Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:15]([S:18](Cl)(=[O:20])=[O:19])[CH2:16][CH3:17]>C1COCC1.C(Cl)Cl>[CH2:15]([S:18]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)(=[O:20])=[O:19])[CH2:16][CH3:17]
Reactant: Nc1ccncc1
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccncc1
Temperature: 50 °C
Reaction time: 19 h
Yield: 73 %

Procedure:
47.6 g of 4-aminopyridine (0.506 mol) and 70.0 ml of triethylamine (51.1 g, 0.506 mol) were dissolved at 50° C. in 500 ml of THF. Likewise at 50° C., 57.3 ml of n-propanesulphonyl chloride (72.2 g, 0.506 mol) were added dropwise to this solution over the course of 1 h. After 19 h of stirring at 50° C. the reaction mixture was diluted with 500 ml of methylene chloride and extracted once with 500 ml of 1 N NaOH. The aqueous phase was adjusted to a pH of 5-6 with concentrated HCl, 100 ml of ethanol were added and then the mixture was extracted 5 times with 200 ml of methylene chloride. These organic phases were dried over magnesium sulphate and then the methylene chloride was removed by distillation. The 74 g of crude product obtained were recrystallized from acetonitrile. This gave 20.8 g of clean product. The constitution of the compound was verified by NMR spectroscopy.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]([CH2:11][CH:12]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]2[O:24][CH2:25][O:26][C:19]=12)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])C(OCC)=O)C.[OH-].[Na+]>C(O)C>[CH2:25]1[O:24][C:20]2[C:19](=[C:18]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][CH2:5][C:4]([OH:27])=[O:3])[CH:23]=[CH:22][CH:21]=2)[O:26]1
Reactant: CCCCCC(CC(C(=O)OCC)C(=O)OCC)c1cccc2c1OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC(CCC(=O)O)c1cccc2c1OCO2
Yield: 83.9 %

Procedure:
To a solution of 1.49 g (3.94 mmol) of 2-(2, 3-methylenedioxyphenyl)heptylmalonic acid diethylester in 10 ml of ethanol was added 6.6 g of 10% aqueous sodium hydroxide, and the resultant mixture was refluxed under heating for 2.5 hours. The reaction mixture was concentrated in vacuo, mixed with 5 ml of water and 0.8 ml of conc. sulfuric acid and refluxed under heating for 4 hours. After cooling, the reaction mixture was shaken with ethyl acetate, and the extract was washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was chromatographed on a silica gel column, eluting with ethyl acetate/hexane (1/2) to give 0.92 g of 4-(2, 3-methylenedioxyphenyl) nonanoic acid as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C1C=CC=CC=1>[CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: Cc1c([N+](=O)[O-])ccc2c1NCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccccc1
Product: Cc1c([N+](=O)[O-])ccc2cc[nH]c12
Yield: 99.5 %

Procedure:
A solution of 2,3-dihydro-7-methyl-6-nitroindole (3.1 g, 17.4 mmol) in 75 mL of benzene is treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 4.34 g, 19.1 mmol). The solution turns black and over the next 15 minutes, turns to green with a green precipitate. This mixture is distributed between 400 mL of aqueous potassium carbonate solution and 500 mL of methylene chloride. The organic solution is removed, dried over magnesium sulfate, filtered and evaporated to dryness on a rotary evaporator to afford 3.05 g of 7-methyl-6-nitroindole as a yellow solid (99% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]=1[CH:10]1[CH2:12][CH2:11]1)=[O:4].[Li+].[OH-]>CO.O>[C:13]([N:8]1[C:9]([CH:10]2[CH2:12][CH2:11]2)=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[N:7]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1cnn(C(C)(C)C)c1C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)n1ncc(C(=O)O)c1C1CC1
Yield: 91.5 %

Procedure:
To a solution of 1-tert-butyl-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (921 mg, 4.14 mmol) in methanol (15 mL) and water (15 mL) was added LiOH (119 mg, 4.97 mmol). The reaction mixture was stirred at reflux overnight, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was diluted with water and the solution was acidified to pH 2 with concentrated HCl. The resulting mixture was then extracted with ethyl acetate three times. The combined organic extracts were concentrated in vacuo to give 1-tert-butyl-5-cyclopropyl-1H-pyrazole-4-carboxylic acid (789 mg, 92%), which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.C1N2CN3CN(C2)CN1C3.Cl.C(Cl)Cl.C([OH:29])C>O>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[O:29]
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: CCO
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc(CC(=O)O)cc1
Yield: 87 %

Procedure:
To a solution of 2-[4-(bromomethyl)phenyl]acetic acid (770 mg, 3.36 mmol) in ethanol (6 mL) and water (6 mL) was added hexamethylenetetramine (1.26 g, 9.0 mmol) and the mixture was heated to reflux for 4 hours. Concentrated HCl (1.5 mL) was added cautiously to the mixture at reflux. The mixture was heated to reflux for 30 minutes and then allowed to cool. Water (20 mL) and DCM (20 mL) were added and the organic phase was passed through a hydrophobic fit and the solvent was removed in vacuo to afford the title compound as an off-white solid (479 mg, 87%). 1H NMR (400 MHz, CDCl3): δ 10.01 (s, 1H), 7.86 (d, J=7.9 Hz, 2H), 7.47 (d, J=7.9 Hz, 2H), 3.75 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][NH:24][CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27]1([CH2:30]Br)[CH2:29][CH2:28]1.C(=O)([O-])O.[K+].[I-].[K+].C([O-])(O)=O.[Na+]>C(#N)C.CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([CH2:30][CH:27]2[CH2:29][CH2:28]2)[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Reactant: BrCC1CC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(CC3CC3)C2)nc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 47.7 %

Procedure:
To a solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (310 mg) and cyclopropylmethyl bromide (116 mg) in acetonitrile (7 ml) was added potassium hydrogencarbonate (85.9 mg) and potassium iodide (28.5 mg) at 20° C. and then the mixture was stirred at 50° C. for 3 hours. The mixed solution was poured into a mixture of water (20 ml) and AcOEt (20 ml). The pH of the aqueous layer was adjusted to ca. 9 with NaHCO3. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (8 g) using a mixed solvent of dichloromethane and MeOH (40:1 to 20:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. Ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cyclopropylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (170 mg) was obtained as colorless syrup.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[N:5][CH:4]=1.[NH2:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1.O>O1CCCC1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>[CH3:12][N:2]([CH3:1])[C:3]1[N:8]=[C:7]([C:9]([NH:13][C:14]2[NH:18][N:17]=[N:16][N:15]=2)=[O:11])[CH:6]=[N:5][CH:4]=1
Reactant: Nc1nnn[nH]1
Reactant: CN(C)c1cncc(C(=O)O)n1
Agent: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)c1cncc(C(=O)Nc2nnn[nH]2)n1

Procedure:
To a suspension of 0.58 g of 6-(dimethylamino)pyrazine-2-carboxylic acid in 10 ml of tetrahydrofuran, 0.53 ml of triethylamine and 0.47 ml of pivaloyl chloride were added dropwise successively at 0 ° C. under stirring. After stirring for 1 hour at 0 ° C., 0.33 g of 5-amino-1H-tetrazole was added to the mixture, and the reaction mixture was stirred for 1 hour at room temperature, and then refluxed for 6 hours. After cooling, 70 ml of water was added to the reaction mixture. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 0.36 g of the desired compound as yellow needles. The obtained crystal was consistent with that of (a).
Reaction SMILES: [Na].[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:4]=1[NH:11][S:12]([C:15]1[N:25]=[C:18]2[N:19]=[C:20]([CH3:24])[CH:21]=[C:22](Cl)[N:17]2[N:16]=1)(=[O:14])=[O:13].Cl.[CH2:27]([OH:29])[CH3:28]>>[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:4]=1[NH:11][S:12]([C:15]1[N:25]=[C:18]2[N:19]=[C:20]([CH3:24])[CH:21]=[C:22]([O:29][CH2:27][CH3:28])[N:17]2[N:16]=1)(=[O:13])=[O:14]
Reactant: Cc1cc(Cl)n2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nc2n1
Reactant: CCO
Agent: Cl
Agent: [Na]
Product: CCOc1cc(C)nc2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nn12
Reaction time: 0.25 h

Procedure:
Sodium (0.69 g, 30 mmol) was added to about 50 ml of ethanol and allowed to react. The mixture was allowed to cool and then 4.0 g (9.8 mmol) of N-(2,6-dichloro-3-methylphenyl)-7-chloro-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide was added with stirring. After 15 minutes to starting material remained by thin layer chromatographic analysis although complete solution was never attained. The mixture was acidified with 6N hydrochloric acid and concentrated under reduced pressure. The residue was triturated with water and the solid removed by filtration and washed with water. It was then dissolved in aqueous sodium hydroxide using a minimum amount of the base and the aqueous solution was twice extracted with ether and acidified with 6N hydrochloric acid. The solid that formed was collected by filtration, washed with water, and dried. This was extracted with about 500 ml of boiling chloroform. The chloroform solution was concentrated to about 150 ml and allowed to cool to form a precipitate which was collected by filtration and dried to obtain 1.7 g (42 percent of theory) of the title compound as a white solid, m.p. 228°-9° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[CH:35]=[CH:34][C:14]3[N:15]([CH3:33])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1.[CH3:36][C@@H:37]1[CH2:39][O:38]1.CCN(C(C)C)C(C)C>CN(C=O)C.CO.C(Cl)Cl>[OH:38][C@H:37]([CH3:39])[CH2:36][N:3]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[CH:35]=[CH:34][C:14]3[N:15]([CH3:33])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([O:28][C:29]([F:30])([F:31])[F:32])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1
Reactant: C[C@@H]1CO1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC3CCNC3)ccc21
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](O)CN1CCC(NC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(OC(F)(F)F)cc4s2)n3C)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [1-((R)-2-hydroxy-propyl)-pyrrolidin-3-yl]-amide (15 mg) was prepared using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid pyrrolidin-3-ylamide dihydrochloride (47 mg), (R)-2-methyl-oxirane (excess) and DIEA (35 uL) in DMF (1 mL). The reaction was stirred at 80° C. overnight. The pure product was isolated through silica gel chromatography using DCM: (10%) methanol in DCM (from 100:0 to 0:100) as eluent system. LC/MS: m/z 534.6.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[OH-].[CH2:16]([N+:20]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>CO>[C:1]([O-:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O-:12])=[O:11].[CH2:29]([N+:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:30][CH2:31][CH3:32].[CH2:29]([N+:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:30][CH2:31][CH3:32]
Reactant: O=C(O)CCCCCCCCC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Product: O=C([O-])CCCCCCCCC(=O)[O-]

Procedure:
The procedure used was the same as described above by titration of sebacic acid (0.814 g, 4.02×10-3 mol) with 1M tetrabutylammonium hydroxide solution in methanol. After removal of solvent, a quantitative yield (2.75 g) of salt was obtained. FIG. 45 shows a 1H NMR spectrum and FIG. 46 shows a 13C NMR spectrum of the salt in CDCl3.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=2[NH2:4])=[CH:15][CH:14]=1
Reactant: CC(C)c1ccc(N)c(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CC(C)c1ccc(N)c(-c2ccc(Cl)cc2)c1

Procedure:
2-bromo-4-isopropylaniline and 4-chlorobenzene boronic acid were combined to form 2-(4-chlorophenyl)-4-isopropylaniline, and
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].N.CO.CC[N:25](C(C)C)C(C)C>C(Cl)Cl>[NH2:25][S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: CCN(C(C)C)C(C)C
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(N)(=O)=O)s2)s1
Reaction time: 1 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step 1 of Example 9 (200 mg; 0.59 mmol; 1 eq.), is dissolved in DCM (10 ml). A solution of ammonia in MeOH (0.59 ml; 2 M; 1.19 mmol; 2 eq.) and DIEA (460.4 mg; 3.56 mmol; 6 eq.) are added. After one hour, the solvents are evaporated. The crude product is purified by preparative HPLC, affording Compound (17) as white-off solid (36 mg; 17%). 1H NMR (DMSO-d6) δ 2.14 (s, 3H), 2.42 (s, 3H), 7.16 (d, J=4.5 Hz, 1H), 7.50 (d, J=4.5 Hz, 1H), 7.72 (s, 2H), 12.30 (s, 1H). M−(ESI): 316.07; M+(ESI): 318.10. HPLC, Rt: 2.16 min (purity: 99.8%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH:9]1(/[CH:14]=[C:15](\B2OC(C)(C)C(C)(C)O2)/[CH2:16][OH:17])[CH2:13][CH2:12][CH2:11][CH2:10]1.[F-].[Cs+]>C1COCC1.C1(P([Pd-4](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)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:15](=[CH:14]\[CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)/[CH2:16][OH:17])=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: CC1(C)OB(/C(=C\C2CCCC2)CO)OC1(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: OC/C(=C/C1CCCC1)c1ccc(Br)cc1
Temperature: 60 °C
Yield: 39.7 %

Procedure:
According to the procedure described for example 26b the use of 4-bromo-1-iodo-benzene (1.42 g, 5.0 mmol), (E)-3-cyclopentyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (1.01 g, 4.00 mmol), caesium fluoride (2.28 g, 15.0 mmol) and tetrakis(triphenylphosphino)palladium(0) (577 mg, 500 μmol) in 120 mL THF with heating to 60° C. for 16 h gives a brown oil. Purify the crude product by column chromatography, eluting with a gradient from 100:0 to 60:40 hexanes:ethyl acetate to obtain (E)-2-(4-bromo-phenyl)-3-cyclopentyl-prop-2-en-1-ol (446 mg) as a yellow oil. MS (m/e): 263 {[(79Br)M−H2O]+H}, 265 {[(81Br)M−H2O]+H}.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[NH:16][CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=O)[O:23]C(C)(C)C)([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:17]([O:21][C:22]([N:16]1[CH:14]2[CH2:13][CH2:12][CH2:11][CH:10]1[CH2:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:15]2)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: c1ccc(CN2CC3CCCC(C2)N3)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCCC1CN(Cc1ccccc1)C2
Temperature: 23 °C
Reaction time: 16 h
Yield: 43.2 %

Procedure:
To a solution of 3-benzyl-3,9-diaza-bicyclo[3.3.1]nonane (755 mg, 3.49 mmol, 1.0 eq) in CH2Cl2 (10 mL) was added di-tert-butylcarbonate (990 mg, 4.54 mmol, 1.3 eq) and triethylamine (0.730 mL, 5.24 mmol, 1.5 eq) and the mixture stirred for 16 hours at 23° C. The reaction mixture was diluted with CH2Cl2 and washed with water. The organic was collected and dried (Na2SO4), filtered, and concentrated to an oil. The crude was purified using silica gel chromatography eluting with ethyl acetate/heptane mixtures which gave the desired product as a colorless oil (477 mg) in 41% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48 (s, 9H) 1.51-1.64 (m, 1H) 1.64-1.75 (m, 2H) 1.75-1.93 (m, 2H) 2.21-2.39 (m, 2H) 2.79-2.92 (m, 3H) 3.40 (s, 2H) 4.06 (br. s., 1H) 4.18 (br. s., 1H) 7.21-7.30 (m, 1H) 7.34 (d, J=4.55 Hz, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=O.Cl.[NH2:15][OH:16].O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[N:15][OH:16]
Reactant: Cc1cc(C)c2c(c1)C(=O)CCC2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2c(c1)C(=NO)CCC2
Temperature: 80 °C
Yield: 93.9 %

Procedure:
A solution of 5,7-Dimethyl-1-tetralone (5.0 g) in ethanol (100 mL) was treated with hydroxylamine hydrochloride (2.2 g) and sodium carbonate monohydrate (3.6 g). The reaction mixture was heated overnight at 80° C. with a condenser and behind a blast shield. Cooled to room temperature after seventeen hours, transferred to a 300 mL flask and concentrated. The residue was triturated in water and filtered to yield the title product as a beige solid (5.1 g).
Reaction SMILES: O[C:2]1([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH2:5][CH:4]([CH3:14])[O:3]1.[C:24]([NH:27][NH2:28])(=[O:26])[CH3:25]>C(O)C.Cl>[C:24]([NH:27][N:28]=[C:2]([C:11]1[C:6]([CH2:5][CH:4]([OH:3])[CH3:14])=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=1)[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)(=[O:26])[CH3:25]
Reactant: COc1ccc2c(c1)CC(C)OC2(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)NN
Agent: Cl
Solvent: CCO
Product: COc1ccc(C(=NNC(C)=O)c2ccc([N+](=O)[O-])cc2)c(CC(C)O)c1
Yield: 66.3 %

Procedure:
To a solution of 4 (1.6 g) in 25 ml of ethanol was added acetic hydrazide (0.4 g) and 2 drops of concentrated HCl. The resulting solution was heated to reflux for 3 hours. The solvent was removed under reduced pressure. The residue was treated with NaHCO3, and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over Na2SO4. Removal of the solvent gave the desired product (1.25 g).
Reaction SMILES: C([O:4][C@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([CH2:15][O:16]C(=O)C)[O:8][C@@H:7]([O:20]CCOCCOCCOCC(O)=O)[C@@H:6]1[NH:34][C:35](=[O:37])[CH3:36])(=O)C.Cl.C(OC(=O)[C@@H](NC(=O)[C@@H](N)CCCCN)CCCCN)C1C=CC=CC=1.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C=O)C>[OH:20][CH:7]1[O:8][C@H:9]([CH2:15][OH:16])[C@H:10]([OH:11])[C@H:5]([OH:4])[C@H:6]1[NH:34][C:35]([CH3:36])=[O:37]
Reactant: CC(=O)N[C@H]1[C@H](OCCOCCOCCOCC(=O)O)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: NCCCC[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 142.2 %

Procedure:
The above prepared (2-{2-[2-((2R,3R,4R,5R,6R)-4,5-diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yloxy)-ethoxy]-ethoxy}-ethoxy)-acetic acid (2.820 g, 5.246 mmol) and (S)-6-amino-2-((S)-2,6-diamino-hexanoylamino)-hexanoic acid benzyl ester hydrochloride (preparation see below, 0.829 g, 1.749 mmol) were dissolved in a mixture of 32 mL of CH2Cl2 and 3.2 mL of DMF, treated successively with Hünig's base (2.096 ml, 12.25 mmol), 1-hydroxy-7-azabenzotriazole (0.714 g, 5.248 mmol) and 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (1.006 g, 5.248 mmol), and stirred over night at ambient temperature. All volatiles were removed i.V., and the crude reaction mixture purified by preparative HPLC (38 runs, Gemini, 5μ, C18) to give after lyophilization 1.650 g of the title product as white powder. MS (ISP): 1945.8 [M+Na]+. NMR (600 MHz, DMSO).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][N:15]=[C:16]([C:18]2[C:22]([OH:23])=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=3)[S:20][CH:19]=2)[CH3:17])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>>[F:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][N:15]=[C:16]([C:18]2[C:22]([OH:23])=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:28][CH:29]=3)[S:20][CH:19]=2)[CH3:17])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)cc1F
Agent: [Na+]
Agent: [OH-]
Product: CC(=NNC(=O)c1ccc(C(=O)O)c(F)c1)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Yield: 84.9 %

Procedure:
From methyl 2-fluoro-4-[(2-{1-[5-(4-t-butylphenyl)-4-hydroxy-3-thienyl]ethylidene}hydrazino)carbonyl]benzoate (56.2 mg, 0.12 mmol) and 0.2 M sodium hydroxide aqueous solution (1.26 mL, 0.25 mmol), 46.3 mg of the desired product was obtained in the same manner as in Synthetic Example 70 as a pale yellow solid (yield 85%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12](OCC)=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].C([Al+]CC(C)C)C(C)C.Cl>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[CH2:12][OH:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)/C=C/c1cccc([N+](=O)[O-])c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(/C=C/CO)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl (E)-3-(3-nitrophenyl)-2-propenoate (8.04 g, 36 mmol) in dichloromethane at 0° C. under nitrogen was added dropwise over 5 minutes diisobutylaluminium hydride (1.0 M solution in dichloromethane, 80 ml, 80 mmol). The mixture was stirred at 0° C. for 10 minutes, then allowed to warm to room temperature over 30 minutes. Hydrochloric acid (1N, 500 ml) was added, the layers were separated and the aqueous layer was extracted with dichloromethane (2×250 ml). The organic layers were combined, washed with brine (2×100 ml), filtered and concentrated in vacuo to give the title compound as a red oil.