Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[NH2:16].[CH3:17][O:18][C:19]([N:21]=[C:22]=[S:23])=[O:20]>CC(C)=O>[CH3:17][O:18][C:19]([NH:21][C:22](=[S:23])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[NH:16][C:22]([NH:21][C:19]([O:18][CH3:17])=[O:20])=[S:23])=[O:20]
Reactant: Nc1ccc(S(=O)c2ccccc2)cc1N
Reactant: COC(=O)N=C=S
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(S(=O)c2ccccc2)cc1NC(=S)NC(=O)OC

Procedure:
2.1 G. 1,2-diamino-4-phenylsulfinylbenzene in 150 ml. acetone is treated with 6 g. methoxy carbonyl isothiocyanate overnight at 20°-25° C. The reaction mixture is stripped and the residue triturated with ether. Recrystallization from methanol yields pure 1,2-bis-(3-methoxycarbonyl-2-thioureido)- 4-phenylsulfinylbenzene.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:18][C:19]1[N:23]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:22]=[N:21][CH:20]=1>CN(C=O)C>[CH:24]1([N:23]2[C:19]([CH2:18][S:8][C:6]3[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=3)=[CH:20][N:21]=[CH:22]2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Cc1cc(O)nc(S)n1
Reactant: ClCc1cncn1C1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2cncn2C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 32.9 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (1.1 g, 7.7 mmol) was dissolved in anhydrous DMF (40 mL), then potassium carbonate (3.19 g, 23.1 mmol) and 5-(chloromethyl)-1-cyclohexyl-1H-imidazole hydrochloride (8.5 mmol) in DMF (10 mL) were added. The mixture was stirred for 3.5 hours at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 12% DCM/MeOH to afford 2-{[(1-cyclohexyl-1H-imidazol-5-yl)methyl]sulfanyl)-6-methylpyrimidin-4-ol (770 mg, 44% yield); 1H NMR (500 MHz, DMSO-d6): δ 1.17-1.30 (m, 2H), 1.62-1.67 (m, 4H), 1.77-1.81 (m, 2H), 1.92-1.95 (m, 2H), 2.23 (s, 3H). 3.92-3.96 (m, 1H), 4.51 (s, 2H), 6.03 (s, 1H), 6.85 (s, 1H), 7.75 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([C:8]([CH3:10])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH2:13]1[CH2:20][O:19][S:16](=[O:18])(=[O:17])[CH2:15][CH2:14]1>CN(C)C=O>[CH2:6]([O:5][C:3]([C:2]([CH3:1])([C:8](=[O:9])[CH3:10])[CH2:20][CH2:13][CH2:14][CH2:15][S:16]([OH:19])(=[O:18])=[O:17])=[O:4])[CH3:7]
Reactant: O=S1(=O)CCCCO1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(CCCCS(=O)(=O)O)C(C)=O
Temperature: 25 °C
Yield: 122.6 %

Procedure:
Ethyl 2-methylacetoacetate (43.2 g) in N,N-dimethylformamide (25 ml) was added to a suspension of sodium hydride (12.0 g of 60% NaH in mineral oil) in N,N-dimethylformamide (100 ml), dropwise with ice-bath cooling. This mixture was allowed to warm to ambient temperature for 30 mins before re-cooling. 1,4-butanesultone (40.8 g) in N,N-dimethylformamide (25 ml) was then added dropwise. The final mixture was heated at 50° C. for 18 hrs, then quenched with 50 ml of water. The solvent was evaporated under vacuum; the residue was partitioned between water and diethyl ether. The aqueous layer was collected, washed with fresh diethyl ether and evaporated under vacuum; final drying was under high vacuum over phosphorus pentoxide. A yield of 103 g of 5-(ethoxycarbonyl)-5-methyl-6-oxoheptane-1-sulfonic acid was obtained.
Reaction SMILES: [F:1][C:2]1[C:10]([Cl:11])=[C:9]([F:12])[C:8]([F:13])=[C:7](Cl)[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O>>[F:1][C:2]1[C:10]([Cl:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(F)c(Cl)c(F)c(F)c1Cl
Product: O=C(Cl)c1cc(F)c(F)c(Cl)c1F

Procedure:
The chlorination of the 2,4,5-trifluorobenzoic acid is carried out in the melt, under pressure and/or in a solvent, for example chlorosulphonic acid or oleum, in the presence of halogen transfer agents, for example iodine. 2,4,5-Trifluoro-3-chlorobenzoic acid is obtained in this reaction. However, since the reaction mixture still contains unchanged starting material and some 2,4,5,-trifluoro-3,6-dichlorobenzoic acid, the crude mixture is treated, without intermediate isolation, with thionyl chloride. The desired 2,4,5-trifluoro-3-chlorobenzoyl chloride is then obtained by fractional distillation. However, it is more favorable to carry out the separation by distillation of the acid fluorides.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1C(=O)O
Reaction time: 2 h
Yield: 90 %

Procedure:
To a 100 mL flask containing 2-nitro-4-(trifluoromethyl)benzoic acid (940.5 mg, 4 mmol) in 30 mL MeOH was added 100 mg of 10% Pd on charcoal After flushing with hydrogen three times, the reaction mixture was agitated under hydrogen atmosphere for 2 h. The mixture was filtered through a plug of Celite, and the filtrate was concentrated to afford 2-amino-4-(trifluoromethyl)benzoic acid (740 mg, 3.6 mmol, 90%).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CCN(CC)CC>C(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]([N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:4]
Reactant: O=C(Br)CBr
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CBr
Yield: 60.5 %

Procedure:
This novel compound was prepared as follows: Bromoacetyl bromide (4.25 g; 21 mmol) was added dropwise to a solution of dioctadecylamine (10 g; 19 mmol) and Et3N (2.13 g; 21 mmol) in CHCl3 (400 mL). After 4 h at room temperature the reaction solution was washed with H2O, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (n-hexane/Et2O=8/2 (v/v) to give the desired product (7.5 g; 11.5 mmol). Yield 61%. K.F.: <0.1%; The 1H-NMR, 13C-NMR, MS and IR spectra were consistent with the postulated structure
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:13][C:14]1[CH:15]=[C:16]([CH2:31][OH:32])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1>>[F:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)[CH2:31][O:32][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OCc1ccc(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(C(F)(F)F)nc3)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to those described for E1 starting from 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.[OH:14][C:15]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[C:24]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[C:20]([O:19][C:17]([C:16]1[C:15]([OH:14])=[C:27]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:25][C:24]=1[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=2)=[CH:36][CH:35]=1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)c1c(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)ccc(C(F)(F)F)c1O
Reactant: COC(=O)CCc1ccc(Br)cc1
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CCC(=O)O)cc3)cc2)ccc(C(F)(F)F)c1O

Procedure:
According to a method similar to Example (31) and Example (17-4), from methyl 3-(4-bromophenyl)propionate (131 mg, 0.51 mmol) and tert-butyl 2-hydroxy-6-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}-3-(trifluoromethyl)benzoate (250 mg, 0.51 mmol) obtained in Example (22-4), the title compound was obtained as a colorless powder (26 mg, yield: 10%).
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]2[C:5]([CH2:6][CH2:7][C@@:8]32[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]3)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[N:24][CH:25]=1.COCCOC>O>[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[CH:18]=[C:17]3[C:5]([CH2:6][CH2:7][C@@:8]43[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]4)=[CH:4][CH:3]=2)[CH:23]=[N:24][CH:25]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: NC1=N[C@@]2(CCc3ccc(Br)cc32)C(F)(F)CO1
Solvent: O
Solvent: COCCOC
Product: NC1=N[C@@]2(CCc3ccc(-c4cncc(Cl)c4)cc32)C(F)(F)CO1
Yield: 19 %

Procedure:
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-6-bromo-5′,5′-difluoro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazin]-2′-amine (intermediate A6.5) with 5-chloropyridin-3-ylboronic acid in a 3:1-mixture of 1,2-dimethoxyethane and water as the solvent yielded the title compound (19% yield) as a white solid. MS (ISP): m/z=349.8 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][S:7][C:6]=2[CH:17]=1.[H-].[Na+].Cl.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl>CN(C)C=O>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][N:10]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[C:9]1[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:17][C:6]=2[S:7][CH:8]=1
Reactant: Fc1ccc2c(Nc3ccncc3)csc2c1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCN(c1ccncc1)c1csc2cc(F)ccc12
Temperature: 0 °C
Yield: 74.2 %

Procedure:
6-Fluoro-3-(4-pyridinylamino)benzo[b]thiophene (3.30 g, 13.5 mmol) was added portionwise as a powder to a suspension of sodium hydride (60% oil dispersion, 1.35 g, 33.8 mmol, washed with hexanes) in 50 mL dimethylformamide. After the anion formation was completed, 3-dimethylaminopropyl chloride hydrochloride (2.56 g, 16.2 mmol) was added as a powder and the resultant mixture was stirred at 70°-75° C. for two hours. After cooling, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution and dried (anhydrous magnesium sulfate), filtered and concentrated to 4.6 g of a brown oil. Elution through silica with 10% methanol in dichloromethane via flash column chromatography yielded 3.3 g of a yellow oil. Kugelrohr distillation (210°-220°/0.1 mm Hg) yielded 2.8 g of a clear colorless oil which eventually solidified to a white solid, mp 82°-84°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]#[N:32])[CH:30]=1)[O:6][C:7]1[C:12]([C:13]#[N:14])=[CH:11][C:10]([NH:15][C:16]([N:18]([CH2:20][CH:21](OC)OC)[CH3:19])=[O:17])=[CH:9][C:8]=1[C:26]#[N:27])#[N:2].Cl>O>[CH3:19][N:18]1[CH:20]=[CH:21][N:15]([C:10]2[CH:9]=[C:8]([C:26]#[N:27])[C:7]([O:6][C:5]3[CH:4]=[C:3]([C:1]#[N:2])[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=3)=[C:12]([C:13]#[N:14])[CH:11]=2)[C:16]1=[O:17]
Reactant: COC(CN(C)C(=O)Nc1cc(C#N)c(Oc2cc(C#N)cc(C#N)c2)c(C#N)c1)OC
Agent: Cl
Solvent: O
Product: Cn1ccn(-c2cc(C#N)c(Oc3cc(C#N)cc(C#N)c3)c(C#N)c2)c1=O

Procedure:
N-[4-(3,5-Dicyanophenoxy)-3,5-dicyanophenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea (0.02 mole), water (30 ml) and concentrated hydrochloric acid (3 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. The mixture is refluxed for a period of about 30 minutes then cooled and extracted with ethyl acetate. The extract is washed with dilute aqueous sodium bicarbonate, with two portion of water and is then dried. The ethyl acetate is removed by mild warming under reduced pressure to yield the desired product 1-methyl-3-[4-(3,5-dicyanophenoxy)3,5-dicyanophenyl]-4-imidazolin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH2:10][CH:11]=[CH2:12])[C:7]([OH:13])=[C:6]([CH2:14][CH:15]=[CH2:16])[CH:5]=1.[CH3:18]I>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH2:10][CH:11]=[CH2:12])[C:7]([O:13][CH3:18])=[C:6]([CH2:14][CH:15]=[CH2:16])[CH:5]=1
Reactant: C=CCc1cc(C(=O)OC)cc(CC=C)c1O
Reactant: CI
Product: C=CCc1cc(C(=O)OC)cc(CC=C)c1OC

Procedure:
3,5-Diallyl-4-methoxybenzoic acid methyl ester was prepared from 3,5-diallyl-4-hydroxybenzoic acid methyl ester and methyl iodide following Method C. The resulting product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26](=[O:27])[CH2:25][CH:24]([C:28]([O:30]C)=[O:29])[CH2:23]2)=[CH:18][CH:17]=1.[OH-].[Na+]>CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26](=[O:27])[CH2:25][CH:24]([C:28]([OH:30])=[O:29])[CH2:23]2)=[CH:20][CH:21]=1
Reactant: COC(=O)C1CC(=O)N(c2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(N4CC(C(=O)O)CC4=O)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 1-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-5-oxopyrrolidine-3-carboxylate (Step 2, 0.5 ng, 1.18 mmol) in MeOH/THF (2 mL: 2 mL) solution was added 1.77 mL of 1 N NaOH. The reaction was stirred at RT for 8 h. The solution was concentrated in vacuo to dryness and acidified with 1 N HCl. The white precipitate was collected by filtration and washed with 50% EtOAc/hexanes to give the title compound as white solid. MS (ESI pos. ion) m/z: 409.3 (M+H). Calc'd Exact Mass for C22H20N2O6: 408.4.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH3:33])=[CH:25][CH:24]=1)[C:10]([O:12][CH2:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>C(Cl)Cl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[NH2:8][C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH3:33])=[CH:25][CH:24]=1)[C:10]([O:12][CH2:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(=O)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCOc1ccc(C[C@H](N)C(=O)OCC(=O)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
2-Oxo-2-phenyl-ethyl (S)-2-tert-butoxycarbonylamino-3-(4-but-2-ynyloxy-phenyl)-propionate (275 mg) was dissolved in methylene chloride (5.0 mL), and trifluoroacetic acid (1.0 mL) was added. The mixture was reacted with stirring for 30 minutes. After completing the reaction, the solvent was distilled off under reduced pressure. An appropriate amount (ca. 5 mL) of toluene was added and the mixture was concentrated in vacuo three times (azeotropic distillation) to obtain 290 mg of the target compound (LCMS m/z 352 (M+1) Rt 1.38 min.).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([C:11]([NH2:13])=O)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:15]>N1C=CC=CC=1>[N:1]1[C:10]2[CH:9]([C:11](=[S:15])[NH2:13])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)C1CCCc2cccnc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: NC(=S)C1CCCc2cccnc21
Reaction time: 8 h

Procedure:
A solution of 5,6,7,8-tetrahydroquinoline-8 -carboxamide (1.2 g.) in pyridine (15 ml.) was treated with P2S5 (0.8 g.) and the mixture heated at reflux for 30 mins. The solvent was removed in vacuo and the residual oil treated with 2N NaOH (5 ml.) and saturated with solid K2CO3 and extracted into chloroform (3× 50 ml.). The combined extracts were dried and the solvent removed in vacuo. The residual oil was dissolved in pyridine (4 ml.) and triethylamine (1 ml.) and the solution saturated with H2S (6 hours) and allowed to stand overnight. Removal of the solvent gave a solid (850 mgs.) which was recrystallised from methanol giving the title compound as the quarter hydrate, colourless needles m.p. 160° C. Found: C, 59.8; H, 6.2; N, 14.0%. C10H12N2S.1/4 H2O requires: C, 59.6; H, 6.4; N, 13.9%.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=O.[ClH:7].[N:8]1([CH2:14][CH:15]=[CH:16][C:17]([OH:19])=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>ClCCl.CN(C)C=O>[ClH:4].[ClH:7].[N:8]1([CH2:14][CH:15]=[CH:16][C:17]([O:19][C:1](=[O:5])[CH:2]=[CH:15][CH2:14][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(O)C=CCN1CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(C=CCN1CCCCC1)OC(=O)C=CCN1CCCCC1
Reaction time: 1 h

Procedure:
Oxalyl chloride (4.2 ml) was added to a stirred solution of 4-(piperidin-1-yl)-but-2-enoic acid hydrochloride (10 g) in dichloromethane (200 ml). Dimethylformamide (2 drops) was then added. The resultant suspension was stirred for 4 h and then concentrated to ˜25 ml. The slurry obtained was stirred a further 1 h and then filtered. The filter pad was washed with dichloromethan (50 ml) and dired in vacuo to give the title compound as a white solid (4.95 g). M.p. 120-124° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][CH3:19])[CH:12]=2)[C:5](=[O:20])[N:4]([CH2:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:3]=1[CH3:32].C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([CH3:35])[CH3:19])[CH:12]=2)[C:5](=[O:20])[N:4]([CH2:21][C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[C:3]=1[CH3:32]
Reactant: CNCc1cccc(CCNc2nc(Cl)c(C)n(CC(=O)OCc3ccccc3)c2=O)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(Cl)nc(NCCc2cccc(CN(C)C)c2)c(=O)n1CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77.1 %

Procedure:
A stirred solution of benzyl 2-[3-chloro-2-methyl-5-(3 [(methylamino)methyl]phenethylamino)-6-oxo-1(6H)-pyrazinyl]acetate (preparation 19) (0.38 g, 0.83 mmol) in CH2Cl2 (10 ml) was treated with formaldehyde (0.31 ml). After stirring at room temperature for 45 mins, the resultant cloudy -mixture was treated with sodium triacetoxyborohydride (253 mg, 1.19 mmol) and stirred at room temperature for a further 2 days. The reaction mixture was diluted with CH2Cl2 (200 ml) and washed with sat. aq NaHCO3, sat aq brine and dried over MgSO4. Removal of the drying agent by filtration followed by evaporation of the solvent gave a crude solid which was purified by chromatography (SiO2, gradient elution with 100% CH2Cl2; 95:5 CH2Cl2:MeOH; 90:10 CH2Cl2:MeOH) to give the desired product (0.30 g, 77%). 1H NMR (CDCl3) δ 2.20 (s, 3H), 2.25 (s, 6H), 2.90 (t, 2H), 3.40 (s, 2H), 3.70 (m, 2H), 4.80 (s, 2H), 5.20 (s, 2H), 6.10 (m, br, 1H), 7.10-7.20 (m, 3H), 7.25 (m, 1H), 7.35 (m, 5H). LRMS m/z=469.2, 471.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(-c2ccc(C(=O)O)c(=O)[nH]2)c1
Product: CC(=O)Nc1cccc(-c2ccc(C(=O)O)c(=O)[nH]2)c1

Procedure:
A mixture of 4.6 g (20 mmol) of 6-(3-aminophenyl)-1,2-dihydro-2-oxonicotinic acid and 100 ml of acetic anhydride is stirred at reflux for 2 hrs. The reaction is cooled and the solid filtered, washed with acetonitrile and ether, and dried to give 4.12 of 6-[3(acetylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:36])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:16]=3)=[N:10][C:9]=2[N:25]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[CH2:32][CH2:31][CH2:30]3)[CH:26]=1)=O)C.[CH2:37]([NH2:39])C>CO>[CH3:37][NH:39][C:4]([C:6]1[C:7](=[O:36])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:23])[CH3:24])[CH:16]=3)=[N:10][C:9]=2[N:25]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[CH2:32][CH2:31][CH2:30]3)[CH:26]=1)=[O:3]
Reactant: CCN
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(CN(C)C)c3)ncc2c1=O
Solvent: CO
Product: CNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(CN(C)C)c3)ncc2c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 14 %

Procedure:
2-(3-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (15 mg, 0.032 mmol) was dissolved in MeOH (1 mL) and ethylamine (1 mL of 1.0 M solution in THF, 1.0 mmol) was added and the reaction mixture was heated at 80° C. After 16 h, the solution was cooled to it and purified by preparative HPLC (C-18 column, 32 mL/min 5-100% MeCN/H2O gradient over 15 min) and lyophilized to provide 2.1 mg of 2-(3-dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide. 1H NMR (TFA salt) (400 MHz, CDCl3) δ (ppm): 9.57 (s, 1H), 9.34 (s, 1H), 8.74 (s, 1H), 6.99-7.37 (m, 7H), 3.89 (br s, 2H), 3.39-3.46 (m, 2H), 2.89-3.02 (m, 4H), 2.60 (s, 6H), 2.13-2.17 (m, 2H), 1.19 (t, 1H, J=7.3 Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. for C28H30N6O2: 482.24, Found: 483.2 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=O)[C:12]([O-:14])=O)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[CH2:16]([NH2:19])[CH2:17][NH2:18].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:12](=[O:14])[NH:18][CH2:17][CH2:16][N:19]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: NCCN
Reactant: Cn1ncc2cc(C(=O)C(=O)[O-])ccc21
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cn1ncc2cc(C3=NCCNC3=O)ccc21

Procedure:
The mixture of 2-(1-methyl-1H-indazol-5-yl)-2-oxoacetate (520 mg, 2.2 mmol), ethylenediamine (0.15 mL, 2.2 mmol), and sodium sulfate in toluene (9 mL) was heated at reflux for 12 hours. The reaction was cooled, and diluted with ethyl acetate. The mixture was filtered through a pad of celite and was washed with ethyl acetate. Concentration and purification with flash column chromatography (EtOAc) gave 3-(1-methyl-1H-indazol-5-yl)-5,6-dihydropyrazin-2(1H)-one. LCMS-ESI+: calc'd for C12H13N4O: 229.3 (M+H+); Found: 229.2 (M+H+).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:10]([C:11]([CH3:13])=[CH2:12])[CH2:9][CH2:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH3:15]OC(OC)N(C)C>C1C=CC=CC=1>[C:1]([CH2:4][CH2:5][C:6]1[CH:10]([C:11]([CH3:13])=[CH2:12])[CH2:9][CH2:8][C:7]=1[CH3:14])([O:3][CH3:15])=[O:2]
Reactant: C=C(C)C1CCC(C)=C1CCC(=O)O
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Product: C=C(C)C1CCC(C)=C1CCC(=O)OC
Yield: 91 %

Procedure:
A mixture of 2 g of 2-(2-carboxyethyl)-3-isopropenyl-1-methyl-cyclopent-1-ene, 150 ml of absolute benzene and 4 ml of dimethoxy-dimethylamino-methane was heated for 5 hours to reflux. The solution was concentrated and the residue, obtained as a red oil, chromatographed on 50 g of silicagel with hexane/ether (19:1). There were obtained 1.95 g (91%) of 2-(2-carbomethoxyethyl)-3-isopropenyl-1-methyl-cyclopent-1-ene; boiling point 0.01 about 70°C; nD20 = 1.4761; IRfilm : μmax = 3100, 1742, 1645, 1440, 1375, 1330, 1255, 1195, 1170, 1085, 1025, 990, 895 and 840 cm-1. The compound has a floral, woody, ester-like fragrance.