Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:10]1[CH2:15][C:14]2[C:16]3[C:29]([OH:30])=[CH:28][C:27]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[C:39]=4[CH3:45])=[CH:26][C:17]=3[O:18][C:19]([CH2:23][CH2:24][CH3:25])([CH2:20][CH2:21][CH3:22])[C:13]=2[CH2:12][CH2:11]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:46].[N:47]1([CH2:52][CH2:53][CH2:54][C:55](O)=[O:56])[CH2:51][CH2:50][CH2:49][CH2:48]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:46].[CH2:1]([N:10]1[CH2:15][C:14]2[C:16]3[C:29]([O:30][C:55](=[O:56])[CH2:54][CH2:53][CH2:52][N:47]4[CH2:51][CH2:50][CH2:49][CH2:48]4)=[CH:28][C:27]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[C:39]=4[CH3:45])=[CH:26][C:17]=3[O:18][C:19]([CH2:23][CH2:24][CH3:25])([CH2:20][CH2:21][CH3:22])[C:13]=2[CH2:12][CH2:11]1)[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CCCN1CCCC1
Reactant: CCCC1(CCC)Oc2cc(CCCCCCCc3cccc(C)c3C)cc(O)c2C2=C1CCN(CC=Cc1ccccc1)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCC1(CCC)Oc2cc(CCCCCCCc3cccc(C)c3C)cc(OC(=O)CCCN3CCCC3)c2C2=C1CCN(CC=Cc1ccccc1)C2

Procedure:
2-Cinnamyl-8-(2,3-dimethylphenyl-n-heptyl)-5,5-di(n-propyl)-10-hydroxy-1,2,3,4-tetrahydro-5H[1]benzopyrano [3,4-d]pyridine, γ-pyrrolidinobutyric acid hydrochloride and dicyclohexylcarbodiimide are reacted in equimolar amounts according to Example 1 to form the desired product.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([C:7](=O)C=CC1C=CC=CC=1)=[O:6])[CH3:3].Cl[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([O:26]O)=O)[CH:19]=1.S(C1C(C)=CC(O)=C(C(C)(C)C)C=1)C1C(C)=CC(O)=C(C(C)(C)C)C=1.C(Cl)CCl>C(Cl)(Cl)Cl>[CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:24]([C:20]2[CH:19]=[CH:18][CH:23]=[CH:22][CH:21]=2)[O:26]1)=[O:6])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)NC(=O)C(=O)C=Cc1ccccc1
Agent: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(C)NC(=O)C1OC1c1ccccc1

Procedure:
A mixture of N-(1-methylethyl)cinnamoylcarboxamide (18 g.), m-chloroperbenzoic acid (23.6 g.), 4,4'-thiobis(6-tert-butyl-m-cresol) (0.3 g.) and ethylene dichloride (250 ml.) was heated under gentle reflux for 1 hour, then chilled in ice. A precipitate (m-chlorobenzoic acid) was separated by filtration and washed with ethylene dichloride. The filtrate and washings were combined, and evaporated under reduced pressure on a rotary evaporator to give an amber oil. The oil was dissolved in chloroform (300 ml.) and the chloroform solution was washed with 5% aqueous sodium bicarbonate solution twice, then with saline. The chloroform solution was dried over magnesium sulfate, then evaporated under reduced pressure in a rotary evaporator to give an oil. The oil solidified on standing. The solid mass was recrystallized from ether giving 8.4 g. of product, m.p. 114°-115°.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(OCC)=O)C.[F:19][C:20]1([F:27])[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1>C1COCC1>[F:19][C:20]1([F:27])[CH2:25][CH2:24][C:23](=[CH:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:22][CH2:21]1
Reactant: O=C1CCC(F)(F)CC1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium hydride (0.298 g, 7.46 mmol) in THF (10 mL) was cooled to 0° C. tert-Butyl diethylphosphonoacetate (1.751 mL, 7.46 mmol) diluted with THF (10 mL) was added dropwise. The reaction mixture was removed from the cooling bath and stirred at room temperature for 30 min. The reaction mixture was then cooled to 0° C. and 4,4-difluorocyclohexanone (1 g, 7.46 mmol) diluted with THF (2 mL) was added. The reaction mixture was stirred at room temperature under nitrogen over night. The reaction was quenched with sat NH4Cl (50 mL). The aqueous phase was extracted with diethyl ether (3×25 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 50% solvent A/B=hexanes/EtOAc, REDISEP® SiO2 40 g). Concentration of the appropriate fractions provided Intermediate S-3A (1.43 g, 83%). 1H NMR (400 MHz, chloroform-d) δ 5.68 (s, 1H), 3.02 (td, J=6.7, 0.9 Hz, 2H), 2.43-2.36 (m, 2H), 2.12-1.97 (m, 4H), 1.51 (s, 9H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1COCC1.CCN(C(C)C)C(C)C.[Cl:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[F:25].Cl>C(Cl)Cl.O>[Cl:18][C:19]1[CH:20]=[C:21]([S:26]([N:2]([CH3:3])[CH3:1])(=[O:27])=[O:28])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
A solution of 2M dimethylamine in THF (5.9 mL, 12 mmol) was diluted with DCM (25 mL) and cooled to 0° C. DIPEA (2.8 mL) was added, followed by and 3-chloro-4-fluorobenzenesulfonyl chloride (2.5 g, 11 mmol) in DCM (25 mL). The resulting mixture was allowed to warm to rt and stirred for 3 hours. Water (5 mL) and 1M hydrochloric acid (16 mL) was added. The organic phase was separated and evaporated under reduced pressure to afford the title compound (2.4 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH:16]([CH:19]=O)[CH:17]=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2:21][NH2:22].O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:19]=[N:21][NH:22][CH:17]=1
Reactant: NN
Reactant: O=CC(C=O)C(c1ccccc1)c1ccc(Cl)cc1Cl
Solvent: O
Solvent: CCO
Product: Clc1ccc(C(c2ccccc2)c2cn[nH]c2)c(Cl)c1

Procedure:
Two grams of [(2,4-dichlorophenyl)phenylmethyl]malonaldehyde in 10 ml of ethanol were heated with 3 ml of anhydrous hydrazine on a steam bath for two hours. The reaction mixture was poured into water and extracted with ether. The ether extract was dried, filtered, and evaporated. The residue was crystallized twice from Skelley B/acetone to provide 1.2 g of the desired title product, m.p. 131° C.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].N1C=CC=CC=1.[O:11]=[C:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=2)[NH:13]1>>[CH:2]([O:4][S:21]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:11])[CH2:20]2)(=[O:22])=[O:23])([CH3:3])[CH3:1]
Reactant: CC(C)O
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: c1ccncc1
Product: CC(C)OS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-propanol (1.8 mL, 23.8 mmol) and pyridine (7.0 mL, 86.4 mmol) at 0° C. was added 2-oxo-2,3-dihydro-1H-indole-5-sulfonyl chloride (5.0 g, 21.6 mmol) in one portion. The resulting suspension was stirred at 0° C. for 45 mins and then warmed RT for 1 h. The reaction mixture was partitioned between DCM and 1M HCl. The organic layer was washed successively with 50 mL of 1M HCl, water, and brine. The organic layers were dried over MgSO4 and concentrated to produce an orange solid. Yield: 4.06 g (74%). 1H-NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1H), 7.74 (dd, J=8.2, 1.9 Hz, 1H), 7.70 (s, 1H), 7.01 (d, J=8.2 Hz, 1H), 4.68-4.58 (m, 1H), 3.75-3.69 (m, 2H), 1.19 (d, J=6.2 Hz, 6H). LC/MS (10-99%): M/Z: M+ (obs)=256.1; tR=2.10 min.
Reaction SMILES: [O:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:2]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][C:17]=1[Cl:25]>C1(C)C=CC=CC=1>[Cl:25][C:17]1[CH:18]=[C:19]([NH:22][C:23]([N:6]2[CH2:7][CH2:8][C:9]3[O:1][N:2]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]=3[CH2:5]2)=[O:24])[CH:20]=[CH:21][C:16]=1[Cl:15]
Reactant: CCOC(=O)c1noc2c1CNCC2
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1noc2c1CN(C(=O)Nc1ccc(Cl)c(Cl)c1)CC2

Procedure:
Ethyl 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-carboxylate (A-06) (for synthesis see above) (0.5 g, 2.55 mmol) was dissolved in toluene (25 ml), and 1,2-dichloro-4-isocyanatobenzene (0.48 g, 2.55 mmol) was added. The reaction mixture was refluxed for 2 h. Toluene was removed in vacuo, the residue was taken up in ethyl acetate and sat. sodium hydrogen carbonate solution, and the phases were separated. The aqueous phase was extracted with ethyl acetate, and then the combined organic phases were washed with sat. sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification of the crude product was carried out by column chromatography (silica gel, diethyl ether/hexane 2:1). Yield: 1.2 g (>99%)
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]([O:8]CC)=O)[C:2]#[CH:3].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:21])=[C:16]([N:18]=[C:19]=[S:20])[CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:21])=[C:16]([N:18]2[C:6](=[O:8])[CH2:5][N:4]([CH2:1][C:2]#[CH:3])[C:19]2=[S:20])[CH:17]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: C#CCNCC(=O)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCN1CC(=O)N(c2cc(Cl)ccc2C)C1=S
Temperature: 25 °C
Yield: 36.9 %

Procedure:
A mixture of ethyl N-propargylaminoacetate (7.0 g), 5-chloro-2-methylphenylisothiocyanate (9.2 g), triethylamine (5.0 g), and methylene chloride (100 mL) was heated at reflux for 3 hours. The reaction mixture was cooled to ambient temperature, washed with 1 N HCl (50 mL), then with water. The organic layer was dried over anhydrous magnesium sulfate, then evaporated to dryness. The residual oil was triturated with hexane. The solid was collected by filtration. Recrystallization from EtOAc afford the title compound (5.1 g) as yellow solid, m.p. 131°-134° C. Anal. Calcd. for. C13H11N2O Cl S: C, 56.01; H, 3.98; N, 10.05. Found: C, 55.90; H, 3.77; N, 9.92. Mass spectrum (EI, M.+) m/z 278.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH3:25])[CH:16]=2)[CH2:10][CH2:9]1)(C)(C)C>C(O)C.Cl.O1CCOCC1>[CH2:24]([O:23][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH3:22])[CH2:14][N:11]1[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]1)[CH3:25]
Reactant: CCOc1cc(CN2CCC(NC(=O)OC(C)(C)C)CC2)ccc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Yield: 66.6 %

Procedure:
A solution of [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (9.71 g, 26.64 mmol) in ethanol (50 mL) and 4 M HCl in dioxane (75 mL) was stirred at rt for 2 h. The hydrochloric acid was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (200 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure yielding 4.69 g (89%) of the title compound as a white solid. The crude material was directly used in the following reaction step without further purification. MS (ISP): 265.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:18](=N)[N:17]([CH3:20])[C:11]2[N:12]=[C:13]([NH2:16])[N:14]=[CH:15][C:10]=2[CH:9]=1.Cl.[OH2:22]>>[NH2:16][C:13]1[N:14]=[CH:15][C:10]2[CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:18](=[O:22])[N:17]([CH3:20])[C:11]=2[N:12]=1
Reactant: Cc1ccccc1-c1cc2cnc(N)nc2n(C)c1=N
Reactant: O
Agent: Cl
Product: Cc1ccccc1-c1cc2cnc(N)nc2n(C)c1=O
Temperature: 25 °C

Procedure:
To a mixture of 6-(2-methylphenyl)-7-imino-8-methyl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamine (0.30 g) from Example 8 and concentrated HCl (0.6 mL) was added water (11 mL). The reaction mixture was refluxed for 20 hours, then allowed to cool to room temperature. The white precipitate from the reaction mixture was filtered and washed with water. The product was dried in vacuo to give 0.21 g of 2-amino-6-(2-methylphenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one; mp 239-241° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][C:5]([C:12]2[N:13]([C:33](Cl)=[O:34])[C:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:4]([O:36][CH2:37][CH3:38])[CH:3]=1.Cl.Cl.[O:41]=[S:42]1(=[O:54])[CH2:47][CH2:46][CH:45]([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH2:44][CH2:43]1>>[Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][C:5]([C:12]2[N:13]([C:33]([N:51]3[CH2:52][CH2:53][N:48]([CH:45]4[CH2:44][CH2:43][S:42](=[O:41])(=[O:54])[CH2:47][CH2:46]4)[CH2:49][CH2:50]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:4]([O:36][CH2:37][CH3:38])[CH:3]=1
Reactant: CCOc1cc(Cl)c(S(C)(=O)=O)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=S1(=O)CCC(N2CCNCC2)CC1
Agent: Cl
Product: CCOc1cc(Cl)c(S(C)(=O)=O)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C2CCS(=O)(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-chloro-2-ethoxy-5-methanesulfonyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 61) was reacted with 1-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-piperazine dihydrochloride (example 22) to give the title compound as a racemic mixture. The enantiomers were separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Regis Technologies Whelk-01 3×25 cm, 35° C. at 100 bar, eluting with 40% methanol in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C36H42N4O6S2Cl3 [(M+H)+] 795.1606, observed 795.1605.
Reaction SMILES: OO.[C:3]([O:21][CH:22]1[CH2:27][C:26]([CH3:29])([CH3:28])[N:25]([OH:30])[C:24]([CH3:32])([CH3:31])[CH2:23]1)(=[O:20])[CH2:4][CH2:5][C:6]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([OH:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1)=[O:7].S([O-])([O-])=O.[Na+].[Na+].[C:39]([OH:43])([CH3:42])([CH3:41])[CH3:40]>>[OH:43][C:39]([CH3:42])([CH3:41])[CH2:40][O:17][N:12]1[C:13]([CH3:16])([CH3:15])[CH2:14][CH:9]([O:8][C:6](=[O:7])[CH2:5][CH2:4][C:3]([O:21][CH:22]2[CH2:27][C:26]([CH3:29])([CH3:28])[N:25]([O:30][CH2:40][C:39]([OH:43])([CH3:42])[CH3:41])[C:24]([CH3:32])([CH3:31])[CH2:23]2)=[O:20])[CH2:10][C:11]1([CH3:19])[CH3:18]
Reactant: CC1(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Reactant: CC(C)(C)O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CC(C)(O)CON1C(C)(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)N(OCC(C)(C)O)C(C)(C)C2)CC1(C)C

Procedure:
Aqueous hydrogen peroxide is added to a mixture of bis(1-oxyl-2,2,6,6-tetramethylpieridin-4-yl) succinate and ferrous chloride tetrahydrate in tert-butyl alcohol at 30-50° C. Excess peroxide is decomposed with aqueous sodium sulfite solution. The organic layer is concentrated and the crude product is purified by flash chromatography on silica gel to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].Br[CH2:15][CH2:16][CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+].CCCCCC.CCOC(C)=O>CC#N>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:2]([O:1][CH2:15][CH2:16][CH2:17][OH:18])[CH:3]=1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCCCCC
Product: COC(=O)c1ccc(OC)c(OCCCO)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3-hydroxy-4-methoxybenzoate (4.94 g, 26.6 mmol), 3-bromo-1-propanol (2.86 mL, 31.9 mmol) and anhydrous K2CO3 (5.51 g, 39.9 mmol) in MeCN (50 mL) is refluxed with stirring overnight, and after cooling is poured into ice/water. The aqueous layer is extracted with AcOEt, and the combined organics are washed with brine, dried (Na2SO4) and concentrated. Purification by flash chromatography on silica gel (hexane/AcOEt 1:2) gives a solid residue which is stirred in a 9:1 mixture of hexane/AcOEt over 30 min. Filtration of the suspension and drying in vacuo gives the title compound as white solid. TLC, Rf (hexane/AcOEt 1:1)=0.09. MS: 241.2 [M+H]+. tR (HPLC, Nucleosil C18HD column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 2.86 min. 1H-NMR (CDCl3): δ 2.13 (m, 2H), 2.59 (m, 1H), 3.92 (s, 3H), 3.93 (s, 3H), 4.29 (m, 2H), 6.92 (m, 1H), 7.60 (s, 1H), 7.73 (m, 1H) ppm.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH2:11])[CH:3]=1.C(N(CC)CC)C.C1(CC(Cl)=O)CC1.[O:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH:11][C:30]([CH:29]2[CH2:27][CH2:28]2)=[O:26])[CH:3]=1
Reactant: Cc1cc(N)ncc1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: O=C(Cl)CC1CC1
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)C2CC2)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
An ice-cooled mixture of 4-methyl-5-nitropyridin-2-amine (1 g, 6.5 mmol), triethylamine (1.31 g, 13 mmol) in tetrahydrofuran (20 mL) was treated with cyclopropyl acetyl chloride (0.75 g, 7.1 mmol) drop wise. After complete addition the reaction mixture was stirred at room temperature for 1 hour, cooled to 0° C. and added cyclopropyl acetyl chloride (0.75 g, 7.1 mmol) followed by stirring at room temperature for 1 hour. The solvent was evaporated under vacuum and water (100 mL) was poured into the reaction mixture and extracted with ethyl acetate (2×150 mL). The organic layer was washed with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue (1.5 g) was taken-up in methanol and water (4:1, 40 mL). Potassium carbonate was added to it and stirred at room temperature for 20 hours. The mixture was concentrated under vacuum. Residue was taken up in water (100 mL) and extracted with ethyl acetate (2×150 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to get the crude compound, which upon purification by silica gel column chromatography using methanol in dichloromethane (1%) as eluent afforded N-(4-methyl-5-nitropyridin-2-yl)cyclopropanecarboxamide (0.6 g, 52%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29][NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7])[CH3:2].[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([N:30]([CH2:29][C:26]1[CH:27]=[N:28][C:23]([Cl:22])=[CH:24][CH:25]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)=[O:8])[CH3:2]
Reactant: Clc1ccc(CNc2ccccn2)cn1
Agent: CCOC(=O)C(C(=O)O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)N(Cc1ccc(Cl)nc1)c1ccccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Phenylmalonic acid monoethyl ester was prepared following the procedure in Journal of Organic Chemistry 2000, 65, 5834-5836. 2-Phenylmalonic acid monoethyl ester (1.02 g, 5.0 mmol) was dissolved in anhydrous dichloromethane (10 mL), and oxalyl chloride (0.52 mL, 6.0 mmol) was added, followed by one drop of N,N-dimethylformamide. The reaction mixture was stirred for 30 min, then concentrated, redissolved in anhydrous dichloromethane (5 mL) and added to a solution of 6-chloro-N-2-pyridinyl-3-pyridinemethanamine (i.e. the product of Example 2, Step A) (1.1 g, 5.0 mmol) and triethyl amine (0.83 mL, 6.0 mmol) in anhydrous dichloromethane (5 mL) at 0° C. The stirred reaction mixture was allowed to warm to room temperature over 30 min. The reaction mixture was poured onto a silica gel cartridge (Bond Elute® manufactured by Varian) and purified using a gradient of 0-50% ethyl acetate/hexanes. A mixture of desired product and starting amine was isolated (1.3 g of 33 mol % recovered amine/67 mol % desired product). 2-Phenylmalonic acid monoethyl ester (0.54 g, 2.6 mmol) was dissolved in anhydrous dichloromethane (3 mL), and oxalyl chloride (0.26 mL, 3.0 mmol) was added, followed by one drop of N,N-dimethylformamide. The reaction mixture was stirred until gas evolution ceased and then concentrated, redissolved in anhydrous dichloromethane (3 mL) and added to the mixture of recovered amine and desired product isolated previously. The reaction mixture was stirred for 30 min and then concentrated, and the crude residue was chromatographed as already described to give the title compound as a solid (0.9 g).
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[CH:4]/[C:5]1([O:11][CH3:12])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.CC(C)=[O:15].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:12][O:11][C:5]1(/[CH:4]=[CH:3]/[C:2]([OH:15])=[O:1])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CC(C)=O
Reactant: COC1(/C=C/CO)CCOCC1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: COC1(/C=C/C(=O)O)CCOCC1

Procedure:
4-(3-hydroxy-trans-prop-1-enyl)-4-methoxy-tetrahydropyran (175 mg, 1.02 mmol), prepared as in Example 1, steps 1-3, was oxidized to the corresponding carboxylic acid by treatment with a slight excess of Jones reagent in cold acetone.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:11](Cl)=[C:10]([C:20]#[N:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:11]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[C:10]([C:20]#[N:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: Cc1ccc2c(c1)c(Cl)c(C#N)c(=O)n2Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c(N1CCNCC1)c(C#N)c(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
A solution of Compound 21 (1.2 g, 3.9 mmol) in dichloromethane was added slowly to a stirred solution of piperazine (1.67 g, 19.4 mmol) in dichloromethane at room temperature. The solution was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was taken in water, sonicated briefly, and filtered. The solids were dissolved in ethyl acetate and washed by water. The organic layer was dried over Na2SO4 and concentrated to yield 1.34 g (96%) of yellow solids. M.P. 152° C. 1H NMR (DMSO-d6): δ 2.34 (s, 3H), 2.94 (m, 4H), 3.54 (m, 4H), 5.44 (s, 2H), 7.16-7.20 (m, 2H), 7.22 (d, J=7.6 Hz, 1H), 7.28-7.31 (m, 3H), 7.40 (d, J=8.8 Hz, 1H), 7.64 (s, 1H). EIMS m/z 359 (M+1).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:16][C:15](=[O:17])[C:14]2=[C:18]([CH3:26])[N:19]=[C:20]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[N:13]2[N:12]=1)[CH2:2][CH3:3].[N+:27]([O-])([OH:29])=[O:28]>FC(F)(F)C(O)=O>[N+:27]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[C:6]([C:11]2[NH:16][C:15](=[O:17])[C:14]3=[C:18]([CH3:26])[N:19]=[C:20]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[N:13]3[N:12]=2)[CH:7]=1)([O-:29])=[O:28]
Reactant: CCCOc1ccccc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1ccc([N+](=O)[O-])cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
Analogously to the procedure of example 41A, 10.0 g (28.4 mmol) of the compound from example 26A are nitrated in 160 ml of trifluoroacetic acid and 40 ml of 70% strength nitric acid. The product is purified by silica gel chromatography using toluene and ethyl acetate in a gradient system.
Reaction SMILES: O[C:2]1([C:12]([OH:14])=[O:13])[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]1[OH:11]>S(=O)(=O)(O)O>[OH:11][C:3]1[CH:4]=[C:5]([C:8]([OH:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:12]([OH:14])=[O:13]
Reactant: O=C(O)C1=CC(O)C(O)(C(=O)O)C=C1
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(C(=O)O)c(O)c1

Procedure:
A solution of 100 mg of 1,2-dihydroxycyclohexa-3,5-diene-1,4-dicarboxylic acid in 5 mL of 5% sulfuric acid is heated at 85° C. for 60 minutes. The solid which forms is collected (by filtration or centrifugation). The filtrate shows the absence of the 270 nm absorbance. The solid is dissolved in 1 N sodium hydroxide, filtered, and the filtrate acidified with acetic acid. The solid is collected and dried to yield 2-hydroxybenzene-1,4-dicarboxylic acid. m.p. >300° C. 1NMR (d6 -DMSO) δ 7.42 (lH), 7.45 (lH), 7.88 (lH). UVmax =311, 247 nm (pH 7.0), ε311 =4.1 mM-1 cm-1.