Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([N:40]1[C@@H:44]([CH:45]([CH3:47])[CH3:46])[CH2:43][O:42][C:41]1=[O:48])[C@H:3]([CH2:15][C:16]1[N:17]=[CH:18][N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1)[CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].BrCC(OCC1C=CC=CC=1)=O>C1COCC1>[O:1]=[C:2]([N:40]1[C@@H:44]([CH:45]([CH3:46])[CH3:47])[CH2:43][O:42][C:41]1=[O:48])[CH:3]([CH2:15][C:16]1[N:17]=[CH:18][N:19]([C:21]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:20]=1)[CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC(=O)OCc1ccccc1)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(CBr)OCc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1C(=O)C(CC(=O)OCc1ccccc1)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
3-{1,4-Dioxo-4-(phenylmethoxy)-2(R)-{[1-triphenylmethyl-1H-imidazol-4-yl]methyl}butyl}-4(S)-(1-methylethyl)-2-oxazolidinone: A 1.0M solution of sodium bis(trimethylsilyl)amide (18.0 mL, 18.0 mmol, Aldrich Chemical Co., Inc., Milwaukee, Wis. USA) was added dropwise (18 min) to a cold (-78° ) solution of the product of the preceding section (8.06 g, 16.3 mmol) in THF (65 mL). After 40 min at -78° , a solution of benzyl 2-bromoacetate (7.48 g, 32.7 mmol) in THF (2 mL) was added dropwise to the solution. The reaction mixture was stirred at -78° for 1.5 h, quenched with an aqueous saturated solution of NH4Cl, allowed to warm to room temperature and then poured into a mixture of H2O (500 mL) and aqueous saturated solution of NH4Cl (100 mL). The resulting mixture was extracted with EtOAc. The EtOAc extract was washed with a saturated aqueous solution of NaHCO3 and then brine, dried (MgSO4) and concentrated under reduced pressure to give 3-{1,4-dioxo-4-(phenylmethoxy)-2{[1-(triphenylmethyl)-1H-imidazol-4-yl]methyl}butyl}-4(S)-(1-methylethyl)-2-oxazolidinone as a mixture of 2(R)- and 2(S)-epimers in a 8 to 1 ratio by weight. Separation of the epimers by flash chromatography (SiO2, eluent: hexane-EtOAc, 1:2) yielded the desired 2(R)-epimer (Rf=0.25, eluent: hexane-EtOAc,1:2). The 1H NMR (CDCl3) of the 2(R)-epimer showed δ7.34-7.28 (m,15H), 7.13-7.08 (m,6H) 6.59 (d, J=1.3 Hz, 1H), 5.06 (s,2H), 4.55-4.45 (m, 1H), 4.38 (td, J=3.9 Hz, 5.4 Hz, 1H), 4.15-4.10 (m,2H), 2.97 (dd, J=10.3 Hz, 16.9 Hz, 1H), 2.88 (dd J=6.3 Hz, 14.3 Hz, 1H), 2.73 (dd, J=7.0 Hz, 14.3 Hz 1H), 2.59 (dd, J=4.4 Hz, 16.9 Hz, 1H), 2.32 (hept d, J=3.9 Hz, 7.0 Hz, 1H), 0.87 (d, J=7.1 Hz, 3H) 0.85 (d, J=6.8 Hz, 3H).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[N:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[C:10]([C:18]#[N:19])[C:11](=[O:17])[NH:12]2.[OH-:20].[NH4+]>C(O)(=O)C>[CH3:6][C:7]1[N:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[C:10]([C:18]([NH2:19])=[O:20])[C:11](=[O:17])[NH:12]2
Reactant: Cc1nccc2[nH]c(=O)c(C#N)cc12
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1nccc2[nH]c(=O)c(C(N)=O)cc12
Reaction time: 8 h

Procedure:
To 200 ml of concentrated sulfuric acid chilled in an ice bath was added with stirring 37 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile and the reaction mixture was allowed to stand at room temperature overnight. The reaction mixture was then poured on ice (1 liter beaker, half filled), the resulting mixture cooled in an ice bath and then neutralized by adding aqueous ammonium hydroxide, followed by addition of acetic acid to make the mixture slightly acidic. The separated solid was collected, washed with water, air-dried, then recrystallized from a large volume of dimethylformamide (1.2 1.) and dried at 95° C. to yield 28.4 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxamide, m.p.>320° C.
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1(CN)CCCCC1.[O:17]=[C:18]1[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH2:38][C:39]1[CH:47]=[CH:46][CH:45]=[CH:44][C:40]=1[C:41](O)=[O:42].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH2:1]([NH:8][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=1[CH2:38][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:18]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: CCCCCCCNC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using heptylamine to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-heptyl-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (75%) as a colorless solid: mp 196-198° C.; 1H NMR (300 MHz, DMSO-d6) δ8.53 (t, J=5.5 Hz, 1H), 7.46-7.27 (m, 3H), 7.23-7.06 (m, 3H), 6.99 (dd, J=7.5, 7.5 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 6.51 (s, 1H), 6.40 (s, 1H), 5.10=-4.92 (m, 2H), 4.85 (d, J=9.4 Hz, 1H), 4.71 (d, J=9.4 Hz, 1H), 4.55-4.39 (m, 2H), 3.23 (q, J=6.8 Hz, 2H), 3.03-2.84 (m, 2H), 1.59-1.44 (m, 2H), 1.38-1.14 (m, 8H), 0.81 (t, J=6.6 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ177.8, 168.7, 161.6, 161.2, 142.8, 136.9, 134.1, 132.6, 130.4, 129.1, 128.1, 127.8, 126.8, 124.1, 123.6, 120.9, 120.3, 119.6, 109.6, 92.9, 80.4, 72.6, 57.4, 41.3, 31.7, 29.4, 28.9, 28.8, 26.9, 22.5, 14.4; MS (ES+) m/z 511.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C@H:9]1[C@H:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1.Br[CH2:32][C:33]#[N:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:28][C:25]([F:26])([F:27])[C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:29])[F:30])[CH:24]=1)[CH2:6][O:7][CH2:8][C@H:9]1[C@H:14]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH2:13][CH2:12][N:11]([CH2:32][C:33]#[N:34])[CH2:10]1
Reactant: N#CCBr
Reactant: Fc1ccc([C@@H]2CCNC[C@H]2COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCN1CC[C@@H](c2ccc(F)cc2)[C@H](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A mixture of (−)-(3S,4R)-3-(3,5-bis-trifluoromethyl-benzyloxymethyl)-4-(4-fluoro-phenyl)-piperidine (150 mg, 0.345 mmol), bromoacetonitrile (45 mg, 0.37 mmol) and potassium carbonate (95 mg, 0.69 mmol) in 4 ml of acetonitrile was stirred at room temperature over night. Quenching with water was followed by extraction with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 163 mg (99.7%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:10][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([O:8][CH3:9])=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(Cl)ccn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(Br)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.6 %

Procedure:
5.76 g (40.1 mmol) of 4-chloro-2-methoxypyridine was dissolved in 20 ml of dimethylformamide, and a dimethylformamide (20 ml) solution of 8.01 g of N-bromosuccinimide (98%, 44.1 mmol) was dropwise added over a period of 30 minutes. After stirring at room temperature for 2 days, an unreacted material was confirmed, and thus 2.85 g of N-bromosuccinimide (98%, 16 mmol) was further added, followed by stirring at room temperature further for 3 days. The reaction mixture was poured into 250 ml of water, followed by extraction with ethyl ether (100 ml each) three times. The organic layer was washed with water (100 ml), a sodium thiosulfate aqueous solution (100 ml) and then a saturated sodium chloride solution (100 ml), dried over magnesium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography to obtain 7.10 g (yield: 30%) of 5-bromo-4-chloro-2-methoxypyridine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[F:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH2:3][CH2:2][N:27]1[CH2:28][CH2:29][CH:24]([C:20]2[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=2)[CH2:25][CH2:26]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Fc1cccc(OCCCCl)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCOc3cccc(F)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-(3-chloropropoxy)-3-fluorobenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 399.2 (M+H)+.
Reaction SMILES: O1CCOCC1.[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:15]1([NH:21]O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:15]1([NH:21][CH2:7]/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ONc1ccccc1
Reactant: C=CCCCCCC
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCCCC/C=C/CNc1ccccc1
Yield: 95 %

Procedure:
A stirred mixture containing dioxane (12mL), 3 mL of 1-octene, 1g of 4A Molecular Sieves, and 0.051 g (0.11 mmol) of (2,6-diPicolinato)MoO2 (hexamethyl phosphoramide)is heated at reflux (ca. 100° C.) under a nitrogen atomosphere while a toluene solution (50 mL)of N-phenyl hydroxylamine (1.26 g, 11.6 mmol) is added dropwise over a 24 hr period. After heating an additional 6-12 hr, the mixture was allowed to cool and the volatiles were removed by evaporation at reduced pressure and the residue chromatographed over silica gel. Elution with pentane afforded phenyl trans-2-octenyl amine (>95% one isomer by NMR, GC/MS) in 20-30 % yield based on the hydroxylamine. Later fractions contained aniline, azobenzene and azoxybenzene.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]1(=O)[O:12][C:10](=[O:11])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12>>[OH:4][CH2:3][C:2]([N:1]1[C:10](=[O:11])[C:9]2[C:8](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]1=[O:12])([CH3:6])[CH3:5]
Reactant: CC(C)(N)CO
Reactant: O=C1OC(=O)c2ccccc21
Product: CC(C)(CO)N1C(=O)c2ccccc2C1=O
Yield: 32.9 %

Procedure:
2-Amino-2-methyl-1-propanol (4.46 g, 50 mmol) and phthalic anhydride (7.41 g, 50 mmol) were heated at 170° C. for 30 minutes. Icewater was added to the cooled reaction mixture and then the mixture was extracted three times with DCM. Organic phase was dried over Na2SO4, filtered and evaporated to dryness. Crude product was purified by CombiFlash (column: silica, eluent: 0-10% MeOH in DCM) to obtain 3.611 g (33%) of the title compound. LC-MS: M+1=220.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH:24]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CCO>[CH:24]1([CH2:30][NH:31][C:2]2[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:17])([F:16])[F:18])[CH2:9][C:10]([F:12])([F:13])[F:11])=[O:7])=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Reactant: NCC1CCCCC1
Solvent: CCO
Product: O=C(c1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
4-Fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (107 mg, 0.307 mmol) and cyclohexylmethylamine (0.050 mL, 0.368 mmol) were stirred in 3 mL of EtOH containing TEA (0.065 mL, 0.460 mmol) at 75° C. for 3 h. The mixture was concentrated. The residue was re-dissolved in EtOAc and washed with 5% KHSO4 solution, saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The title product was purified by flash chromatography using 9:1/hexanes:EtOAc. Yield: 113 mg (83%). 1H NMR (400 MHz, CDCl3) δ 1.05 (m, 2H), 1.24 (m, 4H), 1.69 (m, 2H), 1.75 (m, 2H), 1.83 (m, 1H), 3.17 (t, J=6.64 Hz, 2H), 4.23 (q, J=8.53 Hz, 4H), 6.91 (d, J=8.98 Hz, 1H), 7.51 (d, J=8.89 Hz, 1H), 8.28 (s, 1H), 8.39 (s, 1H).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[C:4]([CH3:11])[CH:3]=1.C([Li])CCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C>C1COCC1.CCCCCC>[CH3:8][C:7]1[CH:6]=[C:5]([O:9][CH3:10])[C:4]([CH3:11])=[CH:3][C:2]=1[B:17]([OH:22])[OH:18]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(C)c(Br)cc1C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C)c(B(O)O)cc1C
Temperature: -62.5 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A solution of 4-bromo-2,5-dimethylanisole (5, 172 g, 0.8 mol) in anhydrous THF (800 ml) was treated dropwise with a solution of n-butyl lithium (2.5 M solution in hexane, 352 mL, 0.88 mol, 1.1 equiv) in hexane at −60-−65° C. under N2. The resulting reaction mixture was stired at −60-65° C. for an additional 30 min before being treated dropwise with B(OiPr)3 (165.44 g, 203.2 mL, 0.88 mol, 1.1 equiv) at −60 to −65° C. The reaction mixture was stirred at −60 to −65° C. for an additional 1 h. The reaction was then quenched with saturated NH4Cl aqueous solution (750 mL) at −60 to −65° C., and the resulting mixture was gradually warmed to 0° C. for 1 h and subsequently to room temperature. The two layers were separated, and the aqueous layer was extracted with EtOAc/THF (1:1, 400 mL). The combined organic extracts were then washed with H2O (400 mL), and saturated NaCl solution (400 mL), dried over MgSO4, and concentrated in vacuo. The residual white solids were then suspended in heptane (500 mL), and the resulting suspension was stirred at room temperature for 30 min. The solids were collected by filtration and washed with heptane (2×200 mL), dried in vacuo at 40-45° C. for overnight. The crude product (6, 116.7 g, 144.0 g theoretical, 81%) was obtained as a white powder.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH2:2][OH:3].N1C=CN=C1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16]>CCOCC.CCCCCC>[C:15]([Si:19]([CH3:22])([CH3:21])[O:3][CH2:2][C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCCCOC(=O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCOC(=O)CO[Si](C)(C)C(C)(C)C

Procedure:
n-Butyl glycolate (231 g; 1.75 mol) and imidazole (345.1 g; 5.07 mol) are placed together at 0° C. The suspension obtained was treated portionwise with t-butyldimethylchlorosilane (303 g; 2.01 mol) during 1.5 hours. After 20 hours at room temperature the reaction mixture was diluted with ether/n-hexane 1:1 (1 l) and suction filtered. The crystals were rinsed thoroughly with ether/n-hexane hexane 1:1 (200 ml). The filtrate was washed in succession with water (2×700 ml) and saturated aqueous sodium chloride solution (500 ml), dried over magnesium sulphate and concentrated. The oil obtained was distilled over a Vigreux column (7.5 cm). Yield: 405 g (94%) as a colourless oil (b.p. 78° C./0.98 mmHg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])O[C:10]=1[C:17]([NH:19][CH:20]1[CH2:23][CH2:22][CH2:21]1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][NH2:25]>CO>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:25]([CH3:24])[C:10]=1[C:17]([NH:19][CH:20]1[CH2:23][CH2:22][CH2:21]1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)NC2CCC2)o1
Reactant: CN
Solvent: CO
Product: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)NC2CCC2)n1C
Temperature: 72.5 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a solution of the compound from example 4 (2.616 g, 8.35 mmol, 1.0 equiv) in methanol (10 ml) was quickly added methylamine (2M in methanol, 20 ml, 40 mmol, 4.79 equiv). The sealed tube was stirred overnight at 70-75° C. The resulting brown solution was evaporated to dryness and purified by chromatography (EtOAc, then 1:4 MeOH/EtOAc) provided the titled compound (1.70 g, 62.24%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:3]=1
Reactant: Cc1ccc(Br)cc1
Reactant: COc1ccc2c(Cl)ccnc2c1
Product: COc1ccc2c(Cl)cc(-c3ccc(C)cc3)nc2c1

Procedure:
The title compound, m. p. 129-131° C., MS: m/e=283 (M+), was prepared from 4-chloro-7-methoxy-quinoline and 4-bromotoluene.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:30]C)=[C:15]3[C:20]=2[C:19]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[N:18][C:17]([C:27]([OH:29])=[O:28])=[CH:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:30])=[C:15]3[C:20]=2[C:19]([CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[N:18][C:17]([C:27]([OH:29])=[O:28])=[CH:16]3)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2ccc(C(C)(C)C)cc2)c2c(CC3CCCC3)nc(C(=O)O)cc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(-c2ccc(O)c3cc(C(=O)O)nc(CC4CCCC4)c23)cc1
Temperature: 120 °C
Yield: 88.1 %

Procedure:
To a stirring solution of 8-(4-tert-butyl-phenyl)-1-cyclopentylmethyl-5-methoxy-isoquinoline-3-carboxylic acid (190 mg, 0.45 mmol) in 3 ml of DMF was added sodium ethane thiolate (383 mg, 4.5 mmol) and resulting mixture was heated at 120° C. for 4 h. Ethyl acetate was added (10 ml) to mixture and washed with 1 N HCl, water and brine and dried over Na2SO4. Evaporation of the solvent under vacuo gave 160 mg of the title compound as a thick liquid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[S:12][CH:11]=[C:10]([CH3:13])[N:6]2[C:7](=[O:9])[CH:8]=1.ClCC1N(C)N=C(C)N=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:35][CH2:36][C:37]2([CH:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)[O:42][C:41](=[O:43])[CH2:40][C:39](=[O:44])[CH2:38]2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH:32]1[CH2:34][CH2:33]1>>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:35][CH2:36][C:37]2([CH:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)[O:42][C:41](=[O:43])[C:40]([CH2:2][C:3]3[N:4]=[C:5]4[S:12][CH:11]=[C:10]([CH3:13])[N:6]4[C:7](=[O:9])[CH:8]=3)=[C:39]([OH:44])[CH2:38]2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH:32]1[CH2:34][CH2:33]1
Reactant: O=C1CC(=O)OC(CCc2ccc(OCC3CC3)c(Cl)c2)(C2CCCC2)C1
Reactant: Cc1csc2nc(CCl)cc(=O)n12
Agent: Cc1nc(CCl)n(C)n1
Product: Cc1csc2nc(CC3=C(O)CC(CCc4ccc(OCC5CC5)c(Cl)c4)(C4CCCC4)OC3=O)cc(=O)n12
Yield: 1 %

Procedure:
The title compound was prepared as described in Example B(53), using 7-(chloromethyl)-3-methyl-5H-(1,3]thiazolo[3,2-a]pyrimidin-5-one (prepared according to a reported procedure: Doria, G.; Passarotti, C.; Sala, R.; Magrini, R.; Sberze, P.; Tibolla, M.; Cesarani, R.; Arcari, G.; Castello, R.; Toti, D. Farmaco Ed. Sci. 1985, 40, 885) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-{-[3-chloro-4-(cyclopropylmethoxy)phenyl]ethyl}-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione (from Step 4, below) in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 1%.
Reaction SMILES: FC1C=CC(CC(N)=O)=CC=1.C(Cl)(=O)C(Cl)=O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:28][C:29](=O)[O:30]C)=[O:27])=[CH:21][CH:20]=1>ClC(Cl)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][C:26]([N:28]=[C:29]=[O:30])=[O:27])=[CH:23][CH:24]=1
Reactant: COC(=O)NC(=O)Cc1ccc(F)cc1
Agent: NC(=O)Cc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(Cl)Cl
Product: O=C=NC(=O)Cc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution/suspension of 4-fluorophenylacetamide (77 mg, 0.50 mmol, see generally, J. Med. Chem. 2003, 46, 4333-4341, the disclosure of which is herein incorporated by referene) in dichloroethane (2 mL) was added oxalyl chloride (0.175 mL, 2.00 mmol). The reaction was heated at 80° C. for 24 h and then 70° C. for two days. By this time, most of the solids had dissolved and the reaction was yellow. LC/MS analysis found a peak with a molecular weight of 211 corresponding to methyl 2-(4-fluorophenyl)acetylcarbamate, resulting from quenching of the isocyanate with methanol. The reaction was concentrated in vacuo to give a yellow slurry. The slurry was redissolved in dichloroethane (2 mL) and again concentrated in vacuo. The resulting residue was redissolved again in dichloroethane (2 mL) to give a 0.25 M solution of 2-(4-fluorophenyl)acetyl isocyanate in dichloroethane, which was used directly in subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]#[CH:24])=[C:10]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].S(=O)(=O)(O)[OH:31]>O.O1CCOCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]([CH3:24])=[O:31])=[C:10]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: O=S(=O)(O)O
Reactant: C#CCOCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(COCC(C)=O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl

Procedure:
A solution of 1-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}-2-propyne (1.06 g) [see Preparation 8], mercuric sulphate (0.10 g) and concentrated sulphuric acid (0.2 ml) in a mixture of water (20 ml) and dioxane (20 ml) was heated at 60° for 2 hours and then evaporated. The residue was partitioned between ether and water and the organic layer washed with saturated aqueous sodium chloride solution and water, dried over sodium sulphate and evaporated to give the title compound (0.93 g), m.p. 119°-121°. This material was confirmed spectroscopically to be identical to the product of Preparation 6.