Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([NH2:8])=[S:7].Br[CH:10]([CH3:18])[C:11](=O)[CH2:12][C:13](OC)=[O:14]>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[S:7][C:10]([CH3:18])=[C:11]([CH2:12][CH2:13][OH:14])[N:8]=1
Reactant: COCCNC(N)=S
Reactant: COC(=O)CC(=O)C(C)Br
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COCCNc1nc(CCO)c(C)s1
Yield: 66.2 %

Procedure:
The title compound (800 mg) was prepared from 750 mg (5.59 mmol) of 2-methoxyethyl thiourea and 1.17 g (5.59 mmol) of methyl 4-bromo-3-oxo-pentanoate according to the method of Intermediate 60, followed by the procedure outlined for the preparation of Intermediate 43 nd purification via silica gel flash column chromatography using chloroform/MeOH 9/1 as eluent: 1H NMR (CDCl3, 400 MHz) δ 3.82 (t, 2H, J=5.5), 3.58 (t, 2H, J=6.9), 3.41 (m, 2H), 3.36 (s, 3H), 2.65 (t, 2H, J=6.9), 2.19 (s, 3H).
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:36][NH:37][O:38][CH3:39]>CN(C)C=O>[CH3:36][N:37]([C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:13])[O:38][CH3:39]
Reactant: O=C(O)c1cccc2ccccc12
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CON(C)C(=O)c1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 7.5 %

Procedure:
3.44 g(20 mmol) of 1-naphthoic acid was dissolved in 20 ml of dimethylformamide, and then 4.6 g(24 mmol) of EDC, 2.02 g(20 mmol) of triethylamine and 3.24 g(24 mmol) of HOBT were added thereto. The resulting mixture was stirred at 0° C. for 5 minutes. To the reaction solution was added 1.85 g(20 mmol) of N,O-dimethylhydroxylamine hydrochloride, which was then stirred at room temperature for 5 hours. The solvent was removed under reduced pressure and then 100 ml of saturated potassium carbonate solution was added to the residue. The resulting solution was extracted with ethyl acetate. Then, the organic layer was washed sequencially with 1N aqueous hydrochloric acid solution, aqueous sodium chloride solution and water, dried over anhydrous sodium sulfate and concentrated to give 3.04 g(1.50 mmol) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:36]1([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:44]3[CH2:45][CH2:46][CH:41]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:42][CH2:43]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: C1CCN(C2CCNCC2)C1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC2)CC1
Product: Cl

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 4-pyrrolidin-1-yl-piperidine in an analogous manner as described in example 25. LR-MS: 647.4 [(M+H)+]
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][NH:16][C:17](=[O:29])[N:18]3[C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])=[C:13]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[CH:12]=2)[CH2:6][CH:5]1[C:37]([OH:39])=[O:38])C=C.[CH3:40]O.Cl.CN(C)[CH2:45][CH2:46][CH2:47]N=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:13]1[CH:12]=[C:11]([CH2:10][N:7]2[CH2:8][CH2:9][NH:4][CH:5]([C:37]([O:39][C:46]([CH3:47])([CH3:40])[CH3:45])=[O:38])[CH2:6]2)[CH:20]=[C:19]2[C:14]=1[CH2:15][NH:16][C:17](=[O:29])[N:18]2[C:21]1[C:22]([Cl:28])=[CH:23][CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: CO
Reactant: C=CCN1CCN(Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CC1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CN(Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CCN1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 1-allyl-4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methyl}piperazine-2-carboxylic acid (EXAMPLE AAA14, 95 mg, 0.16 mmol), methanol (0.02 mL, 0.49 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (47 mg, 0.24 mmol) and 4-(dimethylamino)-pyridine (50 mg, 0.41 mmol) in methylene chloride (1 mL) was stirred at rt for 20 h. Removal of the solvent and subsequent purification by preparative thin layer chromatography using 5% of 2N ammonium in methanol/methylene chloride as eluent provided the title compound as a white solid. 1H NMR (CDCl3, 500 MHz): δ 2.31 (brs, 1H), 2.42 (m, 1H), 2.47 (m, 1H), 2.56 (m, 1H), 2.64 (m, 1H), 3.02 brs, 2H), 3.20 (brs, 1H), 3.32 (m, 1H), 3.42 (m, 2H), 3.65 (s, 3H), 4.25 (dd, 1H, J1=14.2 Hz, J2=6.2 Hz), 4.43 (dd, 1H, J1=14.4 Hz, J2=8.0 Hz), 5.06 (s, 1H), 5.16 (s, 2H), 5.84 (m, 1H), 6.11 (d, 1H, J=13.3 Hz), 6.83 (d, 1H, J=3.2 Hz), 7.30-7.60 (m, 7H). MS (API-ES+): 601 (M+H).
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:6]=1)([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:27])C=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH:1]([S:4]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:6]=1)=[O:27])([CH3:3])[CH3:2]
Reactant: CC(C)Sc1cccc(-c2ccc(Cl)cc2Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)S(=O)c1cccc(-c2ccc(Cl)cc2Cl)c1
Yield: 84.5 %

Procedure:
To 1.0 g (3.4 mmol) of [3-(2,4-dichlorophenyl)phenyl] isopropyl sulfide in 50 ml of chloroform, 0.7 g (4.1 mmol) of m-chloroperbenzoic acid was added at 0° C. with stirring, and the reaction mixture was stirred for 2 hours. The reaction mixture was stirred at room temperature for another 12 hours, and 5% aqueous sodium bicarbonate was added for separation. The chloroform layer was washed with 5% aqueous sodium sulfite and water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 0.9 g of [3-(2,4-dichlorophenyl)phenyl] isopropyl sulfoxide (yield 85.0%) as a colorless dough (nD20 1.6169).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl.Cl[CH2:13][C:14]1[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:17]([CH3:26])=[CH:16][N:15]=1.[OH-].[Na+]>C(O)C>[CH3:26][C:17]1[C:18]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:19][C:14]([CH2:13][S:1][C:2]2[NH:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[N:15][CH:16]=1
Reactant: Cc1cnc(CCl)cc1N1CCCCC1
Reactant: Sc1cc2ccccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnc(CSc2cc3ccccc3[nH]2)cc1N1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
To a solution of 2-mercaptoindole (1.34 g, 8.98 mmol) and 2-chloromethyl-5-methyl-4-piperidinopyridine hydrochloride (2.35 g, 9.00 mmol) in ethanol (90 ml) was added a 2N aqueous sodium hydroxide solution (9.0 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. After the removal of the organic solvent by evaporation under a reduced pressure, a saturated sodium chloride solution was added to the residue and the mixture was extracted with chloroform. The chloroform layer separated was dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue was purified by a silica gel column chromatography [eluent: chloroform and then chloroform-methanol (50:1)] whereby to yield the titled compound (2.51 g) as a crystalline substance.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1.[C:18]1([C:24]#[C:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31]C2CCCCO2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[C:18]1([C:24]#[C:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C(#Cc1ccccc1)CCCCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: CO
Product: OCCCCCC#Cc1ccccc1
Temperature: 55 °C
Yield: 96.7 %

Procedure:
Pyridine toluene-4-sulphonate (0.75 g, 3 mmol) was added to a magnetically stirred solution of 2-(7-phenylhept-6-ynyloxy)-tetrahydro-2H-pyrane (7) (13.62 g, 50 mmol) in dry methanol (300 mL). The reaction mixture was stirred at 55° C. and monitored by TLC. When all the base material had been converted, methanol was distilled out on a rotary evaporator and water (200 mL) was added to the residue. The aqueous phase was extracted with petroleum ether (boiling point 40-60° C.)/Et2O 1:1 (5×50 mL). The combined organic phases were washed with water (2×20 mL) and dried (MgSO4). Distillation on a rotary evaporator yielded 9.1 g (97%) of a yellow viscous oil. TLC and NMR indicated a pure product.
Reaction SMILES: S(Cl)(Cl)=O.[N:5]1[CH:10]=[C:9]([C:11]2(O)[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)[CH:8]=[N:7][CH:6]=1.O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N:7]1[CH:8]=[C:9]([C:11]2[CH:16]3[CH2:15][CH2:14][N:13]([CH2:18][CH2:17]3)[CH:12]=2)[CH:10]=[N:5][CH:6]=1
Reactant: OC1(c2cncnc2)CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: C1=C(c2cncnc2)C2CCN1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
Thionyl chloride (0.35 ml. 4.8 mmol) was added to a rapidly stirred solution of 3-(5-pyrimidinyl)-1-azabicyclo[2.2.2] octan-3-ol (0.5 g, 2.4 mmol) in dichloromethane (15 ml), at 0° C. The solution was warmed to room temperature and stirred for 1 h before adding a second portion of thionyl chloride (0.2 ml) and refluxing for 0.25 h. The mixture was cooled to 10° C., water (10 ml) added and basified to pH >10 with potassium carbonate. Extraction into dichloromethane (3×50 ml). drying (Na2SO4) and evaporation of solvents under reduced pressure gave 3-(5-pyrimidinyl)-1-azabicyclo[2.2.2]oct-2-ene (0.16 g) as a yellow oil which crystallised on standing at 0° C., m/e 188 (M+H)+ ; δ (360 MHz,D2O) 1.86-1.98 (2H, m,CH2); 2.15-2.26(2H,m,CH2): 3.18-3.30 (2H,m,0.5×CH2 and CH); 3.62-3.72(3H,m,CH2 and 0.5×CH2) 7.23(1H,s,vinyl-H): 9.00(2H,s,pyrimidine-H); 9.15(1H,s,pyrimidine H). A solution of 3-(5-pyrmidinyl)-1-azabicyclo[2.2.2]oct-2-ene (0.31 g 1.66 mmol) in ethanol (40 ml) was hydrogenated over 10% pd/C (0.12 g) in a Parr apparatus. After 4 h the suspension was filtered through hyflo, the solvent removed under vacuum and, the residue chromatographed on alumina using dichloromethane/methanol (95:5) as eluant, to give 3-(5-pyrimidinyl)-1-azabicyclo[2.2.2]octane (0.17 g) as a yellow oil. The hydrochloride salt was made. m.p. 267°-270° C. (dec.); (Found C,56.00; H,6.88, N,17.74. C11H15N3.HCl.0.75H2O requires C,55.69; H,6.58; N,17.71%) m/e 189 (M+ for free base); δ (360 MHz,D2O) 1.89-1.94(2H,m,CH2); 2.13-2.24 (2H,m,CH2); 2.38-2.46 (1H, m, CH-bridgehead); 3.34-3.90(7H,m,3×CH2 --N and CH); 8.85(2H,s,pyrimidine-H); 9.09 (1H,s,pyrimidine-H).
Reaction SMILES: N1C=CC(C(O)=O)=C1.[CH3:9][C:10]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[C:13]([CH3:19])[NH:12][C:11]=1C(OCC)=O.[OH-].[K+].C(O)(=O)C>C(O)C>[CH3:19][C:13]1[NH:12][CH:11]=[C:10]([CH3:9])[C:14]=1[C:15]([CH3:17])([CH3:16])[CH3:18]
Reactant: CCOC(=O)c1[nH]c(C)c(C(C)(C)C)c1C
Agent: O=C(O)c1cc[nH]c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1c[nH]c(C)c1C(C)(C)C
Temperature: 180 °C

Procedure:
A procedure reported for the decarboxylation of derivatives of pyrrole-3-carboxylic acid was adapted from Clue, J. Org. Chem. 19:266, 1954. A solution of ethyl 3,5-dimethyl-4-tert-butylpyrrole-2-carboxylate 4g (3.0 g, 0.01 mol) and potassium hydroxide (6.0 g, 0.11 mol) in ethanol (50 ml) was heated at 80° C. for 4 h, combined with ice water (200 ml), and made slightlyacidic by the addition of acetic acid to bring about the precipitation of crude 3,5-dimethyl-4-tert-butylpyrrole-2-carboxylic acid 4 (W=CH3, X=C(CH3)3, R=CO2H). The crude acid was combined with ethanolamine (5 g), heated at 180° C. for 1 h, and diluted with ice water (100 ml) to bring about the precipitation of2,4-dimethyl-3-tert-butylpyrrole 5g as a colorless solid, 1.6 g (79%), mp 70°-71° C. (lit. 69°-71° C.) after drying in avacuum for 24 h; 1H NMR (CDCl3): δ 7.60 (br, 1H), 6.30 (s,1H), 2.25 (s, 3H), 2.15 (s, 3H), 1.28 (s, 9H). By the phosphoric acid method the pyrrole ester 4g was converted to 2,4-dimethylpyrrole 5a.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH2:10][C:11]#N.C([O-])(O)=[O:14].[Na+].[CH3:18][CH2:19][OH:20]>>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH2:10][C:11]([O:20][CH2:19][CH3:18])=[O:14]
Reactant: CCO
Reactant: O=C([O-])O
Reactant: N#CCc1nc2cccnc2[nH]1
Agent: [Na+]
Product: CCOC(=O)Cc1nc2cccnc2[nH]1
Temperature: 0 °C

Procedure:
3H-Imidazo[4,5-b]pyridin-2-ylacetonitrile was suspended in EtOH, and gaseous HCl was bubbled through for 3 hours. The suspension initially dissolved, but a precipitate started forming almost immediately. The reaction mixture was cooled to 0° C. and a cold saturated NaHCO3 solution was carefully added. Solid NaHCO3 was also added until a pH of 7.6 was achieved. The aqueous phase was then extracted with EtOAc, and the organic extracts were dried (Na2SO4). After evaporation of the solvent under reduced pressure, the residue was purified by chromatography on silica gel (10% MeOH in CH2Cl2 with 1% Et3N) providing the desired product as a light brown solid. LC/MS m/z 206.1 (MH+), Rt 0.97 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C1C(=O)N([Br:25])C(=O)C1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:25][C:10]1[C:2]([Cl:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][CH2:4]2
Reactant: CC(C)(C)OC(=O)N1CCc2c(Cl)cccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c1ccc(Br)c2Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a solution of 1,1-dimethylethyl 4-chloro-2,3-dihydro-1H-indole-1-carboxylate (6.36 g, 25.07 mmol) in Dichloromethane (DCM) (100 mL) was added a solution of NBS (4.91 g, 27.6 mmol) in Dichloromethane (DCM) (200 mL). The reaction was stirred at room temperature for 2 hours. LCMS indicated good conversion, so the reaction mixture was poured into sodium bicarbonate (sat., 300 mL), and separated. The aqueous layer was extracted with ethyl acetate (2×300 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (0-30% EtOAc in hexanes, 200 g silica gel column) to afford 1,1-dimethylethyl 5-bromo-4-chloro-2,3-dihydro-1H-indole-1-carboxylate (5.5 g) as an off-white solid. LC-MS (ES) m/z=276, 278 [M+H-t-Bu]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (s, 9H), 3.01-3.18 (m, 2H), 3.88-4.03 (m, 2H), 7.50-7.58 (m, 2H).
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br>>[C:1]1([C:12]2[CH:13]=[CH:14][C:9]([OH:15])=[CH:10][CH:11]=2)([C:12]2[CH:13]=[CH:14][C:9]([OH:15])=[CH:10][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCCC1
Reactant: Oc1ccccc1
Agent: Br
Product: Oc1ccc(C2(c3ccc(O)cc3)CCCCCC2)cc1

Procedure:
Into a solution of 112.7 parts by weight (1.0 partmole) cycloheptanone and 470 parts by weight (5.0 partmole) phenol there was introduced gaseous hydrobromic acid. The mildly exothermic reaction was moderated by external cooling, keeping the reaction temperature between 30° and 37° C. after ca. 1.5 hour of reaction time, the red colored mixture thickened and solids began to form. After an additional four hour contact with a slow stream of hydrobromic acid, all acid was removed by placing the stirred mixture under water aspirator vacuum and the solid phase removed by vacuum filtration. Washing the solids with hot water and recrystallizing them by charcoaling from aqueous menthol, yielded white crystals of 4,4'-cycloheptylidenediphenol, melting point 208°-209° C., that were 99.1% pure by gas chromatography analysis (retention time: 25.35 min.; p-cumylphenol reference retention time: 16.47 min.).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](I)[CH:7]=1.[Cl-].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][Zn+])=[CH:15][CH:14]=1.O.C(OCC)(=O)C>C1COCC1.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>[F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[CH:7]=1
Reactant: Fc1ccc(C[Zn+])cc1
Reactant: N#Cc1ncc(I)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ncc(Cc2ccc(F)cc2)cc1F
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a solution of 3-fluoro-5-iodo-2-pyridinecarbonitrile(2.31 g, 9.3 mmol) in THF (100 mL) was added 4-fluorobenzyl zinc chloride (27.9 mL, 0.5 M in THF, 14.0 mmol) followed by Pd(PPh3)4 (538 mg, 0.47 mmol). The resultant solution was heated at 75° C. (bath temperature) for 3 hours. After cooling to room temperature, water and ethyl acetate were added. The layers were separated and the organic layer was washed with brine. The aqueous layer was acidified with 1 N HCl until it cleared and extracted with ethyl acetate. The combined organics were dried over sodium sulphate. Filtration and concentration followed by purification by silica gel chromatography provided 3-fluoro-5-[(4-fluorophenyl)methyl]-2-pyridinecarbonitrile (1.6 g, 75%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1 H), 7.28 (d, J=8.8 Hz, 1 H), 7.12 (dd, J=8.4, 5.2 Hz, 2 H), 7.03 (t, J=8.4 Hz, 2 H), 4.04 (s, 2 H). MS m/z 231 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH3:14])(O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:15]S(O)(=O)=O.[CH3:20][C:21]#[N:22]>>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([NH:22][C:21](=[O:15])[CH3:20])([CH3:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: CC1(O)CCN(Cc2ccccc2)C1
Reactant: CC#N
Product: CC(=O)NC1(C)CCN(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
A solution of 1-benzyl-3-methylpyrrolidin-3-ol (5.94 g, 31.1 mmol) in MeCN (200 mL) was cooled in an ice bath and conc H2SO4 (25 mL) was added dropwise over 15 min. The ice bath was allowed to melt and the mixture was stirred at rt over the weekend. The mixture was poured onto crushed ice (600 mL). The mixture was evaporated under reduced pressure to remove MeCN. Solid K2CO3 was added in portions to the residue until it was basic. The mixture was extracted with CH2Cl2 (3×150 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4 and concentrated to leave N-(1-benzyl-3-methylpyrrolidin-3-yl)acetamide (4.01 g).
Reaction SMILES: [CH2:1]([N:4]([CH2:12][CH:13]=[CH2:14])[C:5]([CH2:7][CH2:8]C(O)=O)=[O:6])[CH:2]=[CH2:3].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:22])C=CC=CC=1.C([N:34]([CH2:37]C)CC)C>C1C=CC=CC=1>[CH2:12]([N:4]([CH2:1][CH:2]=[CH2:3])[C:5]([CH2:7][CH2:8][N:34]=[C:37]=[O:22])=[O:6])[CH:13]=[CH2:14]
Reactant: C=CCN(CC=C)C(=O)CCC(=O)O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CCN(CC=C)C(=O)CCN=C=O

Procedure:
The reaction of 3-(N,N-diallylcarbamoyl)propionic acid and diphenylphosphoryl azide in a solution of triethyl amine and benzene provided a solution comprising 2-(N',N'-diallylcarbamoyl)ethyl isocyanate (I.R.: 2275 cm-1), which was reacted with 5-fluorouracil to provide 1-[N-[2-(N',N'-diallylcarbamoyl)ethyl]carbamoyl]-5-fluorouracil substantially in the similar method to that of Example 4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.CON(C)[C:21]([C:23]1[CH:31]=[C:30]2[C:26]([CH:27]=[CH:28][NH:29]2)=[CH:25][CH:24]=1)=[O:22].C(O)(C)C>C1COCC1.O>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([C:21]([C:23]2[CH:31]=[C:30]3[C:26]([CH:27]=[CH:28][NH:29]3)=[CH:25][CH:24]=2)=[O:22])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[CH3:12]
Reactant: CCOc1cc(Br)ccc1OC
Reactant: CON(C)C(=O)c1ccc2cc[nH]c2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: CCOc1cc(C(=O)c2ccc3cc[nH]c3c2)ccc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
A stirred mixture of 4-bromo-2-ethoxy-1-methoxy-benzene (6.52 g, 23.7 mmol) and anhydrous THF (20 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (9.5 mL, 23.7 mmol) and stirred for 20 min. Then a mixture of 1H-indole-6-carboxylic acid methoxy-methyl-amide (2.20 g, 10.8 mmol) in anhydrous THF (25 mL) was added and stirred for 1 hour at −78° C. The mixture was quenched with isopropanol (4.9 mL, 65 mmol) and water (15 mL). The mixture was extracted with EtOAc (3×50 mL). The combined organic phases were washed with water (2×50 mL), dried over MgSO4 and concentrated to give an oil, which was purified by flash column chromatography (EtOAc, Hexane) to give (3-ethoxy-4-methoxy-phenyl)-(1H-indol-6-yl)-methanone as an oil (2.30 g). The product was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:45][C:46]([CH3:50])=[CH:47][CH2:48]O>O1CCCC1>[CH3:45][C:46]([CH3:50])=[CH:47][CH2:48][O:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: CC(C)=CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)=CCOC1=CC(=O)c2ccccc2C1=O
Reaction time: 0.08 h
Yield: 59.7 %

Procedure:
To a stirred solution of 2-hydroxynaphthalene-1,4-dione (10.0 g, 57.4 mmol) and triphenylphosphine (15.1 g, 57.4 mmol) in dry tetrahydrofuran (150 ml) at 0° C. under an atmosphere of nitrogen was added diethyl azodicarboxylate (10.0 g, 57.4 mmol). After stirring for a further 5 minutes, a solution of 3-methylbut-2-enol (7.42 g, 86.1 mmol) in dry tetrahydrofuran (10 ml) was added dropwise and stirring was continued for 2 hours. The precipitate was collected, air-dried and recrystallised from aqueous methanol to yield 2-(3-methylbut-2-enyloxy)naphthalene-1,4-dione (8.3 g) as a yellow crystalline solid, m.pt.: 138° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[C:8]([NH:10][CH2:11][C:12]([OH:14])=O)=[O:9])=[O:4].C(Cl)(=O)O.[CH3:25][NH2:26]>O1CCCC1.C(N(CC)CC)C>[CH3:25][NH:26][C:12](=[O:14])[CH2:11][NH:10][C:8](=[O:9])[C:7]1[CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=1
Reactant: CN
Reactant: COC(=O)c1cc(C(=O)NCC(=O)O)cc([N+](=O)[O-])c1
Agent: O=C(O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)CNC(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
Process 2: 8.5 g. (0.03 mole) of N-(3-metoxycarbonyl-5-nitrobenzoyl-glycine (VIa) dissolved in 130 ml. of absolute tetrahydrofuran, is cooled to -15° C., after the addition of 4.2 ml. of triethylamine, and mixed under agitation with 3 ml. of the ethyl ester of chlorocarbonic acid. The reaction mixture is agitated for about 10 minutes at -10° to -5° C., and a solution of 2.8 ml. of methylamine in 20 ml. of absolute tetrahydrofuran, cooled to -15° C., is gradually added thereto dropwise under agitation. Then, the mixture is stirred for another 30 minutes at -15° C. and subsequently overnight at room temperature; the triethylamine hydrochloride is filtered off, the filtrate concentrated under vacuum, and the residue recrystallized from acetonitrile; yield 4.6 g. m.p. 173°-174° C.