Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:33]1[CH2:38][CH2:37][CH:36](O)[CH2:35][CH2:34]1.N(C(OCC)=O)=N[C:42](OCC)=[O:43]>C1COCC1>[O:33]1[CH2:38][CH2:37][CH:36]([C:42]([O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=2)=[O:43])[CH2:35][CH2:34]1
Reactant: COC(=O)c1ccc(O)cc1OC
Reactant: OC1CCOCC1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(=O)C2CCOCC2)cc1OC
Temperature: 0 °C

Procedure:
To a stirred solution of methyl 4-hydroxy-2-methoxybenzoate (713 mg, 3.92 mmol) in dry THF (7.5 mL) was added triphenylphosphine (1.42 g, 5.4 mmol) and the solution was cooled to 0° C. A 2.5 mL volume of tetrahydro-4H-pyran-4-ol (466 mL, 4.90 mmol) and diethyl azodicarboxylate (850 μL, 5.4 mmol) in THF was added dropwise via addition funnel over 0.5 h. The reaction was filtered and the solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column packed in 60:40 hexanes:EtOAc and eluted with same. The appropriate fractions were combined and the solvent removed under reduced pressure to afford methyl 4-(4-tetra-hydropyranoyloxy)-2-methoxy-benzoate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:19]([S:21]([C:24]3[CH:29]=[CH:28][C:27](F)=[C:26]([Cl:31])[CH:25]=3)(=[O:23])=[O:22])[CH3:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1>>[C:1]([O:5][C:6](=[O:32])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:19]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([O:40][C:37]4[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=4)=[C:26]([Cl:31])[CH:25]=3)(=[O:23])=[O:22])[CH3:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN([C@@H]1CCCc2c(OCC(=O)OC(C)(C)C)cccc21)S(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: Oc1ccc(Cl)cc1
Product: CN([C@@H]1CCCc2c(OCC(=O)OC(C)(C)C)cccc21)S(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)c(Cl)c1
Yield: 75 %

Procedure:
Starting with {(R)-5-[(3-chloro-4-fluoro-benzenesulfonyl)-methyl-amino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid tert-butyl ester (100 mg, 0.207 mmol) and 4-chlorophenol (315 mg, 2.45 mmol), using the method analogous to the one described for example 2-2, method D, 2nd step, ((R)-5-{[3-chloro-4-(4-chlorophenoxy)-benzenesulfonyl]-methyl-amino}-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (92 mg, 75%) was obtained as a white powder. MS cald. For C29H31Cl2NO6S 591, obsd. 592 (ESI+) [(M+H)+].
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C:12]2[N:13]3[CH:16]([S:17][CH:18]=2)[C:15]([CH:20](OC(=O)C)[C:21]2[N:32]=[C:31]4[N:23]([C:24]5[CH2:25][CH2:26][CH2:27][C:28]=5[C:29]([O:33][CH3:34])=[N:30]4)[CH:22]=2)(Br)[C:14]3=[O:39])=[O:11])=CC=1)([O-])=O.[H][H]>C1COCC1.P([O-])([O-])([O-])=O>[CH3:34][O:33][C:29]1[C:28]2[CH2:27][CH2:26][CH2:25][C:24]=2[N:23]2[C:31](=[N:32][C:21]([CH:20]=[C:15]3[C:14](=[O:39])[N:13]4[CH:16]3[S:17][CH:18]=[C:12]4[C:10]([OH:11])=[O:9])=[CH:22]2)[N:30]=1
Reactant: COc1nc2nc(C(OC(C)=O)C3(Br)C(=O)N4C(C(=O)OCc5ccc([N+](=O)[O-])cc5)=CSC43)cn2c2c1CCC2
Reactant: [H][H]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: COc1nc2nc(C=C3C(=O)N4C(C(=O)O)=CSC34)cn2c2c1CCC2

Procedure:
6-[acetoxy-(5-methoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (966 mg, 1.4 mmol) was suspended in 20 ml THF and 20 ml pH=6.5 aqueous phosphate buffer. The mixture was then subjected to 45 psi hydrogen for two hours. Then it was filtered through a pad of celite and concentrated in vacuo to remove most of the THF. The solution was then cooled to zero degree and basified to pH=8 with 1 N sodium hydroxide. Then it was purified via reverse phase HPLC using 1 liter of water followed by 5%-25% acetonitrile and water. Water was then removed through concentrate in vacuo and 100 mg of product was collected.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[O:7][CH:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>C1C=CC=CC=1>[CH2:1]([N:5]([C:6]1[O:7][CH:8]=[C:9]([CH3:11])[N:10]=1)[C:15]([NH:14][CH2:12][CH3:13])=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCN=C=O
Reactant: CCCCNc1nc(C)co1
Solvent: c1ccccc1
Product: CCCCN(C(=O)NCC)c1nc(C)co1

Procedure:
A solution of 2-butylamino-4-methyloxazole (15.0 g, 0.0972 mol) and ethyl isocyanate (7.6 g, 0.107 mol) in dry benzene was heated under reflux for 2 hours and then evaporated to dryness. The residual oil was dissolved in ether and the solution was washed with 2 N HCl, dried and evaporated. The residue was distilled under vacuum b.p. 128° C./1.0 mm. IR 3275, 1696, 1590 cm-1.
Reaction SMILES: [CH2:1]([N-]CC)C.[Li+].[C:7]([O:11][C:12]1[CH:17]=[C:16]([F:18])[N:15]=[C:14]([F:19])[C:13]=1[F:20])([CH3:10])([CH3:9])[CH3:8].CI>C1COCC1>[C:7]([O:11][C:12]1[C:17]([CH3:1])=[C:16]([F:18])[N:15]=[C:14]([F:19])[C:13]=1[F:20])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)Oc1cc(F)nc(F)c1F
Reactant: CC[N-]CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(F)nc(F)c(F)c1OC(C)(C)C
Reaction time: 0.83 h

Procedure:
A freshly prepared solution of lithium diethylamide (LDA) (58.21 mmol) in 30 mL of THF at -78° C. was added to 10.0 g (48.74 mmol) of 4-t-butoxy-2,3,6-trifluoropyridine in 50 mL of THF at -78° C, and the reaction was stirred for 50 min. To the reaction mixture was added 4.3 mL (69.07 mmol) of methyl iodide, and the mixture was stirred at -78° C. for 1 hour and stirred at ambient temperature for 16 hours. The reaction was quenched with saturated NH4Cl solution, extracted with hexane, and the extracts washed with water, dried over MgSO4 and concentrated to give 4-t-butoxy-2,3,6-trifluoro-5-methylpyridine as a pale yellow oil, which was taken directly to the next step. MS (220) (M+H)+ ; 1H NMR (CDCl3)∂: 1.47 (m, 9H), 2.12 (m, 3H). 19F NMR (CDCl3, CFCl3 as reference)∂: 75.91 (dd apparent, J1 =15.0, J2 =22.1 Hz), 93.17 (dd apparent, J1 =15.0, J2 =22.1 Hz), 156.54 (m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([NH2:25])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:40]=[C:41]1[CH2:44][CH:43]([C:45](O)=[O:46])[CH2:42]1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH:8]([NH:25][C:45]([CH:43]2[CH2:44][C:41](=[CH2:40])[CH2:42]2)=[O:46])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: C=C1CC(C(=O)O)C1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: C=C1CC(C(=O)NC(c2ccc3ccc(-c4ccccc4)nc3c2)c2nccnc2Cl)C1

Procedure:
C-(3-Chloro-pyrazin-2-yl)-C-(2-phenylquinolin-7-yl)-methylamine (690 mg, 1.99 mmol) was dissolved in 6.0 mL of CH2Cl2 followed by the addition of EDC (600 mg, 2.98 mmol) and HOBT (300 mg, 1.99 mmol). 3-Methylenecyclobutanecarboxylic acid (300 mg, 2.59 mmol) was dissolved in 1.0 mL of CH2Cl2 and added to the homogenous reaction mixture. After 24 h the reaction was concentrated in vacuo and dissolved in EtOAc and the organic layer was washed with sat. NaHCO3. The organic layer was washed with H2O and brine. The organic layers where combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography [Jones Flashmaster, 10 g cartridge, eluting with 50% EtOAc: Hex] to obtain the desired product as a white fluffy solid; 1H NMR (400 MHz, CDCl3): δ=2.82-2.92 (m, 2H), 2.99-3.06 (m, 2H), 4.77-4.80 (m, 2H), 6.81 (d, 1H, J=7.8 Hz), 7.45-7.54 (m, 3H), 7.83-7.88 (m, 3H), 8.10 (d, 2H, J=7.1 Hz), 8.22-8.23 (brm, 1H), 8.39 (d, 1H, J=1.79 Hz), 8.59 (d, 1H, J=2.5 Hz); MS (ES+): 440.93 (M+1), 442.91 (M+3).
Reaction SMILES: C(Cl)(=O)C.C1([C@H](OC(=O)[NH:15][C@@H:16]2[C@@H:25]([O:26][CH3:27])[CH2:24][C:23]3[C:18](=[CH:19][C:20]([C:28](=[O:30])[NH2:29])=[CH:21][CH:22]=3)[C:17]2([CH2:33][CH3:34])[CH2:31][CH3:32])C)C=CC=CC=1>C(O)C>[NH2:15][C@H:16]1[C:17]([CH2:31][CH3:32])([CH2:33][CH3:34])[C:18]2[CH:19]=[C:20]([C:28]([NH2:29])=[O:30])[CH:21]=[CH:22][C:23]=2[CH2:24][C@@H:25]1[O:26][CH3:27]
Reactant: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1NC(=O)O[C@H](C)c1ccccc1
Solvent: CCO
Solvent: CC(=O)Cl
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Acetyl chloride (193 mL, 2710 mmol) was added dropwise to ethanol (260 mL, 4500 mmol) at −5° C. over 40 min keeping the internal temperature below 30° C. The resulting solution was added over 5 min, at 10° C., to a mixture of ((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid (R)-1-phenyl-ethyl ester (49.0 g, 115 mmol) and ethanol (200 mL). The reaction mixture was stirred at room temperature overnight, and concentrated to ˜100 mL by rotary evaporation. Ethyl acetate (100 mL) was added and the resulting slurry was stirred at 0° C. for 30 min and filtered. The filter cake was washed with ethyl acetate and dried to yield the hydrochloride salt of the title compound (30 g, >99% purity). The volume of the filtrate was reduced almost to dryness. Isopropyl alcohol (20 mL) was added and the resulting thick slurry was stirred for 30 min and filtered. The filter cake was washed with ethyl acetate (2×20 mL) and dried under vacuum overnight to yield additional product (5.5 g, >97% purity). 1H NMR (DMSO-d6): δ (ppm) 0.49 (t, 3H), 0.63 (t, 3H), 1.62 (q, 2H), 1.89 (m, 1H), 2.09 (m, 1H), 2.60 (dd, 1H), 3.22 (m, 1H), 3.41 (s, 3H), 3.50 (dd, 1H), 3.82 (q, 1H), 7.19 (d, 1H), 7.31 (br, 1H), 7.70 (d, 1H), 7.71 (s, 1H), 7.98 (br, 1H), 8.15 (br, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]5[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=5)[CH:24]=4)[N:19]=[CH:18][N:17]=3)=[CH:11][C:10]=2[CH3:33])=[CH:4][CH:3]=1.Cl.[CH3:35][P:36]1(=O)[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]5[O:30][C:29]([CH2:31][N:39]6[CH2:40][CH2:41][P:36]([CH3:35])[CH2:37][CH2:38]6)=[CH:28][CH:27]=5)[CH:24]=4)[N:19]=[CH:18][N:17]=3)=[CH:11][C:10]=2[CH3:33])=[CH:4][CH:3]=1
Reactant: CP1(=O)CCNCC1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(-c5ccc(C=O)o5)cc34)cc2C)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(-c5ccc(CN6CCP(C)CC6)o5)cc34)cc2C)cn1
Temperature: 25 °C

Procedure:
5-(4-(4-(6-methylpyridin-3-yloxy)-3-methylphenylamino)quinazolin-6-yl)furan-2-carbaldehyde, 4-methyl-1,4-azaphosphinane 4-oxide hydrogen chloride salt and DIPEA were suspended in dichloromethane (20 mL). Sequentially, acetic acid (3 drops) and sodium triacetoxyborohydride (2 equiv.) were added at room temperature. The mixture was stirred at room temperature until the starting material disappeared. The reaction was quenched with 2N NaOH aqueous solution and extracted with dichloromethane. The combined organic layer and extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 20% methanol in dichloromethane to give the desired product as yellow crystalline solid. LCMS ESI(+) m/z: 554 (M+1). 1H NMR (300 MHz, CDCl3) δ 8.71 (s, 1H), 8.47 (s, 1H), 8.18 (d, 1H), 8.12 (s, 1H), 7.77 (d, 1H), 7.69 (m, 1H), 7.60 (d, 1H), 7.28 (m, 2H), 6.99 (m, 2H), 6.51 (d, 1H), 3.83 (s, 2H), 3.73 (m, 2H), 3.24 (m, 2H), 2.95 (m, 2H), 2.51 (s, 3H), 2.27 (s, 3H), 2.04 (m, 2H), 1.58 (m, 3H).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[N:6]1.[NH:26]1[CH2:31][CH2:30][CH:29]([N:32]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[O:35][CH2:34][C:33]2=[O:42])[CH2:28][CH2:27]1.C(N(CC)CC)C>CCO>[OH:1][CH:2]([CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=2)=[N:6]1)[CH2:3][N:26]1[CH2:27][CH2:28][CH:29]([N:32]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[O:35][CH2:34][C:33]2=[O:42])[CH2:30][CH2:31]1
Reactant: FC(F)(F)c1ccc(-c2nn(CC3CO3)cc2-c2cnccn2)cc1
Reactant: O=C1COc2ccccc2N1C1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1COc2ccccc2N1C1CCN(CC(O)Cn2cc(-c3cnccn3)c(-c3ccc(C(F)(F)F)cc3)n2)CC1
Temperature: 80 °C
Yield: 21.2 %

Procedure:
To a solution of 2-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine (76 mg, 0.220 mmol) and 4-piperidin-4-yl-4H-benzo[1,4]oxazin-3-one (61 mg, 0.231 mmol) in EtOH (1.1 mL) was added triethylamine (0.031 mL, 0.220 mmol). The reaction mixture was heated to 80° C. overnight, concentrated, and purified by column chromatography (silica, 5-10% MeOH/CH2Cl2) to afford 4-(1-{2-hydroxy-3-[4-pyrazin-2-yl-3-(4-trifluoromethyl-phenyl)-pyrazol-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one (27 mg, 21%). TLC (silica, 5% MeOH/CH2Cl2): Rf=0.09. MS (electrospray): m/z 579.2 (579.2, calculated for C30H29F3N6O3, M++H). 1H NMR (400 MHz, CDCl3): 8.53 (s, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H), 7.16 (d, J=5.4 Hz, 1H), 7.00-7.03 (m, 3H), 4.49 (s, 2H), 4.39 (d, J=10.8 Hz, 1H), 3.13 (d, J=11.9 Hz, 1H), 2.96 (d, J=11.9 Hz, 1H), 2.59-2.80 (m, 2H), 2.40-2.55 (m, 3H), 2.17 (t, J=11.9 Hz, 1H), 1.77 (d, J=11.9 Hz, 2H).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][N:5]([CH2:12][CH2:13][C:14](=O)[CH3:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[CH3:4][N:5]([CH2:12][CH2:13][C:14](=[N:2][OH:3])[CH3:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)CCN(C)c1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(CCN(C)c1ccccc1)=NO
Reaction time: 72 h

Procedure:
Add hydroxylamine hydrochloride (4.9 g=70 mmol) in 20 ml water to a solution of 4-(N-methylanilino)-2-butanone (12.4 g=70 mmol) and sodium carbonate (8.6 g=80 mmol) in 60 ml 50% ethanol. Stir for three days, concentrate and extract with ethyl acetate. Dry, concentrate and recrystallize from ether-hexane to obtain product having a melting point 46°-49° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:25][CH3:26].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:33][CH:34](OS([C:40]1[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=1)(=O)=O)[CH3:35].C[N:48](C=O)C>>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([O:1][CH2:35][CH2:34][Cl:33])=[C:3]([O:25][CH3:26])[CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:22])([CH3:23])[CH3:24].[CH3:26][O:25][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:42][CH2:41][CH:40]1[CH2:46][CH2:45][CH2:43][CH2:44][NH:48]1)[N:9]=[CH:8][N:7]=[C:6]2[N:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)OC(C)Cl)cc1
Reactant: COc1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1OCCCl
Product: COc1cc2c(N3CCNCC3)ncnc2cc1OCCC1CCCCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To the DMF solution (10 mL) of tert-butyl 4-(7-hydroxy-6-methoxyquinazolin-4-yl)piperazinecarboxylate (1.88 g, 5 mmol), Cs2CO3 (3.3 g, 10 mmol) added 1-chloroethyl-tosylate (1.8 mL, 10 mmol). The mixture was stirred overnight at room temperature. The solvent was evaporated and the crude residue was purified by RP-HPLC to afford the intermediate tert-butyl-4-[6-methoxy-7-(2-chloroethoxy)quinazolin-4-yl]piperazinecarboxylate as the desired product (850 mg, 40%). MS(ES) 423 (M+H)
Reaction SMILES: [CH2:1]([N:3]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:4]1[C:5]([O:7]C(C)(C)C)=[O:6])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:3]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:4]1[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCN1C(=O)CC[C@H]1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 132.9 %

Procedure:
1,1-Dimethylethyl 1-ethyl-5-oxoprolinate (0.933 g) was dissolved in dichloromethane (˜5 ml) and treated with trifluoroacetic acid (1 ml). The mixture was stirred for 3 hrs at room temperature and then evaporated. The residue was taken up in toluene and evaporated once more. This gave partially pure (>95%) 1-ethyl-5-oxo-proline as an orange/yellow oil (0.914 g) which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9](=[O:18])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.C(O)=O>O1CCOCC1.[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[CH:3][CH:2]=1
Reactant: O=C(C=Cc1ccncc1)C=Cc1ccncc1
Agent: [Pd]
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(CCc1ccncc1)CCc1ccncc1
Temperature: 25 °C

Procedure:
To a slurry of Compound 1 (21.3 g, 67.4 mmol) in 1,4-dioxane (40 mL) was added triethylamine (48.1 mL, 0.346 mol), formic acid (6.54 mL, 0.145 mol) and 10% palladium on carbon (0.7 g) and the resulting mixture heated to reflux. After stirring at reflux for 1 hr, the reaction was cooled to room temperature filtered and concentrated in vacuo. The resulting residue was chromatographed over silica gel (elution with 5% methanol/methylene chloride) to provide the desired material.
Reaction SMILES: Cl.[CH2:2]1[C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]2)[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:4][C:3]1=O.[C-:16]#[N:17].[Na+].[NH3:19]>O.C(OCC)C>[NH2:19][C:3]1([C:16]#[N:17])[CH2:4][C:5]2[C:14]3[C:9]([CH:8]=[CH:7][CH:6]=2)=[CH:10][CH:11]=[CH:12][C:13]=3[CH2:2]1
Reactant: O=C1Cc2cccc3cccc(c23)C1
Reactant: [C-]#N
Reactant: N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: N#CC1(N)Cc2cccc3cccc(c23)C1

Procedure:
1 ml of concentrated hydrochloric acid is added dropwise to a vigorously stirred mixture of 13.7 mmol of 1,3-dihydro-2-phenalenone and 40 mmol of sodium cyanide in 60 ml of water and 80 ml of ethyl ether. After one hour of stirring at 20C., and when settling has taken place, the organic phase is separated, washed with water, dried and evaporated. The residue obtained is treated with 20 ml of a methanolic solution of ammonia (3.5M) with stirring for 5 hours at 20C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=1[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:19]1CCOCC1.C(OC(Cl)=O)C(C)C.[OH-].[NH4+]>O1CCCC1.O>[C:12]([C:11]1[CH:15]=[CH:16][C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:9]([CH3:17])[CH:10]=1)(=[O:13])[NH2:19]
Reactant: Cc1cc(C(=O)O)ccc1C(=O)OC(C)(C)C
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(N)=O)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-tert-butoxycarbonyl-3-methyl-benzoic acid (40 g) was suspended in tetrahydrofuran (160 mL). This solution was cooled to −30 C then N-methyl morpholine (18.7 mL) followed by isobutylchloroformate (24.2 mL) were added. A white precipitate appeared. The solution was stirred for 8 hours then a solution of ammonium hydroxide (100 mL) was added. The reaction mixture was slowly allowed to warm to room temperature over 48 hours. Then water was added and the mixture was extracted with ethyl acetate. The organic extract was washed with water, dried over sodium sulfate and concentrated to give a solid which was further triturated with a mixture of dichloromethane/ethyl acetate, filtered, to give tert-butyl 4-carbamoyl-2-methyl-benzoate (29.9 g) as a white solid. 1H-NMR (CDCl3, 400 MHz): 7.90 (d, 1 H), 7.72 (s, 1 H), 7.65 (d, 1 H), 2.63 (s, 3 H), 1.62 (s, 9 H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][CH:18]=[O:19])=[N:7][CH:8]=1)[CH3:2].C[I:21].[CH:22](NC1C=CC=CC=1CCC1C=CC=CN=1)=O>CC(C)=O>[I-:21].[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][CH:18]=[O:19])=[N+:7]([CH3:22])[CH:8]=1)[CH3:2]
Reactant: O=CNc1ccccc1CCc1ccccn1
Reactant: CI
Reactant: CCc1ccc(CCc2ccccc2NC=O)nc1
Solvent: CC(C)=O
Product: CCc1ccc(CCc2ccccc2NC=O)[n+](C)c1
Product: [I-]
Yield: 74 %

Procedure:
Reaction of 5-ethyl-2-(o-formamidophenethyl)pyridine with methyl iodide in acetone according to the procedure of Example 2 (c) for 2-(o-formamidophenethyl)pyridine provides a 74% yield of analytically pure 5-ethyl-2-(o-formamidophenethyl)-1-methylpyridinium iodide having a melting point of 134.5°-136.5° C.
Reaction SMILES: [Mg].[F:2][C:3]([F:12])([F:11])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[CH2:13]([N:20]1[CH2:28][C:27]2([C:29]([O:31][CH3:32])=[O:30])[CH:22]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>C(OCC)C>[CH2:13]([N:20]1[CH2:28][C:27]2([C:29]([O:31][CH3:32])=[O:30])[CH:22]([C:23]([OH:39])([C:7]3[CH:8]=[CH:9][C:4]([C:3]([F:12])([F:11])[F:2])=[CH:5][CH:6]=3)[CH2:24][CH2:25][CH:26]2[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2c1ccccc1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(O)(c1ccc(C(F)(F)F)cc1)CCC2c1ccccc1
Temperature: 10 °C
Yield: 66.2 %

Procedure:
0.8 g of magnesium turnings was added to a solution of 7.2 g of 4-(trifluoromethyl)bromobenzene in 40 cm3 of dry diethyl ether. The reaction mixture was spontaneously brought to reflux for ten minutes and was then heated at reflux for twenty minutes. The reaction mixture was subsequently cooled and a solution of 5.6 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate in 40 cm3 of dry diethyl ether was added over fifteen minutes at a temperature in the region of 10° C. The reaction mixture was stirred for ten minutes at a temperature in the region of 10° C. and then poured into 150 cm3 of a saturated aqueous ammonium chloride solution. The aqueous phase was separated by settling and extracted with three times 75 cm3 of diethyl ether. The organic phases were combined, washed successively with three times 75 cm3 of distilled water, dried over magnesium sulphate in the presence of 3S charcoal and concentrated under reduced pressure. After crystallization from 25 cm3 of pentane, 5.2 g of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-[4-(trifluoromethyl)phenyl]-4-phenyloctahydroisoindole-3a-carboxylate were obtained in the form of a beige solid, the characteristic of which was as follows: