Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.Cl[Sn](Cl)(Cl)Cl.[CH3:30][O:31]C(Cl)Cl>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]2[S:11][C:12]3[C:13](=[CH:14][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:16][CH:17]=3)[C:30](=[O:31])[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(Cl)Cl
Reactant: CC(C)(C)c1ccc(Sc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc2sc3ccc(C(C)(C)C)cc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.6 %

Procedure:
To a mixture of 12 g of bis-(4-t-butylphenyl)-sulfide, 100 mL of dry CH2Cl2 and 21 g of SnCl4 cooled in an ice bath for a period of 30 min., a solution of 9.27 g of α,α-dichloromethyl methyl ether in 50 mL of CH2CH2 was added dropwise. After addition was complete, a deep red mixture was obtained which was allowed to warm slowly to room temperature, stirred for 2 hours and then slowly poured into water. Extraction with CHCl3, followed by washing of the extracts successively with H2O, 5% NaHCO3, H2O and saturated NaCl solution, drying over (MgSO4), and evaporation of solvent gave a red oil which was chromatographed on silica gel. Elution by means of hexane-ethyl acetate (95/5) removed 4.6 g (37% of 2,7-di-t-butylthioxanthene after which there was obtained 4.65 g (37%) of the ketone which was recrystallized from hexane --CH2Cl2 as yellow crystals, m.p. 176°-178°, 'NMR (CDCl3) δ 1.35 (s, 18H, CH3), 7.5 (m, 4H, aryl), 8.75 (d, 2H, CHCCO). Anal. calculated for C21H24OS: C, 77.73; H, 7.46; S, 9.88. Found C, 77.83; H, 7.58; S, 9.75.
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH:10]([NH:25]C(OC(C)(C)C)=O)[C:9]1=[O:33])=[O:6])([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1>C(Cl)(Cl)Cl>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH:10]([NH2:25])[C:9]1=[O:33])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)C(C)(C)C)c2ccccc2N(CC(=O)C(C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)CN1C(=O)C(N)CN(C(=O)C(C)(C)C)c2ccccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
1-tert-Butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1 g) was dissolved in chloroform (10 ml), 4N HCl-dioxane (5 ml) was added to the solution, and the mixture was stirred at 50° C. for one hour. After the reaction mixture was allowed to cool, crystals so precipitated were collected by filtration. The crystals were neutralized with saturated aqueous sodium bicarbonate, and extracted with methylene chloride, dried over anhydrous sodium sulfate, to thereby obtain 720 mg of the titled compound (Yield: 92%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)C.Cl.[C:16](=N)([O:18][CH2:19][CH3:20])[CH3:17]>O>[CH2:16]([O:18][C:19](=[N:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH3:20])[CH3:17]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(C)=NNc1ccc([N+](=O)[O-])cc1
Yield: 85 %

Procedure:
To a stirred and cooled (ice-bath) mixture of 15 parts of 1-(4-nitrophenyl)hydrazine and 160 parts of absolute ethanol were added 13.5 parts of ethyl ethanimidate hydrochloride. After stirring for 3 hours while cooling, the reaction mixture was poured into water. The precipitated product was filtered off, washed with water and dried, yielding 19 parts (85%) of 1-(1-ethoxyethylidene)-2-(4-nitrophenyl)hydrazine; mp. 101.8° C. (int. 18).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([OH:18])[N:13]=[C:12]2[CH3:19])[CH:5]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([O:22][CH3:21])[CH:24]=3)[N:13]=[C:12]2[CH3:19])[CH:5]=1
Reactant: COc1cccc(CBr)c1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(O)cc2=O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(OC)c3)cc2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.1 %

Procedure:
To a solution of Intermediate 2 (460 mg, 1.68 mmol) in N,N-dimethylformamide (2 mL) was added 3-methoxybenzyl bromide (0.23 mL, 1.68 mmol), potassium carbonate (350 mg, 2.53 mmol) and 18-crown-6 (40 mg). The slurry was stirred at ambient temperature for one hour. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the alkylated product as a white semi-solid (226 mg, 34% yield). MS (M+H): 395
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(C2NC=CN=2)=CN=C(CCN)N=1.Cl[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=1.[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[C:40]1[C:45]([C:46]2[NH:47][CH:48]=[CH:49][N:50]=2)=[CH:44][N:43]=[C:42]([NH:51][CH2:52][CH2:53][NH:54]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:41]=1>>[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[C:40]1[C:45]([C:46]2[NH:50][CH:49]=[CH:48][N:47]=2)=[CH:44][N:43]=[C:42]([NH:51][CH2:52][CH2:53][NH:54][C:24]2[N:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=2)[N:41]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Product: N#Cc1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)amino]-pyridine-3-carbonitrile was prepared from [4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-ylethylamine and 2-chloro-5-cyanopyridine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH3:20])[CH2:13][O:12][C@@:11]([CH3:18])([C:14]([F:17])([F:16])[F:15])[C:10]([NH2:19])=[N:9]2)[C:5]([F:21])=[CH:4][CH:3]=1.[C:22](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:31]1[CH:38]=[CH:37][C:34]([O:35][CH3:36])=[CH:33][CH:32]=1)[C:23]1[CH:30]=[CH:29][C:26]([O:27][CH3:28])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:36][O:35][C:34]1[CH:33]=[CH:32][C:31]([C:22]([NH:19][C:10]2[C@:11]([CH3:18])([C:14]([F:15])([F:17])[F:16])[O:12][CH2:13][C@:8]([C:6]3[C:5]([F:21])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=3)([CH3:20])[N:9]=2)([C:23]2[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[CH:29][CH:30]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: C[C@@]1(c2nc(Br)ccc2F)CO[C@@](C)(C(F)(F)F)C(N)=N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(NC2=N[C@](C)(c3nc(Br)ccc3F)CO[C@@]2(C)C(F)(F)F)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (2R,5R)-5-(6-bromo-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (500 mg, 1.35 mmol, CAS registry 1387561-18-3, WO 2012/095469) in DCM (13.5 ml) was added DMTr-Cl (0.481 g, 1.418 mmol) and triethylamine (0.374 ml, 2.70 mmol), the reaction mixture was stirred under argon at rt for 18 h. The reaction mixture was washed with NaHCO3 saturated aqueous solution and brine. The organic layers were backextracted with DCM. The combined organic layer were dried with Na2SO4. The residue was purified by chromatography (eluent: CyHex/EtOAc gradient) to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.C(O[C:15](OCC)(OCC)[CH2:16][CH3:17])C>>[CH2:16]([C:17]1[O:7][C:6]([C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[N:8][N:9]=1)[CH3:15]
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: CCOC(CC)(OCC)OCC
Product: CCc1nnc(-c2ccc(O)cc2)o1
Yield: 96.7 %

Procedure:
A mixture of 19 parts of 4-hydroxybenzoic acid hydrazide and 89.8 parts of 1,1,1-triethoxypropane was refluxed overnight. After cooling the precipitate was filtered off, washed with petroleumether and dried, yielding 23 parts (96.7%) of 4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenol (interm. 8).
Reaction SMILES: [SH2:1].[CH3:2][O:3][C:4](=[O:15])[C:5]([CH3:14])([N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1)[CH3:6].[BH4-].[Na+]>C(O)(C)C>[CH3:2][O:3][C:4](=[O:15])[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([SH:1])[CH2:9][CH2:8]1)([CH3:14])[CH3:6]
Reactant: COC(=O)C(C)(C)N1CCC(=O)CC1
Reactant: S
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: COC(=O)C(C)(C)N1CCC(S)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
H2S gas was bubbled into a solution of 2-methyl-2-(4-oxopiperidin-1-yl)propionic acid methyl ester (1.28 g, 6.42 mmol) in isopropanol (13 mL) for 10 min. The reaction mixture was then sealed, stirred at RT for 18 h and then left standing for 8 days at RT. After this period of time, nitrogen was bubbled into the solution for 10 min, then NaBH4 (364 mg, 9.63 mmol) was added. The reaction mixture was stirred at RT for 10 min and then heated at 80° C. for 2 h. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was partitioned between diethyl ether and water. The aqueous layer was further extracted with diethyl ether and the combined organic phases were washed with water, followed by brine, then dried over Na2SO4 and concentrated in vacuo. 2-(4-Mercaptopiperidin-1-yl)-2-methylpropionic acid methyl ester (1.497 g, quantitative yield) was obtained as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 3.71 (3H, s), 3.01-2.85 (2H, m), 2.82-2.64 (1H, m), 2.33-2.14 (2H, m), 2.06-1.94 (2H, m), 1.71-1.58 (2H, m), 1.53-1.48 (1H, m), 1.29 (6H, s).
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[CH:5][S:4][CH:3]=1.[Li]CCCC.[C:13](=[O:15])=[O:14]>C1COCC1>[CH3:7][C:6]1[C:2]([C:13]([OH:15])=[O:14])=[CH:3][S:4][CH:5]=1
Reactant: Cc1cscc1Br
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cscc1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-bromo-4-methylthiophene (2.7 g, 15.6 mmol) in THF (35 mL) was added n-BuLi (1.6 M in hexane, 14.6 mL, 23.3 mmol) at −78° C. dropwise over a period of 15 min and the mixture was stirred at −78° C. for 30 min. The CO2 (gaseous) was passed through the reaction mixture for 10 min and the mixture was stirred at the same temperature for 20 min. Thereafter, the reaction mixture was warmed to 0° C., quenched with aqueous 1 M NaOH (60 mL) and washed with EtOAc (2×50 mL). The aqueous layer was acidified to pH ˜5 and extracted with DCM (2×50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 8% MeOH/DCM as eluent) to provide compound A56-1 (1.5 g, 70%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])C=O.[CH3:13][O:14][CH:15](OC)[O:16][CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO>[CH3:13][O:14][CH:15]([O:16][CH3:17])[C:4]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([F:1])[CH:3]=1
Reactant: O=Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(OC)c1ccc([N+](=O)[O-])c(F)c1

Procedure:
A mixture of 0.5 g (2.96 mmole) of 3-fluoro-4-nitrobenzaldehyde, 1 mL of trimethylorthoformate, 0.020 g of p-toluenesulfonic acid monohydrate and 2 mL of methanol was heated at reflux for 1 hour. The mixture was cooled, and 1 mL of saturated aqueous sodium bicarbonate solution was added. The mixture was concentrated under reduced pressure, and the residue was partitioned between 30 mL of ethyl acetate and 30 mL of saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.64 g of 4-dimethoxymethyl-2-fluoro-1-nitro-benzene (IV.2a) as a pale yellow oil. This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[C:21]([NH:24][CH2:25][CH2:26][NH2:27])(=[O:23])[CH3:22]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:27][CH2:26][CH2:25][NH:24][C:21](=[O:23])[CH3:22])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CC(=O)NCCN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5.8 g (30 mmol) 2,4-dichloro-5-nitropyrimidine in 120 mL of tetrahydrofuran (THF) at −78° C. under Argon atmosphere was added 5.2 mL (30 mmol) of N,N-diisopropylethylamine followed by 3.1 mL (30 mmol) of N-acetylethylenediamine. The mixture was stirred at −78° C. for 30 min, allowed to warm to room temperature, and stirred for an additional 3 hours. The solvent was removed in vacuo and the residue purified by flash chromatography eluting with EtOAc to provide the compound of formula (2), N-(2-(2-chloro-5-nitropyrimidin-4-ylamino)ethyl)acetamide as pale yellow solid.
Reaction SMILES: C([Li])(C)(C)C.[OH:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CCCCC.O1CCCC1>[CH:29]1([C:35]([O:6][CH:7]([C:20]2[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(OC(=O)C1CCCCC1)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl lithium (a 1.7 M solution in pentane; 0.33 ml, 0.55 mmol) was added dropwise to a solution of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (170 mg, 0.50 mmol) in tetrahydrofuran (5 ml) at 0 degrees under argon. After 10 minutes, cyclohexanecarboxylic acid chloride (74 microliter, 0.55 mmol) was added. The mixture was stirred at room temperature for 15 hours and quenched with water. Extraction and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was purified by preparative TLC (20×20 cm, 1000u silica plate; developed with 5% ethyl ether/hexane). The title ester was obtained as a pale yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Cl)([O-:15])=[O:14]>O>[CH3:7][N:8]([CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[N+:13]([O-:15])=[O:14])[S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CNS(C)(=O)=O
Reactant: O=[N+]([O-])c1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN(Cc1ccccc1[N+](=O)[O-])S(C)(=O)=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
171 a) To a suspension of potassium carbonate (1.2 g, 8.7 mmol) in was added N-methyl-methanesulfonamide (0.70 g, 6.4 mmol) followed by o-nitrobenzylchloride (1.0 g, 5.8 mmol). The mixture was heated at 50° C. for 18 hours. The mixture was cooled to room temperature and diluted with water (50 mL) and stirred for 30 minutes. The resulting precipitate was filtered and rinsed with water. The solid was dissolved in dichloromethane (25 mL), dried over magnesium sulfate, filtered, evaporated under reduced pressure then placed under high vacuum for 2 hours. N-Methyl-N-(2-nitro-benzyl)-methanesulfonamide was isolated as an orange-brown solid (1.12 g, 78%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.07 (d, J=8.0 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.70 (t, J=7.4 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 4.73 (s, 2H), 2.96 (s, 3H), 2.88 (s, 3H). MS=245 (MH)+. 171 b) N-(2-Amino-benzyl)-N-methyl-methanesulfonamide was prepared from N-methyl-N-(2-nitro-benzyl)-methanesulfonamide (1.12 g, 4.58 mmol) in a manner analogous to
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[CH2:8]([O:15][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)O1
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)CCC(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
A mixture of 5.0 g (0.05 mol) of succinic acid anhydride, 5.4 g (0.05 mol) of benzyl alcohol, 16.25 g (0.05 mol) of cesium carbonate, and 50 ml of N,N-dimethylforamide was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, and then poured into 200 ml of ethyl acetate. The mixture was washed with saturated aqueous NaCl containing 0.35 N HCl (3×100 mL). The ethyl acetate phase, which contains the product, was collected and dried over anhydrous MgSO4. The MgSO4 was removed via filtration, and the ethyl acetate was removed under reduced pressure. The crude product was purified by crystallization in diethyl ether and hexane to provide 7.34 g of succinic acid monobenzyl ester, 70.47%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]\[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[C:17]([N+:25]([O-])=O)[CH:16]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O.O>[CH3:12][O:11][C:7]1[CH:6]=[C:5](/[CH:13]=[CH:14]\[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:23])[F:24])=[C:17]([NH2:25])[CH:16]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(/C=C\c2ccc(OC(F)F)c([N+](=O)[O-])c2)cc(OC)c1OC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(/C=C\c2ccc(OC(F)F)c(N)c2)cc(OC)c1OC
Temperature: 50 °C
Yield: 68.5 %

Procedure:
4.1 grams (10.8 mmol) of (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3′-nitro-4′-difluoromethoxy-phenyl)ethene was dissolved in 10 ml of acetone/water (V/V, 2:1). The mixture was heated to 50°C., and was stirred to dissolve all the solid. 18.8 grams of sodium thiosulphate was added and the reaction mixture was heated to reflux for 6 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature. The organic layer was separated, and the water layer was extracted with 50 ml×4 of ethyl acetate. The organic layer was combined and was washed with saturated brine, and then was dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporator partially and then cooled to get crude product. The crude product was recrystallized from petroleum ether to give 2.6 grams of yellowish crystalline solid in a yield of 68.6%. 1H-NMR (ppm) δ: 7.08 (d, 1H, 2′-H), 6.92 (dd, 1H, 6′-H), 6.76 (d, 1H, 5′-H), 6.62 (s, 2H, 2,6-H), 6.49 (d, 1H, 1a-H), 6.43 (d, 1H, 1a′-H), 6.28 (t, 1H, J2H-F=72 Hz, —CHF2), 5.13 (broad, 2H, NH2), 3.86 (s, 3H, 4-OCH3), 3.70 (s, 6H, 3,5-OCH3).
Reaction SMILES: [C:1]([C:4]1[C:13]([CH3:14])=[CH:12][C:11]2[C:10]([CH3:16])([CH3:15])[CH2:9][CH2:8][C:7]([CH3:18])([CH3:17])[C:6]=2[CH:5]=1)(=[O:3])C.Cl[O-].[Na+].S(=O)(O)[O-:23].[Na+]>O1CCOCC1>[CH3:14][C:13]1[C:4]([C:1]([OH:23])=[O:3])=[CH:5][C:6]2[C:7]([CH3:17])([CH3:18])[CH2:8][CH2:9][C:10]([CH3:16])([CH3:15])[C:11]=2[CH:12]=1
Reactant: O=S([O-])O
Reactant: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1COCCO1
Product: Cc1cc2c(cc1C(=O)O)C(C)(C)CCC2(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 8.2 g (0.0336 mol) of 2-acetyl-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene, 90 ml of 1.19M (0.107 mol) aqueous sodium hypochlorite and 10 ml of dioxane was stirred at room temperature for 0.5 hours and at 60° C. for 2 hours. A further 70 ml of 1.19M (0.0833 mol) of aqueous sodium hypochlorite was then added to the reaction mixture and the mixture stirred at 70° C. for 1 hours. The reaction mixture was then cooled and treated with aqueous sodium bisulfite solution until the mixture was negative to starch/iodide paper. The mixture was washed with ether and then acidified with H2SO4. The mixture was extracted with three portions of ether and the ether extracts were then combined and washed successively with water and saturated NaCl solution and then dried (MgSO4). The ether solution was then concentrated and the title compound obtained as colorless crystals by recrystallization from cold ether.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:38])[C:17]2[CH:22]=[N:21][C:20](S(C)(=O)=O)=[N:19][C:18]=2[N:27]([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[CH2:34][CH2:33][CH2:32]3)[CH:28]=1)=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:38])[C:17]2[CH:22]=[N:21][C:20]([NH:9][CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[N:19][C:18]=2[N:27]([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[CH2:34][CH2:33][CH2:32]3)[CH:28]=1)=[O:14])[CH3:11]
Reactant: NCCCn1ccnc1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCCn3ccnc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(Step F) the title compound was prepared from 3-imidazol-1-yl-propylamine (4.4 μL, 0.036 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(Step E), 15 mg, 0.036 mmol). 19.2 mg of 2-(3-imidazol-1-yl-propylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.22 (s, 1H), 8.45 (s, 1H), 7.50 (br, 1H), 7.32 (d, 1H), 7.22 (s, 1H), 7.15 (d, 1H), 7.03 (br, 1H), 6.78 (br, 1H), 6.10 (br, 1H), 4.36 (q, 2H), 3.75 (m, 2H), 3.10 (m, 2H), 2.97 (m, 4H), 2.14 (m, 2H), 1.92 (m, 2H), 1.40 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H26N6O3: 459.21 (M+H). Found: 459.4.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:13][C:14]1([F:29])[CH2:19][CH2:18][C:17]([CH2:27][NH2:28])([C:20]2[CH:21]=[N:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH:28][CH2:27][C:17]1([C:20]2[CH:21]=[N:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:18][CH2:19][C:14]([F:13])([F:29])[CH2:15][CH2:16]1)=[O:6]
Reactant: COc1ccc(Cl)c(C(=O)O)c1
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Product: COc1ccc(Cl)c(C(=O)NCC2(c3ccc(F)nc3)CCC(F)(F)CC2)c1

Procedure:
From 2-chloro-5-methoxybenzoic acid and C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=413.1, tR (minutes, Method D)=0.72
Reaction SMILES: O=[S:2]1(=O)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)C>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3]1
Reactant: O=S1(=O)CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1ccc2c(c1)CCS2
Reaction time: 0.5 h
Yield: 58 %

Procedure:
A solution of 22.3 g (132 mmole) of the product of Part (ii) in 200 ml tetrahydrofuran was added dropwise with stirring to a mixture of 5.81 g (145 mmole) lithium aluminum hydride (95%) in 400 ml dry ethyl ether, at a rate sufficient to maintain gentle reflux. Refluxing was continued for 30 minutes. The mixture was cooled in ice and quenched by cautious addition of 6 ml water followed by 6 ml 15% (w/v) sodium hydroxide and 18 ml water. The resulting mixture was filtered, the organic phase washed with brine, dried (Na2SO4) and evaporated to provide a yellow oil which was distilled to yield 10.4 g (58%) product, b.p. 129°-131° C. The structure was verified by 1H-NMR spectroscopy.