Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([CH3:9])[CH:7]=O.[Cl:10][C:11]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl.CCCCCC>[Cl:10][C:11]1[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH:14][CH2:7][CH:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH3:9]
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Reactant: CC(C=O)c1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCCCCC
Product: CC(CNCc1cccc(C(F)(F)F)c1Cl)c1cccs1
Yield: 107 %

Procedure:
To a solution of 2-thiophen-2-yl-propionaldehyde (100 mg, 0.7 mmol) in dry dichloromethane (20 ml) was added 2-chloro-3-trifluoromethyl-benzylamine (30 mg, 0.14 mmol) followed by the addition of sodium triacetoxyborohydride (60.5 mg, 0.28 mmol). After the resulting mixture was stirred at room temperature overnight water was added to quench the reaction. The aqueous layer was extracted with ethyl acetate. The combined organic layers was washed with brine, dried over sodium sulfate and concentrated in vacco. The crude mixture was purified by silica gel column chromatograph using EtOAc:Hexane/25:75 as the eluent to give 50 mg (40% yield) of the title compound as an oil. MS m/e 334.4 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:28]([OH:30])=O)[CH2:7][CH2:6]1)(=[O:4])=[O:3].S(Cl)(Cl)=O.[CH3:35][N:36]([CH:38]=O)[CH3:37]>>[CH3:1][S:2]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][CH:21]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:28]([NH:5][C:11]2[CH:12]=[CH:13][C:14]([CH2:38][N:36]([CH3:35])[CH:37]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:15][CH:10]=2)=[O:30])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)N1CCC(C(=O)O)=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc21
Solvent: O=S(Cl)Cl
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(N5CCOCC5)cc4)ccc3N(S(C)(=O)=O)CC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In DMF (10 ml) was dissolved 1-methanesulfonyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.3 g). To the solution was added, under ice-cooling, thionyl chloride (0.15 ml), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was suspended in THF (50 ml). The suspension was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.19 g) and triethylamine (0.5 ml) in THF (5 ml), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate/ethanol to give 1-methanesulfonyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.26 g) as pale crystals.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[CH2:12][C:11]=2[CH:27]=1)(=O)=O.[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:36][CH2:37][CH2:38][C:39]#[C:40][Sn](CCCC)(CCCC)CCCC.[Li+].[Cl-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:36][CH2:37][CH2:38][C:39]#[C:40][C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[CH2:12][C:11]=2[CH:27]=1
Reactant: CCCC[Sn](C#CCCOC1CCCCO1)(CCCC)CCCC
Reactant: CCOC(=O)CC1Cc2ccc(OS(=O)(=O)C(F)(F)F)cc2Cc2ccccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CCOC(=O)CC1Cc2ccc(C#CCCOC3CCCCO3)cc2Cc2ccccc21
Reaction time: 1.5 h
Yield: 82.7 %

Procedure:
A mixture of ethyl (±)-10,11-dihydro-3-(trifluoromethanesulfonyloxy)-5H-dibenzo[a,d]cycloheptene-10-acetate (1.34 g, 3.13 mmole), 4-(2-tetrahydropyranyloxy)-1-tributylstannyl-1-butyne (1.66 g, 3.76 mmole), LiCl (398 mg, 9.39 mmole), bis(triphenylphosphine)palladium dichloride (110 mg, 0.094 mmole), and anhydrous dioxane (31 mL) was heated at reflux under argon. After 1.5 hr, the reaction was concentrated to remove most of the dioxane, and the residue was taken up in Et2O (100 mL). 10% KF (50 mL) was added and the mixture was stirred briskly for 0.5 hr. The aqueous layer was removed and the Et2O layer was filtered through a mixture of celite® and MgSO4. The filtrate was concentrated and the residue was chromatographed on silica gel (10% EtOAc/hexanes) to afford the title compound (1.12 g, 83%) as a pale yellow oil: TLC (20% EtOAc/hexanes) Rf0.40; 1H NMR (400 MHz, CDCl3) δ7.21-7.30 (m, 1 H), 7.06-7.20 (m, 5 H), 7.00 (d, J=7.8 Hz, 1 H), 4.69 (t, J=3.6 Hz, 1 H), 4.31 (d, J=15.2 Hz, 1 H), 4.11-4.23 (m, 2 H), 3.76-3.97 (m, 4 H), 3.59-3.68 (m, 1 H), 3.48-3.57 (m, 1 H), 3.34 (dd, J=15.2, 4.1 Hz, 1 H), 2.97 (dd, J=15.2, 9.5 Hz, 1 H), 2.70 (t, J=7.3 Hz, 2 H), 2.65 (dd, J=15.7, 4.8 Hz, 1 H), 2.51 (dd, J=15.7, 9.5 Hz, 1 H), 1.78-1.92 (m, 1 H), 1.68-1.78 (m, 1 H), 1.44-1.68 (m, 4 H), 1.27 (t, J=7.1 Hz, 3 H); MS (ES) m/e 455 (M+Na)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[C:22]([NH:31][CH2:32][C:33]3[O:34][CH:35]=[CH:36][N:37]=3)=[N:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][CH:26]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:38](O)=[O:39])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1>C(#N)C.C(=O)([O-])O.[Na+].C(N(CC)CC)C>[C:27]([C:24]1[N:23]=[C:22]([NH:31][CH2:32][C:33]2[O:34][CH:35]=[CH:36][N:37]=2)[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]2[CH2:11][C@@H:10]([C:38]([N:63]3[CH2:68][CH2:67][O:66][CH2:65][CH2:64]3)=[O:39])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13]2)=[O:20])=[CH:26][N:25]=1)([CH3:29])([CH3:28])[CH3:30]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ncco1)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ncco1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[({2-tert-butyl-4-[(1,3-oxazol-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]piperidine-3-carboxylic acid (125 mg), HOBt (52 mg) and WSC.HCl (64 mg) were dissolved in acetonitrile (3 ml), morpholine (20 μl) and triethylamine (94 μl) were added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:9) to ethyl acetate was concentrated under reduced pressure to give the object compound (110 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].II.C([O:12][CH3:13])=O.Cl>C1COCC1>[CH2:7]=[CH:6][CH2:5][CH2:4][CH2:3][CH2:2][CH:13]([OH:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2]
Reactant: COC=O
Reactant: C=CCCCCBr
Agent: Cl
Agent: II
Solvent: C1CCOC1
Product: C=CCCCCC(O)CCCCC=C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A stirring bar and Mg (1.2 g) were placed in a 500 ml-capacity three neck flask, and the flask was connected to a condenser and sufficiently dried. Then, a nitrogen atmosphere was established in the flask, and THF (20 ml) and I2 were added thereto. 1-bromo-5-hexene (7) (8 g, 5 mmol) and THF (10 ml) were added to the brown suspension thus obtained to start a reaction, and heat developed when a color of I2 disappeared. Immediately after the start of the heat development, the flask was placed in an ice bath. Then, after generation of a Grignard reagent, HCOOMe (1.5 ml, 5 mmol) was slowly dropped into the flask, and the mixture thus obtained was stirred for 30 minutes. When generation of alcohol was recognized by thin-layer chromatography, diluted hydrochloric acid was added to the mixture to stop the reaction. An organic layer was extracted with AcOEt and dried over Na2SO4, and the solvent was distilled off under reduced pressure. Thereafter, the organic layer was purified by flash chromatography on silica gel (hexane:ethyl acetate=10:1), (hexane:ethyl acetate=4:1). Thus, intended 1,12-tridecadiene-7-ol (8) (2.55 g, 1.3 mmol, yield: 26%) was obtained. 1HNMR values of 1,12-tridecadiene-7-ol (8) are shown below.
Reaction SMILES: C[O:2][CH:3](OC)[C:4](=[CH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:5]#[N:6]>Cl>[C:5]([C:4](=[CH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH:3]=[O:2])#[N:6]
Reactant: COC(OC)C(C#N)=CC1CCCCC1
Agent: Cl
Product: N#CC(C=O)=CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
2-(Dimethoxymethyl)-3-cyclohexylacrylonitrile, obtained from Example 3 (4.18 g, 0.02 mol) and 6N HCl (50 mL) were stirred together overnight at room temperature. The product was extracted with ethyl acetate (200 mL), the extract was dried) (MgSO4) and the ethyl acetate was evaporated in vacuo to give a 2.5 g (76%) of a brown oil which was used directly. A sample was distilled in a kugelrohr apparatus to give a pale yellow oil from which an analytical 2,4-dinitrophenyl hydrazone derivative was obtained as orange needles, mp 228-30° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=[CH:5][CH:4]=1.CN(C=O)C.C(N=C=NCCCN(C)C)C.[NH2:35][C:36]1[S:37][C:38]2[CH:44]=[C:43]([N+:45]([O-:47])=[O:46])[CH:42]=[CH:41][C:39]=2[N:40]=1>>[N+:45]([C:43]1[CH:42]=[CH:41][C:39]2[N:40]=[C:36]([NH:35][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[N:18][C:10]=3[NH:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[S:37][C:38]=2[CH:44]=1)([O-:47])=[O:46]
Reactant: COc1ccc(Nc2ncccc2C(=O)O)cc1
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ncccc2C(=O)Nc2nc3ccc([N+](=O)[O-])cc3s2)cc1
Temperature: 27 °C
Reaction time: 9 h

Procedure:
To a stirred solution of 2-(4-methoxy phenylamino)nicotinic acid (29, 244 mg 1 mmol) in dry DMF (10 mL) hydroxy benzotriazole HOBt (1.2 mmol) were added at 0° C. After 10 min 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) (1.2 mmol) was added and finally 2-amino-6-nitrobenzothiazole (37, 137 mg, 0.7 mmol) were added, then the resulting mixture was stirred at room temperature (27° C.) for 8-10 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (5) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1>CN(C=O)C.C(OCC)(=O)C>[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([S:2][CH3:1])[CH:10]=1
Reactant: Brc1cncc(Br)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
Sodium thiomethoxide (1.6 g, 23 mmol) was added to a solution of 3,5-dibromopyridine (5 g, 21 mmol) in DMF (25 mL). After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate and washed several times with brine. The extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude material was chromatographed on silica (10% ethyl acetate/hexanes) to give the title compound (3.8 g, 89% yield) as a clear oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([O:30][CH3:31])=[O:29])[CH2:17][CH2:16]1)=O)(C)(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:31][O:30][C:28](=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]([N:18]1[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1)=[O:32]
Reactant: COC(=O)c1ccccc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccccc1C(=O)N1CCNCC1
Reaction time: 2 h

Procedure:
TFA (1.2 mL) was added to a stirred solution of 4-(2-Methoxycarbonyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.58 mmol) in DCM (5 mL) at 0° C. The resulting mixture was stirred at the same temperature for 2 hours. DIPEA (1.5 mL) was added to the cold reaction mixture and the mixture was concentrated under reduced pressure to afford 2-(piperazine-1-carbonyl)-benzoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:23])[CH:8]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.O>CN(C)C=O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[O:23][C:14]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)=[N:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)C(NC(=O)c1ccc(F)cc1)C(=O)c1ccc(Cl)s1
Solvent: O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1nc(-c2ccc(F)cc2)oc1-c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.7 %

Procedure:
To a solution of methyl 3-(5-chlorothiophen-2-yl)-2-(4-fluorobenzoylamino)-3-oxopropionate (7.25 g) in N,N-dimethyl-formamide (80 ml) was added dropwise phosphorus oxychloride (5.7 ml) under ice-cooling, and the mixture was then stirred at room temperature for 3 days. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane:ethyl acetate=100:1), and then, triturated with diethyl ether-hexane to obtain methyl 5-(5-chloro-thiophen-2-yl)-2-(4-fluorophenyl)oxazol-4-carboxylate (2.8 g) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:32])([CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1>C(O)(=O)C.[Pd]>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([N:20]2[CH2:21][CH2:22][N:17]([CH2:16][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])([OH:32])[CH2:10][N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)[CH2:18][CH2:19]2)=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(CC(O)(Cn3cncn3)c3ccc(Cl)cc3Cl)CC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(N2CCN(CC(O)(Cn3cncn3)c3ccc(Cl)cc3Cl)CC2)cc1
Reaction time: 4 h

Procedure:
To a solution of the product of part (i) (0.55 g, 1.15 mmole) in acetic acid (20 ml) was added 10% palladium-on-charcoal (50 mg) and the mixture was hydrogenated at 15 psi (103 kPa) for 4 hours. The catalyst was then removed by filtration, the solvent removed under reduced pressure, and the residue partitioned between methylene chloride and water. The organic phase was separated, washed again with water, dried over magnesium sulphate and concentrated under reduced pressure to yield the title compound as a foam, m.p. 60° (0.485 g, 94%).
Reaction SMILES: [CH2:1]1[CH2:5][C:4]2([CH2:12][C:10](=[O:11])[O:9][C:7](=[O:8])[CH2:6]2)[CH2:3][CH2:2]1.BrBr.[OH-:15].[Na+]>>[O:8]=[C:7]1[CH2:6][C:4]2([CH2:3][CH2:2][CH2:1][CH2:5]2)[CH:12]([C:10]([OH:9])=[O:11])[O:15]1
Reactant: O=C1CC2(CCCC2)CC(=O)O1
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Product: O=C1CC2(CCCC2)C(C(=O)O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3,3-Tetramethylene glutaric anhydride (5 g, 30 mmol) was heated to 105° C. and irradiated with a sun lamp while bromine (2 ml, 38.7 mmol) was added dropwise. After the bromine color dispersed, the reaction was cooled to room temperature and 2.4M NaOH (50 ml) was added and the mixture was heated to reflux for 2 hours. The solution was cooled to room temperature and the pH was adjusted to pH 2 and stirred in a ice water bath for 0.5 hour. The precipitate (unreacted 3,3-tetrametylene glutaric acid) was filtered and discarded. The filtrate was extracted three times with ethyl acetate and the combined organics were washed with brine and dried over MgSO4. Evaporation yielded the title acid as a colorless oil, 5 g, 90%. NMR (CDCl3, 300 MHz) δ 7.95 (broad s, OH), 4.65 (s, 1, methine), 2.61 and 2.35 (ab, 2, methylene), 1.9-1.45 (m, 8, tertramethylene).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:18][C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:17])OCC)[S:11][C:7]=2[CH:6]([C:19]#[N:20])[CH2:5]1)[CH2:2][CH3:3].[CH2:21]([NH:25][CH2:26][CH:27]=[O:28])[CH2:22][CH:23]=[CH2:24]>>[CH2:21]([N:25]([CH2:26][CH:27]=[O:28])[C:13]([NH:12][C:10]1[S:11][C:7]2[CH:6]([C:19]#[N:20])[CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:18][C:8]=2[N:9]=1)=[O:17])[CH2:22][CH:23]=[CH2:24]
Reactant: CCCC1Cc2nc(NC(=O)OCC)sc2C(C#N)C1
Reactant: C=CCCNCC=O
Product: C=CCCN(CC=O)C(=O)Nc1nc2c(s1)C(C#N)CC(CCC)C2
Temperature: 125 °C

Procedure:
Ethyl N-(5-propyl-7-cyano-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbamate (0.08 mol) and the dimethyl acetal of 2-but-3-enylaminoacetaldehyde (30 ml.) as charged into a glass reaction vessel equipped with a stirrer, reflux condenser and gas addition tube. The reaction mixture is blanketed with nitrogen gas and is heated 125° C. for a period of about 8 hours. After this time the reaction mixture is distilled to remove excess starting material. The residue is purified by elution chromatography using ethyl acetate as the eluant. The chromatographed solution is then stripped of solvent to yield the desired product dimethyl acetal of 2-[1-but-3-enyl-3-(5-propyl-7-cyano-4,5,6,7-tetrahydrobenzothiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [CH2:1]1[C:6]([OH:10])([C:7]([OH:9])=[O:8])[O:5][C@H:4]([C@H:11]([OH:14])[CH2:12][OH:13])[C@H:3]([OH:15])[C@@H:2]1[OH:16]>O>[C:7]([OH:9])(=[O:8])[C:6]([CH2:1][C@@H:2]([C@@H:3]([C@H:4]([C@H:11]([CH2:12][OH:13])[OH:14])[OH:5])[OH:15])[OH:16])=[O:10]
Reactant: O=C(O)C1(O)C[C@@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O1
Solvent: O
Product: O=C(O)C(=O)C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO

Procedure:
The specific rotation and spectral data were obtained after L-KDO had been converted to its ammonium salt: [α]25D−37.2° (c 0.68, H2O) [for D-KDO:[α]27D+42.3° (c 1.7, H2O) Unger, Adv. Charbohydr. Chem. Biochem., 381:323 (1981); authentic sample from Sigma [α]25D+40.1° (c 2.1, H2O)]. Since KDO has an axial 5-OH group, it is known that it exists as a mixture of pyranose and furanose forms, and readily cyclizes to the corresponding lactone. The 1H and 13C NMR data of the predominant form are: 1H MMR (D2O) δ4.03 (1H, ddd, J4-3ax=13.0 Hz, J4-3eq=5.5 Hz, J4-5=3.0 Hz, H-4), 4.00 (1H, m, H-5) 3.87 (1H, dt, J7-8b=3.0 Hz, J7-6J7-8a=5.5 Hz, H-7), 3.84 (1H, m, H-6), 3.78 (1H, dd, J8b-8a=12.0 Hz, J8b-7=3.0 Hz, H-8b), 3.60 (1H, dd, J8a-8b=12.0 Hz, J8a-7=5.5 Hz, H-8a), 2.00 (1H, t, J3ax-3eq=J3ax-4=13.0 Hz, H-3ax), 1.86 (1H, dd, J3eq-3ax=13.0 Hz, J3eq-4=5.5 Hz, H-3eq). 13C NMR (D2O+CD3CN) δ177.3, 96.8, 72.0, 71.3, 67.0, 66.6, 63.4, 34.0. 1H and 13C NMR spectra were identical with those of D-KDO from Sigma. HRMS (FAB) calcd for C8H14O8Na(M+Na+) 261.0586, found 261.0591.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH3:23][CH:24]([NH2:27])[CH2:25][OH:26]>>[CH2:18]([C:13]1[C:12](/[CH:11]=[CH:10]/[C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:27][C@@H:24]([CH3:23])[CH2:25][OH:26])=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CC(N)CO
Reactant: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)OC)cn1
Product: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)N[C@@H](C)CO)cn1
Yield: 36 %

Procedure:
As described in example 10, 6-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester (100 mg, 0.28 mmol), and L-2-amino-1-propanol instead of DL-2-amino-1-propanol, was converted to the title compound (41 mg, 36%) which was obtained as a colorless oil after purification by chromatography (silica, dichloromethane:methanol 100:0 to 96.5:3.5). MS: m/e=364.4 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[Cl:17][C:18]1[N:23]=[N:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[N:23]=[N:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([NH:12][C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:15]([CH3:16])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)=[O:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Reactant: O=C(O)c1ccc(-c2ccc(Cl)nn2)cc1
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(Cl)nn4)cc3)cn12

Procedure:
Operations similar to Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4-(6-chloro-3-pyridazinyl)benzenecarboxylic acid, to provide the title compound as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][C:23]([C:25]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)=[N:22][C:21]=3[C:38]([O:40]CC)=[O:39])=[CH:16][CH:15]=2)[CH2:10][C:9]1([CH3:44])[CH3:43])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][C:23]([C:25]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)=[N:22][C:21]=3[C:38]([OH:40])=[O:39])=[CH:16][CH:15]=2)[CH2:10][C:9]1([CH3:44])[CH3:43])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1nc(-c2ccc(C(F)(F)F)c3[nH]ccc23)oc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)C(C)(C)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(-c4ccc(C(F)(F)F)c5[nH]ccc45)nc3C(=O)O)cc2)CC1(C)C

Procedure:
4-{4-[4-Ethoxycarbonyl-2-(7-trifluoromethyl-1H-indol-4-yl)-oxazol-5-yl]-phenyl}-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.2 g, 0.3 mmol) and NaOH (0.024 g, 0.6 mmol) in 5 mL of methanol, water and THF were stirred at 50° C. overnight. The organic solvent was removed in vacuo, the remaining solution adjusted to pH 5, and the resultant title compound was collected as a white solid by filtration, and dried under reduced pressure.
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[CH:3]/[CH2:4]Cl.[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C1C=CC=CC=1.[OH-].[K+]>O>[CH:2]([CH:3]1[CH2:4][C:8]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]([O:15][CH2:16][CH3:17])=[O:14])=[CH2:1]
Reactant: ClC/C=C/CCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: C=CC1CC1(C(=O)OCC)C(=O)OCC
Temperature: 60 °C
Yield: 65.7 %

Procedure:
To illustrate yet another variation of the present process a reaction vessel fitted with a suitable stirrer, Dean-Stark trap, and condenser was charged with 866 g (6.9 mol) trans 1,4-dichlorobutene-2, 640 g (4.0 mol) diethyl malonate, 1.2 g (0.08 mol percent based on malonate) tricaprylylmethylammonium chloride and 1.8 liters benzene. The reactor and its contents were heated to 60° C. with stirring and incremental additions of flaked solid (85%) potassium hydroxide made over a 4.75-hour period while azeotropically removing water of reaction. A total of 528 grams solid KOH were charged. After 5.5 hours the theoretical amount of water was removed and the reaction mixture was cooled, filtered to remove potassium salts and the benzene solution concentrated. The crude brown oil, upon distillation at reduced pressure, yielded the desired diethyl 2-vinylcyclopropane-1,1-dicarboxylate (65.7% yield).