Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:5]1[CH2:7][O:6]1)CC=C.[CH3:8][C:9](=[CH:11][CH3:12])[CH3:10]>>[CH3:8][C:9]([CH3:10])=[CH:11][CH2:12][CH2:1][CH:5]1[CH2:7][O:6]1
Reactant: C=CCCC1CO1
Reactant: CC=C(C)C
Product: CC(C)=CCCC1CO1

Procedure:
2-(But-3-enyl)oxirane (1.000 g, 10 mmol) and 2-methylbut-2-ene (10 g, 102 mmol) were stirred at room temperature for 24 hr in a sealed scintillation vial with Zhan catalyst 1 (0.057 g, 0.086 mmol). Solvent was removed under reduced pressure and the residue purified by column chromatography (0-10% EtOAc/n-hexane/silica) to give 2-(4-methylpent-3-enyl)oxirane as a colorless oil. 1H NMR (CDCl3): δ 5.2-5.1 (m, 1H), 2.95-2.88 (m, 1H), 2.75 (dd, 1H J1=5.0, J2=4.1), 2.48 (dd, 1H J1=5.0, J2=2.8), 2.15 (2H, q, J=7.4), 1.70 (s, 3H), 1.63 (s, 3H), 1.60-1.50 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](=[N:15]/[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[CH:20][CH:19]=2)/[C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1.Cl>O1CCCC1.CO.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](=[N:15]/[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[CH:20][CH:19]=2)/[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(/C(=N/OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)C(=O)O)cc1
Yield: 90 %

Procedure:
Ethyl Z-2-(4-methoxyphenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate (1.20 g) was dissolved in tetrahydrofuran (5 ml)-methanol (10 ml), and 0.5N aqueous solution of sodium hydroxide (10 ml) was added and the mixture was heated under reflux for 1 hour. 1N HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate to obtain Z-2-(4-methoxyphenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetic acid (1.02 g, yield 90%) as colorless crystals. m.p. 183-184° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:13]3[C:14]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:3][CH2:2]1.[CH:24]([C:26]1([C:30]([O:32][CH3:33])=[O:31])[CH2:29][CH2:28][CH2:27]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[F:23][C:20]([F:21])([F:22])[CH2:19][O:18][C:14]1[C:13]2[C:9]([O:8][CH2:7][CH:4]3[CH2:5][CH2:6][N:1]([CH2:24][C:26]4([C:30]([O:32][CH3:33])=[O:31])[CH2:29][CH2:28][CH2:27]4)[CH2:2][CH2:3]3)=[N:10][O:11][C:12]=2[CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)COc1cccc2onc(OCC3CCNCC3)c12
Reactant: COC(=O)C1(C=O)CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(OCC(F)(F)F)c34)CC2)CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole (0.33 g, 1.0 mmol, EXAMPLE 2, Step 2) and methyl 1-formylcyclobutanecarboxylate (0.17 g, 1.2 mmol, J. Org. Chem. 1993, 58, 6843-6850) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (0.42 g, 2.0 mmol) at room temperature. After being stirred at room temperature for 16 h, sat. aq. sodium hydrogencarbonate (20 mL) was added to the mixture. The mixture was extracted with dichloromethane (30 mL×2). The combined extract was dried over magnesium sulfate and concentrated in vacuo to give 0.46 g (quant.) of the title compound as a colorless oil.
Reaction SMILES: N([O-])=O.[Na+].C[O:6][C:7](=[O:29])[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]23[CH2:27][CH:22]4[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]4)[CH2:19]2)[CH2:25]3)=[CH:14][C:13]=1N.[ClH:30]>O>[C:18]12([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][CH2:8][C:7]([OH:6])=[O:29])=[C:13]([Cl:30])[CH:14]=3)[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2
Reactant: Cl
Reactant: COC(=O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1.00 g of sodium nitrite in 5 ml of water is added dropwise, whilst stirring, to a suspension of 5 g of 4-[4-(1-adamantyl)-2-amino-phenoxy]-butyric acid methyl ester in 10 ml of concentrated hydrochloric acid and 30 ml of water. After completion of the addition, the mixture is stirred for a further 3 hours at 0° C. The reaction solution is then filtered cold. The filtrate, kept at 0° C, is then added in portions to a solution of 5 g of freshly prepared copper-(I) chloride in 20 ml of concentrated hydrochloric acid at 0° C, whilst stirring. After completion of the addition, the temperature is allowed to rise to about 25° C and the mixture is then heated on a water bath until the evolution of nitrogen has ceased. It is then filtered, the residue is well rinsed with methylene chloride, and the filtrate is partitioned between 3 times 50 ml of methylene chloride and 50 ml of water. The organic phases are combined and evaporated in vacuo. The evaporation residue is dissolved in 100 ml of ethanol and 20 ml of 2 N sodium hydroxide solution and the mixture is left to stand for 24 hours at about 25° C. It is then evaporated to dryness in vacuo and the evaporation residue is partitioned between 150 ml of 2 N hydrochloric acid and twice 50 ml of methylene chloride. The organic phases are washed until neutral, dried over sodium sulphate and evaporated in vacuo. Chromatography of the evaporation residue on 100 g of silica gel, with ether as the migrating agent, and subsequent crystallisation from ethanol, gives 4-[4-(1-adamantyl)-2-chlorophenoxy]-butyric acid of melting point 164°-166° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[NH2:10][OH:11]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5](=[N:10][OH:11])[NH2:6]
Reactant: NO
Reactant: N#Cc1ccnc(Cl)c1
Solvent: CO
Product: NC(=NO)c1ccnc(Cl)c1
Reaction time: 1 h

Procedure:
A solution of 2-chloroisonicotinonitrile (Aldrich, 0.73 g, 5.27 mmol), and hydroxylamine (Aldrich, 50 wt %, 0.348 g, 5.27 mmol) in methanol (10 mL) was heated to reflux and stirred for 1 hour. The volatiles were removed under reduced pressure to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 6.09 (s, 2H), 7.67 (dd, J=5.4, 1.4 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 8.40 (d, J=5.2 Hz, 1H), 10.22 (s, 1H) ppm; MS (DCI/NH3) m/z 172 (M+H)+, 174 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([C:14]2[CH:26]=[CH:25][C:17]3[N:18]([CH:22]([CH3:24])[CH3:23])[C:19](=[O:21])[NH:20][C:16]=3[CH:15]=2)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[CH3:27]I>CN(C)C=O>[Cl:3][C:4]1[C:5]([C:14]2[CH:26]=[CH:25][C:17]3[N:18]([CH:22]([CH3:23])[CH3:24])[C:19](=[O:21])[N:20]([CH3:27])[C:16]=3[CH:15]=2)=[N:6][CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: CC(C)n1c(=O)[nH]c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)n(C)c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Temperature: 0 °C
Reaction time: 6 h
Yield: 80.8 %

Procedure:
0.23 g of an 80% strength by weight suspension of sodium hydride in mineral oil was added at 23° C. to 25 ml of anhydrous dimethylformamide. The mixture was then treated dropwise with a solution of 2.50 g of 5-(3-chloro-5-trifluoromethylpyridin-2-yl)-1-(1-methylethyl)benzimidazol-2-one in 25 ml of dimethylformamide and, after stirring for 15 minutes, with 1.05 g of methyl iodide. After stirring for 6 hours, the reaction mixture was poured into 300 ml of ice water. The aqueous phase was extracted three times with 100 ml of tert-butyl methyl ether each time, after which the combined organic phases were washed twice with 50 ml of water each time, dried over sodium sulfate and concentrated. Chromatography on silica gel using cyclohexane/ethyl acetate (4:1) as the eluent gave 2.1 g of colorless crystals. Yield: 75%; m.p.: 108-109° C.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:15][CH3:16])[C:9]=2[O:13][CH3:14])[C:4]1=[O:17].[C:18]([BH3-])#N.[Li+].O1[CH2:27][CH2:26]OCC1.Cl>C(O)C.CC(C)=O>[ClH:1].[CH:26]([NH:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:15][CH3:16])[C:9]=2[O:13][CH3:14])[C:4]1=[O:17])([CH3:27])[CH3:18]
Reactant: C1COCCO1
Reactant: [BH3-]C#N
Reactant: COc1ccc2c(c1OC)CCC(N)C2=O
Agent: Cl
Agent: [Li+]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1ccc2c(c1OC)CCC(NC(C)C)C2=O

Procedure:
In a mixture of 3 volume parts of dry acetone and 5 volume parts of dry ethanol, there is dissolved 0.075 part of 3,4-dihydro-2-amino-5,6-dimethoxy-1(2H)-naphthalenone hydrochloride. While the solution is held at 0° C. and with stirring, 0.080 part of the molecular compound of 1 mole of lithium cyanoborohydride and 2 moles of dioxane is added in small portions. After the addition has been completed, the mixture is stirred at 0° C. for 3 hours and, then, 1N hydrochloric acid is added in sufficient amounts to bring the pH to 2 or less. The acetone and ethanol are distilled off under reduced pressure and the residue is neutralized by the addition of a 5% aqueous solution of sodium hydrogen carbonate, after which the basic matter is extracted with ethyl ether. The ethyl ether layer is washed with water and dehydrated over anhydrous sodium sulfate. Then, dry hydrogen chloride gas is bubbled into the solution. The ethyl ether is distilled off and the residue is recrystallized from a mixture of ethanol and ethyl ether. The procedure gives 3,4-dihydro-2-isopropylamino-5,6-dimethoxy-1(2H)-naphthalenone hydrochloride. Melting point: 141°-157° C. (decomp).
Reaction SMILES: Cl.[CH3:2][CH:3]([NH:5][CH2:6][C:7]1([NH2:11])[CH2:10][NH:9][CH2:8]1)[CH3:4].[F:12][C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:15]([CH:19]=[CH:20][C:21]=1[F:22])[C:16](F)=[O:17]>C(=O)(O)[O-].[Na+].O1CCOCC1.O>[F:12][C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:15]([C:16]([N:9]2[CH2:10][C:7]([CH2:6][NH:5][CH:3]([CH3:4])[CH3:2])([NH2:11])[CH2:8]2)=[O:17])[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: CC(C)NCC1(N)CNC1
Reactant: O=C(F)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)NCC1(N)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.6 %

Procedure:
To a mixture of the 3-{[(1-methylethyl)amino]methyl}azetidin-3-amine hydrochloride (20 mg, 0.079 mmol) in saturated sodium bicarbonate solution (1.0 mL) and dioxane (1.0 mL) was added 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (31 mg, 0.079 mmol), prepared using procedures similar to those described in Reference 1, and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×5 mL). The combined extract was washed with water then brine solution (5 mL each), dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by reverse phase HPLC to afford 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-methylethyl)amino]methyl}azetidin-3-amine (15 mg, 37% yield). 1H NMR (400 MHz, d4-Methanol): 7.46-7.43 (dd, 1H), 7.35-7.33 (dd, 1H), 7.31-7.27 (m, 1H), 7.08-7.01 (dd, 1H), 6.63, 6.58 (td, 1H), 4.09-4.07 (d, 1H), 3.91-3.85 (dd, 2H), 3.76-3.73 (d, 1H). 2.80-2.74 (m, 1H), 2.73 (s, 2H), 1.07-1.05 (d, 6H); MS (EI) for C20H22F3IN4O: 519 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=O)[C:4]=2[CH:3]=[CH:2]1.Cl.CN(C)CCCN=C=NCC.O.N1(O)C2C=CC=CC=2N=N1.[Cl:36][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][C:46]=1[O:47][CH:48]([CH3:50])[CH3:49])[C:40]([NH:42]O)=[NH:41]>CN(C=O)C.O>[Cl:36][C:37]1[CH:38]=[C:39]([C:40]2[N:42]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[CH:2][NH:1]4)[O:12][N:41]=2)[CH:44]=[CH:45][C:46]=1[O:47][CH:48]([CH3:50])[CH3:49]
Reactant: CC(C)Oc1ccc(C(=N)NO)cc1Cl
Reactant: O=C(O)c1cccc2[nH]ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(-c2noc(-c3cccc4[nH]ccc34)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
Under an atmosphere of nitrogen a mixture of 1H-indole-4-carboxylic acid (3.88 g, 24.05 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (4.61 g, 24.05 mmol) and benzotriazol-1-ol hydrate (3.68 g, 24.05 mmol) in anhydrous DMF (61.4 ml) was stirred at ambient temperature for about 1 h. To the reaction mixture a solution of 3-chloro-N-hydroxy-4-isopropoxybenzamidine (5.0 g, 21.87 mmol) in DMF (11.51 ml) was added. The mixture was stirred and heated at about 140° C. for about 2 h. The mixture was cooled to ambient temperature and poured into water (IL). The product was partitioned between ethyl acetate and the aqueous phase. The organic layer washed with 1N HCl (4×150 mL), 1N NaOH (2×150 mL) and water (2×300 mL), dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the crude product was purified by elution through Florisil with heptane/ethyl acetate (2:1) to give 3-(3-chloro-4-isopropoxyphenyl)-5-(1H-indol-4-yl)-1,2,4-oxadiazole (2.76 g, 35.7%). LCMS (Table 1, Method b) Rt=2.69 min, m/z 354.17 (M+H)+.
Reaction SMILES: ClC[C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=3)[N:20]=2)[CH:6]=[CH:5][N:4]=1.O.[NH2:28][C:29]1[N:34]=[C:33]([SH:35])[NH:32][C:31](=[O:36])[CH:30]=1.[C:37](=O)([O-])[O-].[Na+].[Na+].O>C(O)(C)C>[NH2:28][C:29]1[N:34]=[C:33]([SH:35]([C:3]2[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]3[CH:16]=[CH:17][C:18]4[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=4)[N:20]=3)[CH:6]=[CH:5][N:4]=2)[CH3:37])[NH:32][C:31](=[O:36])[CH:30]=1
Reactant: Nc1cc(=O)[nH]c(S)n1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CCl
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1[SH](C)c1nc(N)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
A suspension of 0.7 g (1.7 mmol) of 6-[3-(2-chloromethyl-3-methylpyridin-4-ylsulfanyl)propylsulfanyl]-3-nitroimidazo[1,2-b]pyridazine, 0.275 g (1.7 mmol) of 6-amino-2-mercapto-3H-pyrimidin-4-one monohydrate and 0.18 g (1.7 mmol) of sodium carbonate in 20 ml of isopropanol is heated under reflux for 2.5 h. The suspension is then added to 250 ml of water and stirred at room temperature for 30 min. The precipitate is filtered off, washed with water, dried in a high vacuum and suspended in hot methanol. After filtering and drying again, 0.83 g (94%) of the title compound is isolated as a pale beige solid. M.p.: 244-246° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:35]([O:37][CH3:38])=[O:36].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:26][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:35]([O:37][CH3:38])=[O:36])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2ccc(F)c(Cl)c2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)NCCO[C@@H](c1ccc(F)c(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 4.3 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chloro-4-fluorophenyl)methyl)piperidine-1-carboxylate (1 g, 2.6 mmol) and DMAP (79 mg, 0.62 mmol) in dry CH2Cl2 (20 mL), Et3N (657 mg, 6.5 mmol) was added. The resulting mixture was cooled to 0-5° C. under ice-water bath, a solution of methyl chloroformate (1.22 g, 13 mmol, 5 eq) was added dropwise. After addition, the reaction mixture was stirred for 1-2 hr at rt. Water (20 mL) was added to quench the reaction. The aqueous layer was extracted with CH2Cl2 (3×20 mL), the combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative HPLC to afford (R)-tert-butyl 3-((R)-(3-chloro-4-fluorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (50 mg, yield 4.3%). 1H NMR (CDCl3, 400 MHz) δ 7.27 (m, 1H), 7.12 (m, 2H), 4.30 (s, 1H), 3.91 (d, 2H), 3.66 (s, 3H), 3.10-3.40 (m, 5H), 2.90 (m, 1H), 1.75 (s, 1H), 1.55 (d, 1H), 1.46 (s, 9H), 1.33 (m, 2H), 1.04 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]2)[N:3]=1.C(Cl)Cl.[CH3:19][O:20][C:21](Cl)=[O:22]>C(N(CC)CC)C>[N:10]1([C:4]2[N:3]=[C:2]([NH:1][C:21]([O:20][CH3:19])=[O:22])[N+:7]([O-:8])=[C:6]([NH:9][C:21]([O:20][CH3:19])=[O:22])[CH:5]=2)[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]1
Reactant: Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Nc1cc(N2CC=CCC2)nc(NC(=O)OC)[n+]1[O-]

Procedure:
45 G. of 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]pyrimidine-3-oxide are mixed in 600 ml. of methylene chloride with 90 ml. of triethylamine and cooled to 5° C. 90 Ml. of chloroformic acid methyl ester are added dropwise while stirring. The mixture is stirred at 5° C. for 30 minutes and at room temperature for 18 hours. Then, the mixture is treated with 100 ml. of methanol and subsequently extracted with 400 ml. of methylene chloride, washed with water, dried over sodium sulfate and evaporated under reduced pressure. Recrystallization of the residue from methanol yields dimethyl 6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidinedicarbamate-3-oxide having a melting point of 202°-203° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[OH:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[OH:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[CH:6]=2)(=[O:3])=[O:4])=[CH:25][CH:24]=1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Reactant: Nc1ccc(O)cc1
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(S(=O)(=O)Nc3ccc(O)cc3)cc2c2cc[nH]c12
Yield: 20.5 %

Procedure:
This compound is prepared according to synthesis 25, from 440 mg (0.75 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 161 mg (1.48 mmol) of 4-hydroxyaniline. After trituration in ethanol/diisopropyl ether mixture, then washing with water and drying, 33 mg (11%) of 8-(4-hydroxy-phenylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:1]([N:17]1[C:13](=[O:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCCCCCCCCO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCCCCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a mixture of 10-undecen-1-ol (4.23 g, 24.8 mmol), phthalimide (3.65 g, 24.8 mmol) and triphenylphosphine (6.51 g, 24.8 mmol) in anhydrous tetrahydrofuran (30 ml), a solution of DEAD (3.9 ml, 24.8 mmol) in anhydrous tetrahydrofuran (10 ml) was slowly added while keeping the temperature below 8-10° C. After 2 hours further DEAD (1.0 ml, 6.37 mmol) and triphenylphosphine (1.3 g, 4.96 mmol) were added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was triturated with diethyl ether (50 ml). The solid was removed by filtration and washed with diethyl ether (2×50 ml). The combined filtrates were concentrated and the residue was triturated with hexane (50 ml) at 40° C. The resulting solid was removed by filtration and washed with hexane (2×50 ml). The combined filtrates were concentrated and the residue was purified by column chromatography eluting with 10:2 hexane:ethyl acetate mixture. The product was obtained as a low-melting white solid (4.9 g, 66% yield).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1>>[ClH:1].[CH:13]1([O:19][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:22]3[C:21]([CH3:20])=[CH:25][C:24]([CH3:26])=[N:23]3)[N:11]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: OC1CCCCC1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Cc1cc(C)[nH]n1
Product: Cc1cc(C)n(-c2nc(OC3CCCCC3)c3ccccc3n2)n1
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, cyclohexanol and 3,5-dimethylpyrazole. Mp. 152.9-153.5° C.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[CH2:13]([O:15][C:16]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=[O:17])[CH3:14].C(I)C=C>C1COCC1.CCCCCC.CN(P(N(C)C)(N(C)C)=O)C>[CH2:13]([O:15][C:16]([C:18]1([CH2:3][CH:1]=[CH2:2])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:20][CH2:19]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)NC(C)C
Agent: C=CCI
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 100.9 %

Procedure:
In a 250-mL RBF was weighed 6.1 g (60 mmol) of diisopropylamine and dissolved in THF. This solution was cooled to −78° C. To this was added 24 mL of 2.5 M (60 mmol) of butyllithium in hexane and stirred for 15 min, warmed up to 0° C. for 20 min, re-cooled to −78° C. To this was added piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (12.87 g, 50 mmol) in THF (10 mL). There was almost no color change. This was stirred at −78° C. for 45 min. Then, a mixture of 5 g of HMPA and 10.92 g of allyl iodide was added via cannula. The solution was still clear, very light in yellow. This mixture was stirred at −78° C. for 20 min, then, the dry ice bath was removed and the stirring was continued to allow the reaction mixture warm to r.t. over 40 min. The reaction mixture was poured into ice (˜50 g), sat'd NH4Cl aq. (50 mL) and ether (50 mL). The two layers were separated, the aqueous layer was extracted with ether (3×50 mL). The combined organic layers were washed with brine, dried (K2CO3), filtered, and concentrated in vacuo to obtain 15 g (100%) of the title compound as a yellow liquid,
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH:16]([CH3:18])[CH3:17])=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)([O-:21])=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)\[CH:16]([CH3:18])[CH3:17])=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: COc1ccc(/C(=C/C=C/C(=O)O)C(C)C)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(/C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.6 %

Procedure:
As in Example 115, (E,E)-5-(4-methoxyphenyl)-6-methyl-2,4-heptadienoic acid (2,4 g) and 4-nitrophenol (1.63 g) in 15 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (2.02 g) and the mixture was stirred at room temperature for 18 hours. Crystallization of the crude product from 2-propanol-hexane yielded 2.85 g of (E,E)-5-(4-methoxyphenyl)-6-methyl-2,4-heptadienoic acid 4-nitrophenyl ester, mp 95°-96.5° C.