Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH3:27][NH:28][CH2:29][CH2:30][CH3:31]>C(#N)C>[CH3:27][N:28]([CH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:18][CH:19]=2)[O:14]1)[CH2:29][CH2:30][CH3:31]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCCNC
Solvent: CC#N
Product: CCCN(C)CC1CCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), N-methylpropan-1-amine (N—,N—) (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 297 (M+, 2), 131 (5), 87 (6), 86 (bp), 77 (5), 58 (7).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][N:13]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(O[N:29]1[N:37]=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.O.NN>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:29][NH2:37])=[O:17])=[CH:14][N:13]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)O)cn2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)NN)cn2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.4 %

Procedure:
To a solution of 6-(1-tert-butoxycarbonylamino-cyclopropyl)-nicotinic acid (0.50 g, 1.8 mmol) in DMF (3 mL) was added HATU (0.68 g, 1.8 mmol), Et3N (0.25 mL, 1.8 mmol) and the mixture allowed to stir at room temperature for 20 min. Hydrazine monohydrate (0.09 mL, 1.8 mmol) was then added and the reaction stirred for 1 h. The mixture was diluted with water and extracted with EtOAc (3×100 mL). The combined extracts were washed with water, brine and dried with MgSO4. The mixture was filtered and concentrated to give [1-(5-hydrazinocarbonyl-pyridin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester (0.51 g, 1.7 mmol) as a yellow solid, m/z 293.7 [M+H]+.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.C(O)C>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])[CH:3]=1
Reactant: O=C(c1csc(Br)c1)N1CCCCC1
Reactant: OB(O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCO
Product: O=C(c1csc(-c2ccccc2Cl)c1)N1CCCCC1
Temperature: 140 °C
Yield: 58.1 %

Procedure:
(5-Bromo-thiophen-3-yl)-piperidin-1-yl-methanone (75 mg, 0.27 mmol) was dissolved in dimethoxyethane (1 mL) and ethanol (1 mL). 2-Chlorophenylboronic acid (0.54 mmol), [1,1′-bis(diphenylphosphino)ferrocine]dichloropalladium (II) (0.014 mmol) and caesium carbonate (0.41 mmol) were added and the reaction mixture heated to 140° C. using microwave irradiation for 1 hour. The solvent was removed under vacuum and the residue dissolved in ethyl acetate. The organic solution was washed with water, dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified by column chromatography on silica, eluting with 0%-25% ethyl acetate in petroleum ether. The fractions containing the desired product were concentrated under vacuum to give the title compound (48 mg). LCMS m/z 306.02 [M+H]+ R.T.=11.48 min (Analytical Method 2). 1H NMR (400 MHz, CHCl3-d): δ 7.5 (m, 3H), 7.4 (s, 1H), 7.3-7.4 (m, 2H), 3.6 (m, 4H), 1.7-1.5 (m, 6H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].[CH3:19][S:20][CH2:21][C:22](=O)[CH3:23]>O1CCCC1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[C:22]([CH3:23])[CH2:21][S:20][CH3:19])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Reactant: CSCC(C)=O
Solvent: C1CCOC1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CSC
Temperature: 25 °C
Reaction time: 22 h
Yield: 86.1 %

Procedure:
To a 20 ml volume two-necked flask, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39) (0.50 g), tetrahydrofuran (anhydrous) (9 ml), and 1-methylsulfanyl-2-propanone (7-0-1) (0.23 g) were added and stirred at room temperature for 22 hours under a nitrogen atmosphere. Additional 1-methylsulfanyl-2-propanone (7-0-1) (0.12 g) was added thereto, and the mixture was further stirred at room temperature for 7 hours. Then, the reaction mixture was concentrated under reduced pressure. After the concentration, the residue was subjected to column chromatography (hexane:ethyl acetate=1:1) to gave 0.58 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfanyl-2-propylidene)hydrazine ((4-4)-(1)-39).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:47]1[NH:52][CH2:51][CH2:50][N:49]2[CH2:53][CH2:54][CH2:55][C@H:48]12>CN(C)C(=O)C.CC1CCCO1>[Cl:1][C:2]1[C:3]([C:4]([N:52]2[CH2:51][CH2:50][N:49]3[CH2:53][CH2:54][CH2:55][C@@H:48]3[CH2:47]2)=[O:6])=[CH:7][C:8]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])(=[O:14])=[O:13])=[C:9]([F:11])[CH:10]=1
Reactant: C1C[C@@H]2CNCCN2C1
Reactant: O=C(O)c1cc(S(=O)(=O)Nc2ccccc2F)c(F)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CC1CCCO1
Product: O=C(c1cc(S(=O)(=O)Nc2ccccc2F)c(F)cc1Cl)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-chloro-4-fluoro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid (0.9 g, 2.59 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1.08 g, 2.85 mmol) in N,N-dimethylacetamide (6.4 mL) and 2-methyltetrahydrofuran (15 mL) was added (R)-octahydropyrrolo[1,2-α]pyrazine (0.46 g, 3.68 mmol) in 2-methyltetrahydrofuran (4 mL). The reaction was stirred at ambient temperature overnight and diluted with 2-methyltetrahydrofuran (15 mL). The organic solution was washed with 6% NaHCO3/6% NaCl (10 mL), and the aqueous layer was extracted with 2-methyltetrahydrofuran (15 mL). The combined organic layers were washed with 6% NaHCO3/6% NaCl (10 mL) and saturated NaCl (2×10 mL), and then concentrated. The residue was concentrated from ethanol (2×10 mL) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH2:20][CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: NCCCN1CCOCC1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Clc1nc(NCCCN2CCOCC2)c2cc[nH]c2n1
Yield: 123.2 %

Procedure:
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (105 mg, 0.56 mmol), 3-morpholinopropylamine (0.164 mL, 1.12 mmol) and triethylamine (0.150 mL, 1.08 mmol) in nBuOH (3 mL) was stirred at 60° C. overnight. It was then purified by HPLC to give 2-chloro-N-(3-morpholinopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a solid (204 mg).
Reaction SMILES: [ClH:1].[CH2:2]([O:5][NH2:6])[CH2:3][CH3:4].[OH-].[Na+].S(O)(O)(=O)=O.CS[C:16](=[NH:18])[NH2:17]>O>[ClH:1].[CH2:2]([O:5][NH:6][C:16]([NH2:18])=[NH:17])[CH2:3][CH3:4]
Reactant: CSC(=N)N
Reactant: CCCON
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCCONC(=N)N

Procedure:
To a solution of 113.2 g. of propoxyamine hydrochloride in 200 ml. of ice cold water there is added 81.2 g. of 50% aqueous sodium hydroxide solution. The mixture is stirred for thirty minutes and 141.0 g. of S-methyl-2-thiopseudourea sulfate and 200 ml. of water are added. The mixture is stirred at room temperature for two hours and then heated to reflux for one hour. The mixture is treated with 81.2 g. of 50% aqueous sodium hydroxide filtered and evaporated in vacuo. The residue is slurried in 200 ml. of absolute ethanol, the suspension filtered and the filtrate evaporated to an oil. The crude oil is dissolved in 300 ml. of chloroform, the mixture is cooled and filtered to give a clear solution of the guanidine free base. The chloroform solution is made acidic with methanolic hydrogen chloride and then evaporated in vacuo to give propoxyguanidine hydrochloride as a clear viscous oil (m.p. of picrate 179°-80° C.).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][C:2]1([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>C(Cl)Cl>[CH3:22][S:19]([O:11][CH2:10][CH2:9][C:2]1([CH2:6][CH2:7][O:8][S:19]([CH3:22])(=[O:21])=[O:20])[O:3][CH2:4][CH2:5][O:1]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1(CCO)OCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1(CCOS(C)(=O)=O)OCCO1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,2′-(1,3-dioxolane-2,2-diyl)diethanol (1.3 g, 8.0 mmol) in methylene chloride (100 mL) was added triethylamine (3.4 mL, 24 mmol) at room temperature. The solution was cooled down to −40° C. and then mesyl chloride (1.65 mL, 20 mmol) was added dropwise. The reaction mixture was stirred at −40° C. for 30 min, then warmed up to 0° C. gradually. The reaction was quenched with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with methylene chloride. The combined organic extracts were washed with brine, dried over Na2SO4, then evaporated to afford the crude product, 1,3-dioxolane-2,2-diyldiethane-2,1-diyl dimethanesulfonate: MS (m/e): 319 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([C:15]([CH3:17])=[CH2:16])[N:3]=1.[H][H]>[Pd].C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1
Reactant: [H][H]
Reactant: C=C(C)c1nc(N)nc(-c2ccco2)c1C#N
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)c1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-isopropenyl-pyrimidine-5-carbonitrile, hydrogen and palladium on charcoal in THF. ES-MS m/e (%): 229 (M+H+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: NCCCCC(=O)O
Product: O=C(O)CCCCN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Yield: 72.4 %

Procedure:
3-nitrophthalic anhydride (0.5 g, 0.0026 mol) and 5-aminopentanoic acid (0.30 g, 0.0026 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.55 g (73%) 123 as pale yellow flat crystals: mp=158–160° C.; Rf 0.69 (A): Rf 0.90 (C): Rf 0.73 (D): 1H NMR (DMSO-d6) δ 1.53 (m, 2H), 1.58 (m, 2H), 2.24 (t, J=7.1 Hz, 2H), 3.57 (t, J=6.7 Hz, 2H), 8.04 (dd, J=8.0, 7.5 Hz, 1H), 8.16 (d, J=7.5 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H); IR (cm−1): 2800–3130 (OH), 3096 (C═CH), 2691 (C—H), 1774 (C═O), 1723 (bs, C═O), 1616 (C═C), 1543 (N═O), 1466 (C═C), 1443 (C═C), 1396 (C—O), 1358 (N═O), 1209 (C—O), 1050 (C—O), 722 (C═CH); MS m/z (rel intensity) 291 (92), 247 (31), 191 (100).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[C:3]=1[N+:10]([O-:12])=[O:11].C([O-])(O)=O.[Na+].[CH3:18][C:19]1[O:23][C:22](B(O)O)=[CH:21][CH:20]=1>C1COCC1.CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][C:19]1[O:23][C:22]([C:2]2[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[C:3]=2[N+:10]([O-:12])=[O:11])=[CH:21][CH:20]=1
Reactant: Cc1ccc(B(O)O)o1
Reactant: Nc1nc(N)c([N+](=O)[O-])c(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc(N)nc(N)c2[N+](=O)[O-])o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A solution of 6-chloro-5-nitropyrimidine-2,4-diamine (10 g, 60% pure, 32 mmol) in THF (300 mL) was treated with saturated aq NaHCO3 (75 mL), 5-methylfuran-2-boronic acid (7.33 g, 0.058 mol) and Pd(PPh3)4 (1 g, 0.865 mmol) and refluxed with vigorous stirring under argon overnight. The mixture was cooled to room temperature, diluted with EtOAc (400 mL) and water (300 mL), filtered to remove insoluble material and the filtrate was extracted with EtOAc (2×100 mL). The combined organic phase was dried (MgSO4), concentrated in vacuo and the resulting solid triturated with dichloromethane and filtered to give the title compound (6 g, 72%) as a yellow solid; mp 196.3-196.9° C.; IR νmax (Nujol)/cm−1 3442, 3169, 2930, 1629, 1463, 1377, 1027, and 790; NMR δH (400 MHz, DMSO) 7.40 (2H, br s), 7.09 (2H, br s), 6.87 (1H, dd, J 0.5, 3.2 Hz), 6.26 (2H, dd, J 1.0, 3.3 Hz) and 2.28 (3H, s).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[C:12]([CH2:25][O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])=[N:13][N:14]([CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH:15]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Cl:39][C:40]([Cl:47])([Cl:46])[CH2:41][O:42][C:43](Cl)=[O:44]>CCOC(C)=O.O>[Cl:39][C:40]([Cl:47])([Cl:46])[CH2:41][O:42][C:43](=[O:44])[NH:10][C:8]1[N:7]([C:11]2[C:12]([CH2:25][O:26][Si:27]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:29])[CH3:30])[CH:34]([CH3:36])[CH3:35])=[N:13][N:14]([CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH:15]=2)[N:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[CH:9]=1
Reactant: CC(C)[Si](OCc1nn(CCOC2CCCCO2)cc1-n1nc(C(C)(C)C)cc1N)(C(C)C)C(C)C
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)[Si](OCc1nn(CCOC2CCCCO2)cc1-n1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To a solution of Intermediate 74f (0.44 g, 0.85 mmol) in EtOAc (5 mL) was added 1N aqueous NaOH solution (1.7 mL, 1.7 mmol) followed by 2,2,2-trichloroethylchloroformate (0.13 mL, 0.93 mmol). The reaction was stirred at RT for 4 h then treated with another portion of 2,2,2-trichloroethylchloroformate (35 μL, 0.25 mmol) and stirred over the weekend. The reaction was treated with another portion of 2,2,2-trichloroethylchloroformate (35 μL, 0.25 mmol) and stirred for 1 h then diluted with EtOAc and water and the layers were separated. The aqueous layer was then extracted with EtOAc (2×). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-4% MeOH in DCM, to give the title compound (0.47 g, 80%). 1H NMR (300 MHz, CDCl3): 0.96 (18H, d, J=6.8 Hz), 1.01-1.17 (3H, m), 1.25 (9H, s), 1.38-1.51 (4H, m), 1.54-1.75 (2H, m), 3.36-3.45 (1H, m), 3.58-3.68 (1H, m), 3.68-3.77 (1H, m), 3.97-4.07 (1H, m), 4.24 (2H, t, J=4.7 Hz), 4.51 (1H, t, J=3.2 Hz), 4.59 (2H, s), 4.69-4.73 (2H, m), 6.26 (1H, s), 7.63 (1H, s), 7.74 (1H, s).
Reaction SMILES: Br.Br.[NH2:3][C:4]1[CH:5]=[N:6][C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[N:14]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1>[OH-].[Na+].O1CCOCC1>[NH2:3][C:4]1[CH:5]=[N:6][C:7]2[CH2:13][CH2:12][N:11]([C:23](=[O:24])[CH2:22][C:19]3[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=3)[CH2:10][CH2:9][C:8]=2[N:14]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: Nc1cnc2c(n1)CCNCC2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1cnc2c(n1)CCN(C(=O)Cc1ccc(Cl)cc1)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5.8 gm (17.9 mmols) of 2-amino-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine dihydrobromide were dissolved in 50 ml of 2 N sodium hydroxide, and the solution was admixed dropwise with an ice-cooled solution of 7.5 gm of p-chlorophenyl-acetyl chloride in 50 ml of dioxane. The resulting mixture was stirred overnight and then evaporated, and the residue was extracted with chloroform. The chloroform extract was dried and then evaporated, and the residue was triturated with carbon tetrachloride and suction-filtered.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OC(NCCCC(OC1C(C)=CC=CC=1C)=O)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: Oc1ccccc1
Agent: Cc1cccc(C)c1OC(=O)CCCNC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NCCC(=O)Oc1ccccc1

Procedure:
The title compound was prepared from N-(tert-butoxycarbonyl)-β-alanine and phenol in a similar manner as described for 2,6-dimethylphenyl 4-[(tert-butoxycarbonyl)amino]butanoate. Mass Spectrum (M-tert-Bu)+H+ 211.09.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][C@@H:4]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:5]([CH2:23][CH:24]=C)([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].I([O-])(=O)(=O)=O.[Na+].C(OCC)C.[OH2:48]>[Os](=O)(=O)(=O)=O>[CH:24]([CH2:23][C:5]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])([C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])[C@H:4]([C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])[CH2:3][CH:2]([CH3:36])[CH3:1])=[O:48]
Reactant: C=CCC(C(=O)OCc1ccccc1)(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)OCc1ccccc1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOCC
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(CC=O)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.23 g of 1,2-dibenzyl 1-tert.butyl 4-methyl-1-(prop-2-en-1yl)-1,1,2(R)-pentanetricarboxylate, 3 ml of a 1% aqueous solution of osmium tetroxide, 2.44 g of sodium periodate, 15 ml of diethyl ether and 15 ml of water was stirred at room temperature for 1 hour. A further 3.25 g of sodium periodate were added and the mixture was stirred at room temperature for 24 hours. The ether layer was separated and the aqueous layer was extracted with diethyl ether. The combined ether layers were washed repeatedly with 5% aqueous ascorbic acid solution and saturated sodium chloride solution. After drying over magnesium sulfate, the solution was evaporated and the residue was purified by flash chromatography on silica gel using hexane/diethyl ether (8:1) for the elution. There was obtained 0.955 g of 1,2-dibenzyl 1-tert.butyl 1-(formylmethyl)-4-methyl-1,1,2(R)-pentanetricarboxylate in the form of a colorless oil; MS: 497 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]([O:13]CC)=[O:12])[CH2:7][CH2:6]1)=[O:4].O.[OH-].[Li+]>CO.O>[CH3:1][N:2]([CH3:16])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: CCOC(=O)C1CCN(C(=O)N(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)C(=O)N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
Ethyl 1-(N,N-dimethylcarbamoyl)piperidine-4-carboxylate (2.28 g, 10.0 mmol) obtained in Step 1 was dissolved in a mixed solvent of methanol (30 mL) and water (10 mL), lithium hydroxide monohydrate (2.10 g, 50.0 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and 6 mol/L hydrochloric acid was added to the resulting residue to adjust the pH to 1, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure to afford 1-(N,N-dimethylcarbamoyl)piperidine-4-carboxylic acid (830 mg, 42%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[C:16]3[C:17]([OH:21])=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH:13]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:22](O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:22]([O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]2[C:16]3[C:17]([OH:21])=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH:13]=2)=[CH:8][CH:9]=1)=[O:3])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(CCc2coc3cccc(O)c23)cc1
Reactant: OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc(CCc2coc3cccc(O)c23)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.8 %

Procedure:
To a solution of 3-[2-(4-carboxyphenyl)ethyl]-4-hydroxybenzofuran (0.25 g) in tetrahydrofuran (1 mL) were added benzyl alcohol (96 mg), triphenylphosphine (0.26 g) and diethyl azodicarboxylate (40% toluene solution, 0.43 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1) to give the title compound (0.26 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1([C:15](OC)=[O:16])[CH:12]2[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:14][CH:6]1[CH2:7]3)[CH2:11]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][C:5]1([CH2:15][OH:16])[CH:6]2[CH2:14][CH:10]3[CH2:9][CH:8]([CH2:13][CH:12]1[CH2:11]3)[CH2:7]2
Reactant: COCCC1(C(=O)OC)C2CC3CC(C2)CC1C3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCC1(CO)C2CC3CC(C2)CC1C3
Reaction time: 14 h

Procedure:
To a solution of EXAMPLE 56B (135 mg) in tetrahydrofuran (5 mL) was added dropwise lithium aluminum hydride (0.535 mL) at room temperature. The reaction mixture was stirred for 14 hours and sodium hydroxide (0.324 mL) was carefully added. The reaction mixture was stirred at room temperature for 60 minutes, filtered and concentrated.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:11][C:12]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14](F)[CH:13]=1.[CH2:27]([OH:29])[CH3:28].ClCCl>C1COCC1>[NH2:11][C:12]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([O:29][CH2:27][CH3:28])[CH:13]=1
Reactant: CCO
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1OCC
Temperature: 60 °C
Reaction time: 16 h

Procedure:
KHMDS (1.92 g, 9.64 mmol) was added to a mixture of ethyl 4-amino-2-fluoro-5-nitro-benzoate (2.00 g, 8.77 mmol) and ethanol (0.56 mL, 9.64 mmol) in 70 mL THF at 0° C. The mixture was stirred at 60° C. for 16 h. Then KHMDS (1.92 g, 9.64 mmol) and ethanol (1.2 mL, 20.7 mmol) were added at ambient temperature and the mixture was stirred at 60° C. for 2 h. 100 mL dichloromethane were added and the mixture extracted with sat. NH4Cl (aq). The organic layer was evaporated, the residue mixed with ethyl acetate, washed with sat. NaCl (aq), dried over Na2SO4, filtered and evaporated. The residue was purified twice by chromatography (silica gel; eluens: petrol ether/ethyl acetate=1:1 and 2:1).