][CH2:30][CH2:29]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:32]([C:28]5([OH:27])[CH2:31][CH2:30][CH2:29]5)=[O:33])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C1(O)CCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)C1(O)CCC1

Procedure:
The title compound, colorless semi-solid (73 mg, 69%), MS (ISP) m/z=427.4 [(M+H)+], was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 1-hydroxy-cyclobutane-carboxylic acid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH3:22][O:23][CH2:24][C:25]1[N:26]=[CH:27][NH:28][CH:29]=1>>[CH3:22][O:23][CH2:24][C:25]1[N:26]=[CH:27][N:28]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH:29]=1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: COCc1c[nH]cn1
Product: COCc1cn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2[N+](=O)[O-])cn1
Yield: 44 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (50 mg, 0.157 mmol) is reacted with 4-methoxymethyl-1H-imidazole according to the GPB affording 36 mg (44%) of a yellow powder. Rt=2.20 min.
Reaction SMILES: [CH:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][NH:11][C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[ClH:22].[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(O)C>[ClH:22].[C:23]([N:11]1[CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7][C:6]2[CH:1]=[N:2][CH:3]=[CH:4][C:5]1=2)(=[O:25])[CH3:24]
Reactant: c1ccc2c(c1)CNc1ccncc1O2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)N1Cc2ccccc2Oc2cnccc21

Procedure:
A solution of 5,6-dihydropyrido[3,4-b][1,4]benzoxazepine (2.8 g) in acetic anhydride (15 ml) was stirred for one hr at ambient temperature. The reaction mixture was poured over ice, basified with sodium carbonate solution and extracted with ether. The organic extract was washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was purified by flash chromatography (silica, ethyl acetate) to give 3 g (88%) of producet, mp 130°-133° C. The product was converted to the hydrochloride salt by treatment with ethereal hydrogen chloride in ethanol. Recrystallization from ethanol-ether gave the analytical sample, mp 225°-227° C. (dec).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:23]([CH3:25])[CH3:24]>>[CH3:24][N:23]([CH3:25])[C:14]([C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)=[O:15]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Product: CN(C)C(=O)C1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Prepare by the method of example 20.8 using 1-tert-butoxycarbonyl-4-phenyl-piperidine-4-carboxylic acid (4.0 mmol) and (CH3)2NH. Purify to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([OH:23])[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].[Cu]I.CN1CCCC1=O>[CH3:22][O:21][C:19]1[CH:18]=[C:17]([CH:16]=[C:15]([O:14][CH3:13])[CH:20]=1)[O:23][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: COc1cc(O)cc(OC)c1
Agent: [Cu]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: COc1cc(OC)cc(Oc2ccc([N+](=O)[O-])cc2C=O)c1
Temperature: 120 °C
Yield: 72 %

Procedure:
2-Chloro-5-nitrobenzaldehyde (5.57 g), 3,5-dimethoxyphenol (4.62 g), potassium carbonate (8.29 g), copper powder (0.2 g), copper (I) iodide (0.6 g) and N-methyl-2-pyrrolidone (60 ml) were mixed together and then stirred under heating at 120° C. for 30 minutes. After cooling the reaction mixture to room temperature, the reaction mixture was filtered. The filtrate was diluted with water and extracted with ethyl acetate. The exacted solution was sequentially washed in water and then an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The residue after filtration and concentration was purified by silica gel column chromatography (elution solvent; hexane:ethyl acetate=8:2 to 6:4), to recover 2-(3,5-dimethoxyphenoxy)-5-nitrobenzaldehyde (6.54 g; yield of 72%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13](=[O:14])[NH:12][CH2:11][CH2:10][N:9]2[CH2:15][C:16]2[CH:17]=[C:18]([C:27]([O:29]CC)=[O:28])[C:19](=[O:26])[N:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[CH:21]3)[CH:5]=[CH:6][CH:7]=1.[C:32]1(I)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CNCCNC.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13](=[O:14])[N:12]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:11][CH2:10][N:9]2[CH2:15][C:16]2[CH:17]=[C:18]([C:27]([OH:29])=[O:28])[C:19](=[O:26])[N:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[CH:21]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(CN2CCNC(=O)C2c2cccc(F)c2)c2ccccn2c1=O
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Product: O=C(O)c1cc(CN2CCN(c3ccccc3)C(=O)C2c2cccc(F)c2)c2ccccn2c1=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 1-{[2-(3-fluorophenyl)-3-oxopiperazin-1-yl]methyl}-4-oxo-4 H-quinolizine-3-carboxylate (0.100 g, 0.236 mmol), phenyliodide (48.2 mg, 0.236 mmol), N,N′-dimethylethylenediamine (4.5 mg, 0.051 mmol), copper (I) iodide (4.5 mg, 0.024 mmol), and 1 N cesium carbonate (0.59 mL, 0.59 mmol) was heated under nitrogen to 100° C. for 18 hours. The reaction was then cooled to room temperature and concentrated in vacuo. The resultant residue was redissolved in 1 mL DMSO, and saturated aqueous LiOH (0.3 mL) was added. After 2 hours, the mixture was acidified with 6 N HCl to pH ˜3, filtered, and purified by reverse phase HPLC to provide the title compound which gave a proton NMR consistent with theory and a mass ion (ES+) of 471.9 for M+H+ [C27H22FN3O4: 471.48]: 1H NMR (400 MHz, DMSO-d6) δ 9.38 (d, J=7.2 Hz, 1H), 8.42 (s, 1H), 7.98-7.92 (m, 2H), 7.61-7.58 (m, 1H), 7.58-7.39 (m, 2H), 7.39-7.29 (m, 5H), 7.19 (d, J=9.8 Hz, 1H), 7.01-6.97 (m, 1H), 3.99 (s, 1H), 3.98-3.96 (m, 2H), 3.86 (d, J=13.5 Hz, 1H), 3.68-3.64 (m, 1H), 3.24-3.20 (m, 1H), 3.00-2.93 (m, 1H).
Reaction SMILES: N.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1.[Na].C(O)(=O)C(O)=O>CCOCC.O.CCO>[CH3:11][Si:10]([CH3:13])([CH3:12])[CH:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1
Reactant: COc1ccc([Si](C)(C)C)cc1
Agent: N
Agent: O=C(O)C(=O)O
Agent: [Na]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: C[Si](C)(C)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
Ammonia (100 mL) was condensed at −78° C. (4-methoxyphenyl)trimethylsilane (18.0 g, 0.1 mol, 1.0 eq) in anhydrous Et2O (110 mL) was added followed by EtOH (80 mL) and sodium (23.0 g, 1.0 mol, 10.0 eq) portionwise at −33° C. Additional EtOH (50 mL) was added and ammonia was allowed to evaporated over 16 h. Then water (250 mL) was added to the residue and the mixture was extracted with Et2O (250 mL×3). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was dissolved in EtOH (20 mL) and H2O (20 mL) and oxalic acid (2.71 g, 0.03 mol, 0.3 eq) was then added. The resulting colorless solution was stirred at room temperature for 2 h. Water (100 mL) was then added and the mixture was extracted with Et2O (100 mL×3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc=10:1) to furnish 4-(trimethylsilyl)cyclohexanone as a light yellow oil (14.0 g, 72% yield). 1H NMR (300 MHz, CDCl3) δ: 2.44-2.39 (m, 2H), 2.33-2.22 (m, 2H), 2.11-2.05 (m, 2H), 1.53-1.47 (m, 2H), 0.96-0.87 (m, 1H), 0.00 (s, 9H).