Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH2:6].Cl[C:8]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].O>CN(C)C(=O)C>[S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][C:8](=[O:9])[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1nncs1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(Nc1nncs1)Oc1ccccc1
Yield: 75.6 %

Procedure:
1,3,4-Thiadiazol-2-amine (253 mg, 2.50 mmol) in N,N-dimethylacetamide (3 mL) was stirred with phenyl chloroformate (392 μL, 3.13 mmol) at room temperature for one day. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water and hexane and dried under reduced pressure to give the title compound as a colorless solid (418 mg, yield 76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][CH:14]=O)[N:9]=[CH:8][CH:7]=[CH:6]2.[O:16]1[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[O:16]1[C:20]2([CH2:25][CH2:24][N:23]([CH2:14][CH2:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][C:3]=3[O:2][CH3:1])[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: COc1cc2cccnc2cc1CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc2cccnc2cc1CCN1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.8 %

Procedure:
1.45 g of (6-methoxyquinolin-7-yl)acetaldehyde and 0.63 g of 1,4-dioxa-8-azaspiro[4.5]decane were dissolved in 20 ml of methylene chloride. Thereafter, 0.42 ml of acetic acid and 0.74 g of sodium triacetoxyborohydride were added to the reaction solution, and the obtained mixture was then stirred at room temperature for 3 hours. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol), so as to obtain 445 mg of the subject compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:29](=O)[CH2:30][CH:31]([CH3:33])[CH3:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:20]=2)[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(OCc3ccccc3)cc2)CC1
Reactant: CC(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
4-(4-Benzyloxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (40a, 3.0 g, 7.84 mmol) was dissolved in CH2Cl2 (50 mL) and treated with isovaleraldehyde (0.84 mL, 7.84 mmol). The reaction was stirred for 30 minutes, then cooled to 0° C., treated with NaBH(OAc)3, and stirred overnight. The reaction was diluted with EtOAc (400 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 6% MeOH/CH2Cl2 to give 3.3 g (93%) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][N:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][C@H:28]([CH3:30])[O:27][C@H:26]([CH3:31])[CH2:25]2)=[CH:20][C:19]=1[C:32]1[CH:36]=[CH:35][O:34][C:33]=1[CH3:37].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:30][C@H:28]1[O:27][C@@H:26]([CH3:31])[CH2:25][N:24]([C:21]2[CH:22]=[CH:23][C:18]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[C:19]([C:32]3[CH:36]=[CH:35][O:34][C:33]=3[CH3:37])[CH:20]=2)[CH2:29]1
Reactant: Cc1occc1-c1cc(N2C[C@@H](C)O[C@@H](C)C2)ccc1Br
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
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: C1COCCO1
Solvent: O
Product: Cc1cc(-c2ccc(N3C[C@@H](C)O[C@@H](C)C3)cc2-c2ccoc2C)ccn1
Temperature: 100 °C

Procedure:
2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (313 mg, 1.428 mmol) was added to a solution of cis-4-[4-bromo-3-(2-methyl-3-furanyl)phenyl]-2,6-dimethylmorpholine (500 mg, 1.428 mmol) in a mixture of 1,4-dioxane (6 mL), water (1.000 mL) and sodium carbonate (303 mg, 2.86 mmol). The solution was degassed using argon gas and then charged with tetrakis(triphenylphosphine)palladium(0) (165 mg, 0.143 mmol). After addition, the reaction mixture was stirred and heated in the microwave at 100° C. overnight. Crude LCMS showed starting material and desired product so 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.5 equivalents), tetrakis(triphenylphosphine)palladium(0) (0.05 equivalents) and sodium carbonate (1.0 equivalent) were added and the reaction mixture was stirred and heated at 100° C. in the microwave for a further 1 hour. Crude LCMS showed desired product and no starting material can be seen. The reaction mixture was washed with ethyl acetate (200 mL), water (100 mL), filtered and then evaporated to dryness. The residue was dissolved in dichloromethane (˜10 ml) and purified on silica by using a Biotage SP4 chromatographic system (40+M cartridge, eluted with 0-50% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure. This solid was dissolved in 1:1 MeCN:DMSO (3×0.9 mL) and purified by MDAP. Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound as a yellow oil (169 mg, 0.443 mmol, 31.0% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C1(C)C=CC=CC=1.[C:23](#[N:26])[CH:24]=[CH2:25]>C1C=CC=CC=1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:25][CH2:24][C:23]#[N:26])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=CC#N
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c1c(n2CCC#N)CCN(C)C1
Reaction time: 0.25 h
Yield: 52.6 %

Procedure:
2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.5 g, 7.5 mmol) was taken in 20 ml of benzene: toluene mixture (1:1) along with acrylonitrile (1 ml, 15 mmol), cooled to 0° C., followed by addition of triton base (0.3 ml). The contents were stirred for 15 min. Acrylonitrile and triton base (same amount) were added and stirred at RT for 1 h. The reaction was monitored by TLC and LCMS. On completion of the reaction, reaction mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain solid material, which was crystallized using diethyl ether to yield 3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propanenitrile (yield: 1 g). 1H NMR (CDCl3) 7.25 (s, 1H), 7.18-7.15 (d, 1H), 7.08-7.03 (d, 1H), 4.38-4.32 (t, 2H), 3.70-3.65 (m, 2H), 2.95-2.90 (m, 4H), 2.78-2.70 (t, 2H), 2.58 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[C:25]([CH:30]([CH3:32])[CH3:31])[CH:24]=1.N1CCCCC1>ClCCl>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][C:2]2[C:3](=[O:21])[O:4][C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:6][C:7]=2[OH:8])=[C:25]([CH:30]([CH3:32])[CH3:31])[CH:24]=1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: CC(C)c1cc(Cl)ccc1S
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)c1cc(Cl)ccc1SC1=C(O)CC(c2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 2.1 mmol of 4-chloro-2-isopropylbenzenethiol, and 2.1 mmol of piperidine in 30 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p. 95-96° C.). 1H NMR (DMSO-d6) δ 1.16 (d, 6 H), 3.23 (m, 1 H), 3.73 (bs, 2 H), 5.60 (d, 1 H), 6.45 (d, 1 H), 7.14 (d, 1 H), 7.32-7.48 (m, 10 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([Cl:18])=[CH:13][N:12]=1>CN(C=O)C.C1COCC1>[Cl:10][C:11]1[N:16]=[C:15]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[C:14]([Cl:18])=[CH:13][N:12]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Clc1ncc(Cl)c(OC2CCOCC2)n1
Temperature: 25 °C

Procedure:
To a solution of tetrahydro-4-pyranol (0.36 g, 3.54 mmol) in DMF (5 mL) was added sodium hydride (60% dispersion, 0.17 g, 4.25 mmol). The resulting mixture was added to a solution of 2,4,5-trichloropyrimidine (650 mg, 3.5 mmol) in THF at 0° C. The combined mixture was then allowed to warm to room temperature. To the reaction was then added water and the product was extracted with a 1:1 EtOAc-Heptane mixture. The extract was then dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (0-30% EtOAc in heptane) to give 2,5-dichloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrimidine. 1H-NMR (CDCl3): δ 8.33 (s, 1H), 5.42 (m, 1H), 4.09-3.90 (m, 2H), 3.65 (m, 2H), 2.19-1.99 (m, 2H), 1.87 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([Cl:9])[CH:3]=1.C(OC([NH:17][C@@H:18]([C@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23])[C:19](O)=[O:20])=O)(C)(C)C.O(Cl)Cl.FC(F)(F)C(O)=O>N1C=CC=CC=1>[NH2:17][C@@H:18]([C@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23])[C:19]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[Cl:9])=[O:20]
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(Br)cc1Cl
Agent: ClOCl
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](c1ccccc1)[C@H](N)C(=O)Nc1ccc(Br)cc1Cl
Temperature: -20 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
4-Bromo-2-chloro-aniline (325 mg, 1.58 mmol) and (S,S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid (440 mg, 1.58 mmol) in pyridine (5 mL) were cooled to −30° C. Phosporus oxychloride (0.158 mL, 1.7 mmol) was added and stirred at −20° C. for 2 hours. The mixture was poured into ice water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in dichloromethane (5 mL) at 0° C. and trifluoroacetic acid (3 mol) added. Stirring was continued for 2 hours at 0° C. The mixture was evaporated and the residue dissolved in ether. The ether solution was basified with saturated aqueous sodium bicarbonate and extracted with ether. The organic extracts were washed with brine, dried over sodium sulfate and evaporated to give (2S,3S)-2-amino-N-(4-bromo-2-chloro-phenyl)-3-phenyl-butyramide (325 mg, 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[S:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:29]([C:34](O)=[O:35])#[C:30][C:31]([OH:33])=[O:32]>>[O:35]=[C:34]1[C:29](=[CH:30][C:31]([OH:33])=[O:32])[S:15][C:14](=[N:13][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[N:16]1[C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=1
Reactant: O=C(O)C#CC(=O)O
Reactant: COc1cc(NC(=S)Nc2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Product: COc1cc(N=C2SC(=CC(=O)O)C(=O)N2c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Yield: 57.1 %

Procedure:
Prepared by the method described in Example 1 from N,N'-bis(3,4,5-trimethoxyphenyl)thiourea (26.8 g, 66 mmoles) and acetylenedicarboxylic acid (9.8 g, 86 mmoles). Recrystallization from ethanol gave the product (19 g), mp 250°-252° C.
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(Cl)([Cl:16])=O>C(Cl)(=O)C>[Cl:16][CH:3]([O:2][CH3:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COC(COc1ccccc1)OC
Solvent: CC(=O)Cl
Product: COC(Cl)COc1ccccc1

Procedure:
To 36 g of phenoxyacetaldehyde dimethyl acetal was added, dropwise, 40 ml of acetyl chloride and 0.5 ml of thionyl chloride. After 15 h at room temperature the solution was evaporated and the residue distilled under vacuum, 110°-120° C./1 mm, to yield the title compound as a colourless oil.
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14](O)=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].N1C=CC=CC=1.[F:27]C1N=C(F)N=C(F)N=1>C(Cl)Cl>[CH:1]([N:3]([CH2:12][C@@H:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([F:27])=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)F
Reaction time: 4 h
Yield: 99.1 %

Procedure:
To a solution of (2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)hexanoic acid (9) (1.7 g, 6.1 mmol) in DCM (20 mL) was added pyridine (0.53 g, 6.7 mmol), followed by 2,4,6-trifluoro-1,3,5-triazine (0.86 g, 6.4 mmol) dropwise. The reaction mixture was stirred for 4 h and TLC indicated completion of the reaction. The reaction mixture was washed with 10% aqueous citric acid and brine, dried over Na2SO4, and concentrated to provide the title compound (1.7 g, 100%) as red oil. 1H NMR (300 MHz, DMSO) δ ppm 0.86 (t, J=6.7 Hz, 3H), 1.16-1.38 (m, 4H), 1.57 (m, 2H), 3.03 (m, 1H), 3.87 (m, 2H), 4.91 (s, 2H), 7.41 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]([CH2:12][CH3:13])[C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Br[CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([CH2:17][O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH2:12][CH3:13])[C:8]([NH:10][CH3:11])=[O:9])=[CH:14][CH:15]=2)=[CH:19][CH:20]=1)#[N:23]
Reactant: CCC(Oc1ccc(O)cc1)C(=O)NC
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCC(Oc1ccc(OCc2ccc(C#N)cc2)cc1)C(=O)NC

Procedure:
In analogy to the procedure described in Example 3b), the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-butyramide with 4-bromomethyl-benzonitrile in 2-butanone using potassium carbonate as the base yielded the (RS)-2-[4-(4-cyano-benzyloxy)-phenoxy]-N-methyl-butyramide as a white solid; MS: m/e=325 (M+H)+.
Reaction SMILES: CNC1CCC(C2C3C(=CC=C(NC(C4SC=CC=4)=N)C=3)NC=2)=CC1.[CH2:26]([O:28]C(=O)CN1C2C(=CC=C([N+]([O-])=O)C=2)C=C1)C.CN1[CH2:50][CH:49]=[C:48]([C:51]2[C:59]3[C:54](=[CH:55][CH:56]=[C:57]([N+:60]([O-:62])=[O:61])[CH:58]=3)[NH:53][CH:52]=2)[CH2:47][CH2:46]1>>[N+:60]([C:57]1[CH:58]=[C:59]2[C:54](=[CH:55][CH:56]=1)[NH:53][CH:52]=[C:51]2[C:48]1[CH2:47][CH2:46][C:26](=[O:28])[CH2:50][CH:49]=1)([O-:62])=[O:61]
Reactant: CCOC(=O)Cn1ccc2ccc([N+](=O)[O-])cc21
Reactant: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: CNC1CC=C(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Product: O=C1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1

Procedure:
Compound 120 (0.26 g, 0.557 mmol) was treated with 1 N aqueous HCl solution at room temperature and the resulting solution was refluxed for 2 h. The reaction was brought to room temperature, filtered and washed with water (5 mL). The solvent was evaporated and crude was recrystallised from ethanol/ether to obtain compound 121 (0.23 g, 94%) as a solid in 2:3 ratio of diastereomers. 1H NMR (DMSO-d6) δ 1.22-1.29 (m, 3H), 1.53-1.62 (m, 2H), 1.80-2.16 (m, 6H), 2.74-3.23 (m, 4H), 7.08 (d, 1H, J=8.4 Hz), 7.24-7.52 (m, 3H), 7.68-7.72 (m, 1H), 8.14-8.18 (m, 2H), 8.59 (s, 1H), 8.97-9.09 (m, 2H), 9.64 (s, 1H), 11.20, 11.27 (2s, 1H), 11.42 (s, 1H); ESI-MS m/z (%): 367 (MH+ for free base, 18), 322 (100), 184 (19), 119 (39); ESI-HRMS calculated for C21H27N4S (MH+, free base), calculated: 367.1959; observed: 367.1950.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])(OCC)=O>O>[C:24]1(=[O:33])[N:1]([CH:2]([CH2:3][C:4]2[N:8]=[CH:7][NH:6][CH:5]=2)[C:9]([OH:11])=[O:10])[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]12
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(Cc1c[nH]cn1)N1C(=O)c2ccccc2C1=O
Reaction time: 1.5 h
Yield: 64 %

Procedure:
To a stirred solution of histidine (3.17 g, 20.0 mmol) and sodium carbonate (2.23 g, 21 mmol) in 50 mL of water is added N-carboethoxyphthalimide (4.52 g, 20.0 mmol). After 1.5 hour, the reaction slurry is filtered. The filtrate is stirred and the pH adjusted to 1-2 with 4N hydrochloric acid. The resulting slurry is filtered and the solid washed with water and dried in vacuo (60° C., <1 mm) to afford 3.65 g (64%) of 2-phthalimido-3-(imidazol-4-yl)propionic acid as a white powder: mp 280°-285° C.; 1H NMR (DMSO-d6, 250 M Hz) δ 12.5 (br s, 1H), 7.90-7.60 (m, 6H), 6.80(s, 1H), 4.94 (t, 1H, J=7.8), 3.36 (d, 2H, J=7.8); 13C NMR (DMSO-d6) δ 170.1, 167.1, 134.8, 134.6, 133.2, 131.1, 123.2, 116.3, 52.4, 25.8; Anal. Calculated for C14H11N3O4. Theoretical: C, 58.95; H, 3.89; N, 14.73. Found: C, 58.80; H, 3.88; N, 14.66.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].I[CH2:10][CH2:11][CH2:12][CH3:13]>[Ag]=O.CCOCC>[CH2:10]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCI
Reactant: CCOC(=O)[C@H](C)O
Agent: O=[Ag]
Solvent: CCOCC
Product: CCCCO[C@@H](C)C(=O)OCC
Reaction time: 72 h
Yield: 44 %

Procedure:
Silver oxide (77.5 g, 0.3 mol) was added to a mixture of (S)-(+)-ethyl lactate (49.4 g, 0.4 mol) with 1-iodobutane (100 g, 0.5 mol) over 2 hours, followed by allowing the mixture to stand at room temperature for 3 days, adding ether (30 ml) for dilution, filtering the resulting mixture, distilling off ether, washing the residue with 2N-NaOH aqueous solution, drying it over anhydrous MgSO4 and distilling under reduced pressure, to obtain (S)-ethyl 2-butoxypropionate (30.7 g, b.p. 64° C./7 mmHg), adding thereto 5N-NaOH aqueous solution (50 ml), agitating the mixture at room temperature for 5 hours, pouring it in 6N-hydrochloric acid (75 ml) to extract the resulting organic layer with ether, washing the resulting organic layer with water and distilling off ether, to obtain (S)-2-butoxypropionic acid (21. 4 g).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17][C:16]=3[CH:27]=2)=[O:10])=[C:7]([F:30])[CH:6]=1.C(N(CC)CC)C.Cl[C:39]([O:41][CH3:42])=[O:40]>CN(C)C1C=CN=CC=1.ClCCl>[F:30][C:7]1[CH:6]=[C:5]([CH:4]=[N:3][NH:2][C:39]([O:41][CH3:42])=[O:40])[CH:29]=[CH:28][C:8]=1[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]2[O:20][CH:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17][C:16]=2[CH:27]=1)=[O:10]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)CC1CCc2cc(NC(=O)c3ccc(C=NN)cc3F)ccc2O1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC1CCc2cc(NC(=O)c3ccc(C=NNC(=O)OC)cc3F)ccc2O1

Procedure:
436 mg (1.0 mmol) of the amidine from Example 69, 0.3 ml triethylamine, and 20 mg 4-dimethylaminopyridine were dissolved in 29 ml dichloromethane followed by addition of 104 mg (1.1 mmol) methyl chloroformate at 0° C. After stirring overnight at room temperature a white precipitate of the title compound had been formed. It was filtered with suction and washed successively with water and with ether. Yield: 0.35 g (77%) of a pale yellow powder, m.p. 202-204° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:19](O)(=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)C1C=CC=CC=1>C1C=CC=CC=1>[C:20]1([CH:19]2[N:13]([CH2:12][CH2:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:14][CH:15]([CH2:16][OH:17])[O:18]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(CCNCC(O)CO)cc1OC
Reactant: O=C(O)c1ccccc1
Solvent: c1ccccc1
Solvent: O=Cc1ccccc1
Product: COc1ccc(CCN2CC(CO)OC2c2ccccc2)cc1OC
Yield: 2750 %

Procedure:
A solution of 3 (195 g, 0.76 mol), benzoic acid (3.0 g), benzaldehyde (270 ml), C6H6 (180 ml) was heated to reflux while collecting the H2O in a Dean-Stark trap. After 21/2 hours, 13 ml of H2O was collected and the solution cooled, washed with saturated Na2CO3. The aqueous layer was washed with CHCl3 (2X) and the combined extracts dried, filtered and concentrated to dryness to yield 232 g of 5 which contains 26 mol % benzaldehyde. This corresponds to 209 g of 5; 'H NMR (CDCl3) δ 2.6 (6H, m), 3.4 (2H, m), 3.75 (7H, d, m), 4.3 (1H, m), 4.8 (1H, d), 6.7 (3H, m), 7.4 (5H, bs). ##STR150##
Reaction SMILES: [OH-].[Na+].[N:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[N+:4]=[N-:5].O.S([O-])(O)(=O)=O.[Na+]>CO>[N:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N+:4]=[N-:5]
Reactant: COC(=O)CCCCCCCCCCN=[N+]=[N-]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NCCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
Crunched sodium hydroxide (709 mg, 17.7 mmol) was added to a solution of methyl 11-azidoundecanoate (4.03 g, 17.7 mmol) in methanol (75 ml). The reaction mixture was stirred for 16 h at room temperature. Water (50 ml) was added. The mixture was acidified to pH 2 by addition of a 10% aqueous solution of sodium hydrogensulphate and was extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over sodium sulphate. The solvent was removed in vacuo. The residue was dissolved in methanol (50 ml). Crunched sodium hydroxide (1.42 g, 35.4 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. Water (50 ml) was added. The mixture was acidified to pH 2 by addition of a 10% aqueous solution of sodium hydrogensulphate and was extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over sodium sulphate. The solvent was removed in vacuo to give 3.13 g of 11-azidoundecanoic acid.