Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])O.[Na+].[Na+].[C:8]1([S:22]([O-:25])(=[O:24])=[O:23])[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([S:18]([O-:21])(=[O:20])=[O:19])[C:12]=2[CH:11]=[CH:10][CH:9]=1>>[C:8]1([S:22]([OH:25])(=[O:24])=[O:23])[C:17]2[CH:16]=[C:15]([S:1]([OH:5])(=[O:4])=[O:3])[CH:14]=[C:13]([S:18]([OH:21])(=[O:20])=[O:19])[C:12]=2[CH:11]=[C:10]([S:1]([OH:3])(=[O:5])=[O:4])[CH:9]=1
Reactant: O=S(=O)(O)O
Reactant: O=S(=O)([O-])c1cccc2c(S(=O)(=O)[O-])cccc12
Agent: [Na+]
Product: O=S(=O)(O)c1cc(S(=O)(=O)O)c2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c2c1

Procedure:
To 100 ml of 30% fuming sulfuric acid at 200° C., is added 25 g of 1,5-naphthalenedisulfonic acid disodium salt. The mixture is refluxed at 180°-185° C. for 18 hours then cooled to 50°-60° C. and filtered, giving 25.6 g of 1,3,5,7-naphthalenetetrasulfonic acid as a tan solid. The entire 25.6 g is added to 200 ml of thionyl chloride and then 2.0 ml of dimethylformamide are added. The mixture is warmed gently until hydrogen chloride is evolved, then heated until bubbling, then allowed to stand at room temperature for 13/4 hours and finally refluxed for 3 hours. The mixture is filtered while warm and the filtrate is evaporated to 20 ml. The solid is collected by filtration and washed with dichloromethane and ether, giving 3.0 g of 1,3,5,7-naphthalenetetrasulfonyl chloride as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8](Br)=[CH:7]2.[CH3:13][S-:14].[Na+]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([S:14][CH3:13])=[CH:7]2
Reactant: C[S-]
Reactant: Nc1cccc2cc(Br)cnc12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1cnc2c(N)cccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.2 %

Procedure:
A mixture of 8-amino-3-bromoquinoline (200 mg) and sodium thiomethoxide (109 mg) in N,N-dimethylformamide (2 ml) was stirred at ambient temperature for 2 days. After diluted with ethyl acetate, the resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by chromatography on silica gel (n-hexane-ethyl acetate) to give 8-amino-3-methylthioquinoline (113 mg) as an oil.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C:8](=[N:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.CO.O>C1COCC1>[C:1]([N:5]1[CH2:6][CH2:7][CH:8]([NH:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN=C1CCN(C(C)(C)C)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNC1CCN(C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a solution of tert-butyl 2-(1-tert-butylpiperidin-4-ylidene)hydrazinecarboxylate (400 mg, 1.49 mmol) in THF (40 mL) was added DIBAl-H (15 mL, 15 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 25° C. overnight. Methanol (5 mL) was added at −78° C. After being stirred at room temperature for 1 h, water (10 mL) was added. The solid was filtered off and washed with EtOAc. The combined filtrate was partitioned and extracted with EtOAc (3×50 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography eluting with EtOAc/petroleum ether (1:10) to give tert-butyl 2-(1-tert-butylpiperidin-4-yl)hydrazinecarboxylate (350 mg, 87% yield) as colorless oil. LCMS (ESI) m/z: 272.4 [M+H+].
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[Cl:20].CN([CH:24]=[O:25])C>C1COCC1>[Cl:20][C:19]1[C:14]([Cl:13])=[CH:15][N:16]=[CH:17][C:18]=1[CH:24]=[O:25]
Reactant: Clc1ccncc1Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cncc(Cl)c1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 66.9 %

Procedure:
To a solution of diisopropylamine (9.7 mL, 69.1 mmol) in THF (60 mL) at −30° C. was added n-butyllithium (2.5 M in hexanes, 27.6 mL, 69.1 mmol). The reaction mixture was stirred for 15 minutes then cooled to −78° C. A solution of 3,4-dichloropyridine (8.53 g, 57.6 mmol) in THF (20 mL) was added dropwise over 20 minutes then the mixture was stirred at −78° C. for 2.5 hours. DMF (5.4 mL, 69.1 mmol) was added and the reaction was warmed to room temperature. The reaction mixture was quenched with ammonium chloride (sat. aq., 300 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-30% ethyl acetate in pentane) to afford the title compound as a white solid (6.78 g, 67% yield). 1H NMR (400 MHz, CDCl3): δ 10.49 (s, 1H), 8.92 (s, 1H), 8.82 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][NH2:14]>>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:13][NH2:14])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NN
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: NNC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
4-Nitro benzoic acid can be reacted with hydrazine to give 4-nitrobenzoic acid hydrazide. This acid hydrazide can be reacted with 2,4-dichlorobenzaldehyde to yield the corresponding acid hydrazone adduct of 2,6-dichlorobenzoldehyde. Treatment of this material with acetic anhydride according to the method of J. Chem. Research Synopsis, 1995, 88-89 can lead to the corresponding N-acetylated 4,5-dihydrooxadiazole. Basic hydrolysis can yield the N-deacetylated product which can be reduced with tin dichloride or with iron powder and ammonium chloride to yield the corresponding aniline. This racemic aniline can be treated with 2,2-dichloroacetyl chloride and triethylamine to yield (±)-2,2-dichloro-N-[4-[5-(2,6-dichlorophenyl)-2-(4,5-dihydrooxadiazolyl)phenyl]acetamide.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[F:8][C:9]1[CH:10]=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]=[CH:13][C:14]=1[C:15]1[C:16]([NH2:21])=[N:17][CH:18]=[CH:19][CH:20]=1.O>CN(C)C(=O)C>[F:8][C:9]1[CH:10]=[C:11]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:12]=[CH:13][C:14]=1[C:15]1[C:16]2=[N:21][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2][N:17]2[CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(-c2ccccc2)cc1F
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(-c4ccccc4)cc3F)C2=N1
Temperature: 60 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
A solution of 2-chloroethanesulfonyl chloride (208.2 mg) in N,N-dimethylacetoamide (2 mL) was added dropwise to a suspension of 3-(3-fluorobiphenyl-4-yl)pyridin-2-amine (149.5 mg) in N,N-dimethylacetoamide (2 mL) and additional N,N-dimethylacetoamide (1 mL) was used to complete the addition of above solution. After being stirred at 60° C. for 3 h, the mixture was cooled to room temperature. Water (10 mL) was added dropwise to the reaction mixture and the whole was stirred at room temperature for 0.5 hr. The precipitate was collected by filtration, washed with water (10 mL) and THF (3 mL), and dried in vacuo at 60° C. to give the title compound (143 mg) as an off-white powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:39]=[CH:38][C:8]2[N:9](C(OC(C)(C)C)=O)[C:10]([NH:12][CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)=[N:11][C:7]=2[CH:6]=1)=O.[H-].[Li+].[Al+3].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:21]1([CH2:20][N:17]2[CH2:16][CH2:15][CH:14]([CH2:13][NH:12][C:10]3[NH:9][C:8]4[CH:38]=[CH:39][C:5]([CH2:3][OH:2])=[CH:6][C:7]=4[N:11]=3)[CH2:19][CH2:18]2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc2c(c1)nc(NCC1CCN(Cc3cccc4ccccc34)CC1)n2C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc2[nH]c(NCC3CCN(Cc4cccc5ccccc45)CC3)nc2c1
Reaction time: 3 h

Procedure:
After dissolving 2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-benzimidazole-1,5-dicarboxylic acid 1-tert-butyl ester 5-methyl ester (940 mg, 1.78 mmol) in dry tetrahydrofuran (18 ml) under a nitrogen stream, aluminum lithium hydride (135 mg, 3.56 mmol) was added at 0° C., and the mixture was stirred for 3 hours. Saturated aqueous sodium sulfate was added, and then the solvent was distilled off under reduced pressure. Since the residue contained water, it was dissolved in ethyl acetate and washed with saturated brine, and the solvent was then distilled off under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (dichloromethane/methanol/TEA=90/5/5) to obtain {2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazol-5-yl-}-methanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31].[Cl-].[NH4+]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C.CCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)CCCI
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Combine 1-t-butoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.5 g, 4.74 mmol) in tetrahydrofuran (45 mL) and dimethylformamide (5 mL). Cool in an ice bath. Add sodium hydride (0.23 g, 60% in oil, 5.7 mmol). Warm to ambient temperature. After about 90 minutes, when the gas evolution ceases, add 1-iodo-4,4,4-trifluorobutane (1.35 g, 5.7 mmol). After 18 hours, add ice and then a saturated aqueous solution of ammonium chloride. Evaporate the reaction mixture to remove most of the tetrahydrofuran, dilute with ethyl acetate and extract with water and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 60% ethyl acetate/hexane to give 1-t-butoxycarbonyl-4-(1-(4,4,4-trifluorobutyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf =0.40 (silica gel, ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14](=[O:16])[CH3:15].[N:17]([O-])=O.[Na+]>[CH]Cl.O>[CH3:7][N:6]1[C:2]2[N:1]=[N:17][CH:15]=[C:14]([OH:16])[C:3]=2[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5]1
Reactant: CC(=O)c1c(-c2ccccc2)nn(C)c1N
Reactant: O=N[O-]
Agent: [CH]Cl
Agent: [Na+]
Solvent: O
Product: Cn1nc(-c2ccccc2)c2c(O)cnnc21
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
A suspension of 1-(5-amino-1-methyl-3-phenyl-pyrazol-4-yl)ethanone (241 mg, 1.12 mmol) in cHCl (6.7 mL) and water (1 mL) was cooled to −5° C. A solution of sodium nitrite (155 mg, 2.24 mmol) in water (0.6 mL) was added and the reaction mixture was stirred at −5° C. for 20 min, then at room temperature for 10 min, then at 65° C. for 30 min and finally cooled to room temperature. The reaction mixture was filtered and the solid was washed with cHCl (2 mL), suspended in MeOH/CH2Cl2 (9:1), filtered and dried, to yield the title compound as a solid (125 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[H-].[Na+].[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15]Cl>CN(C)C=O>[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15][N:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
Imidazole-4-carboxaldehyde (1 g, 10.4 mmol) was added portionwise to a solution of sodium hydride (463 mg, 60% dispersion in mineral oil, 11.4 mmol) in N,N-dimethylformamide (15 ml), and the solution stirred for 30 minutes at room temperature. 2-(Trimethylsilyl)ethoxymethyl chloride (2.03 ml, 11.4 mmol) was added and the reaction stirred at room temperature for 18 hours. The reaction was quenched by the addition of aqueous ammonium chloride solution, and the mixture extracted with ethyl acetate (2×). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with methanol:ethyl acetate (3:97), to give the title compound, 1.8 g, 77% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:15]=2)=[N:4][O:5][N:6]=1.[H-].[Na+].Cl[CH2:26][C:27]#[N:28].O>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:26][C:27]#[N:28])=[CH:18][CH:17]=3)[C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:15]=2)=[N:4][O:5][N:6]=1
Reactant: Nc1nonc1-c1nc2cnccc2n1-c1ccc(O)cc1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#CCOc1ccc(-n2c(-c3nonc3N)nc3cnccc32)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 2.4 %

Procedure:
To a solution containing 150 mg of the product from Example 38 (0.51 mmols) in 2.6 mL of dry DMF was added 25 mg of NaH (0.61 mmols, 60% suspension in oil). After stirring at ambient temperature for 5 min, 0.033 mL of chloroacetonitrile (0.51 mmols) was added to the reaction via syringe. The reaction was warmed to 60° C. for 16 h. After cooling to room temperature, 1 mL of water was carefully added to the reaction mixture. The mixture was diluted with 20 mL of EtOAc and washed with 2N NaOH (3×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in a minimum volume of DMSO and filtered through a 0.45 m acrodisc filter. The resulting solution was purified on the Gilson reverse-phase HPLC to afford the title product (4 mg, 2%). MS (ES+) m/e 334 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7](SC)[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([N:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]3)[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: CSC1=Nc2ccc(Cl)cc2S(=O)(=O)N1
Product: CN1CCN(C2=Nc3ccc(Cl)cc3S(=O)(=O)N2)CC1
Temperature: 140 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
A mixture of 3.2 g of 7-chloro-3-methylthio-2H-1,2,4-benzothiadiazine 1,1-dioxide and 1.1 g of 1-methylpiperazine is heated with stirring in an oil bath at 140° C. for 2 hours. After cooling, the resultant solid is recrystallized from a mixture of dimethylformamide and water to give 3.1 g of the desired product, m.p. above 300° C.
Reaction SMILES: [CH2:1]([N:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Na+].[Cl-].[CH2:24]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH2:24])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C1CCOC1
Reactant: CCCCCCN(CCCCCC)c1ccc(C=O)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Product: C=Cc1ccc(N(CCCCCC)CCCCCC)cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To Methyltriphenylphosphonium bromide (3.07 g, 8.59×10−3 mol) in 50 ml of dry THF was added w-BuLi (2.2 M solution in hexane, 4.00 ml, 8.80×10−3 mol) dropwise at −78° C. After 2.5 h, the reaction mixture was gradually warmed up to 0° C., and again cooled to −78° C. N,N-dihexyl-4-formylaniline (2.26 g, 7.81×10−3 mol) in 15 ml of dry THF was slowly added to the reaction mixture. The reaction mixture was stirred overnight and meanwhile gradually warmed up to 10° C. Aqueous NaCl was added to the reaction mixture and the organic layer was extracted with petroleum ether. The organic layer was dried over Na2SO4. After the solvent was evaporated, the residue was chromatographed on silica gel with 1:1 hexane:CHCl3. Yield=0.775 g (35% based on 2.26 g of N,N-dihexyl-4-formylaniline). 1H NMR (250 MHz, CDCl3): δ 7.27 (d, 2H, J=8.8 Hz, Ph-H), 6.61 (dd, 1H, J=10.9, 17.8 Hz, vinyl-H), 6.58 (d, 2H, J=8.9 Hz, Ph-H), 5.49 (dd, 1H, J=1.1, 17.6 Hz, vinyl-H), 4.97 (dd, 1H, J=0.9, 10.8 Hz, vinyl-H), 3.25 (t, 4H, J=1.7 Hz, NCH2), 1.48-1.66 (m, 4H, NCH2CH2—), 1.20-1.42 (m, 12H, —CH2—), 0.89 (t, 6H, J=6.6 Hz, —CH3). CI MS m/z: 288.269 ((M+H)+) (calcd 288.269).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])[CH:2]=[CH2:3]>CO.[Pd]>[OH:14][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: C=CCc1cc(C(=O)OC)ccc1O
Agent: [Pd]
Solvent: CO
Product: CCCc1cc(C(=O)OC)ccc1O
Temperature: 0 °C
Yield: 48.1 %

Procedure:
A solution of 363 g of methyl 3-allyl-4-hydroxybenzoate in 1.5 L of methanol was hydrogenated for 1 hr in a Parr® type shaker at 40 psi and ambient temperature using 1.5 g of 10% palladium on carbon as the catalyst. The reaction was filterd through Solka-Floc® and the cake washed with 1 L of methanol. The combined filtrate was concentrated and the oil flushed with ether. Hexanes (1.5 L) were added and the resulting suspension cooled to 0° C. The product was collected by filtration, washed with hexanes and dried affording 176.6 g of methyl 4-hydoxy-3-n-propylbenzoate. A second crop of 166.4 g was obtained by concentrating the filtrate, diluting with hexanes and filtering, bringing the total to 343 g (94.3% yield).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:47])[CH2:14][C@@H:15]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[NH:16][C:17]([C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:41])[CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]2)[CH2:20]1)=[O:18])(C)(C)C>>[NH:31]1[CH2:32][CH2:33][CH:28]([CH2:27][CH2:26][C:25]([N:21]2[CH2:22][CH2:23][CH2:24][C@@H:19]([C:17]([NH:16][C@H:15]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[CH2:14][C:13]([OH:47])=[O:12])=[O:18])[CH2:20]2)=[O:41])[CH2:29][CH2:30]1
Reactant: CC(=O)NC[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1
Yield: 50 %

Procedure:
Trifluoroacetic acid (3 ml) was added to N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propanoyl]-3-piperidylcarbonyl]-3(S)-acetylaminomethyl-β-alanine tert-butyl ester. The solvent was evaporated in vacuo. The residue was neutralized with saturated aqueous NaHCO3 and purified by HP-20 resin eluting with isopropanol/water (0-50% to give N-[(R)-1-[3-(4-piperidyl)propanoyl]-3-piperidylcarbonyl]-3(S)-acetylaminomethyl-β-alanine (120 mg, 50.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][C:9]2([C:17]3[S:18][CH:19]=[CH:20][N:21]=3)[CH2:14][O:13]C(C)(C)[O:11][CH2:10]2)=[CH:5][CH:4]=1>CO.O.O.[Cu](Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)([CH2:14][OH:13])[CH2:10][OH:11])=[CH:22][CH:23]=1
Reactant: COc1ccc(COC2(c3nccs3)COC(C)(C)OC2)cc1
Agent: Cl[Cu]Cl
Solvent: O
Solvent: CO
Product: COc1ccc(COC(CO)(CO)c2nccs2)cc1
Temperature: 70 °C

Procedure:
To a solution of the 2-(5-(4-methoxybenzyloxy)-2,2-dimethyl-1,3-dioxan-5-yl)thiazole (Example 11B) (8.0 g, 23.85 mmol) in methanol (239 mL) was added copper(II) chloride dihydrate (12.20 g, 71.6 mmol) in a single portion. The mixture was heated to 70° C. for 1 hour. The reaction was cooled to room temperature and concentrated to a volume of ˜50 mL under reduced pressure. The solution was diluted with saturated aqueous ammonium chloride solution (100 mL) and ethyl acetate (150 mL). The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×100 mL). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound. MS ESI(+) m/z 296.3 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:3]([NH:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=2)=[N:8][C:7]=1[CH3:18])=[O:4].[S:27]1[CH:31]=[C:30]([CH:32]=O)[N:29]=[CH:28]1.C(Cl)Cl.CN(C)C=O.ClCCCl>>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C@H:2]([NH:1][CH2:32][C:30]2[N:29]=[CH:28][S:27][CH:31]=2)[C:3]([NH:5][C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=3)=[N:8][C:7]=2[CH3:18])=[O:4])=[CH:25][CH:24]=1
Reactant: O=Cc1cscn1
Reactant: Cc1cc(-c2nc(C)c(NC(=O)[C@@H](N)Cc3ccc(F)cc3)s2)ccn1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(-c2nc(C)c(NC(=O)[C@H](Cc3ccc(F)cc3)NCc3cscn3)s2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A mixture of (2S)-2-amino-3-(4-fluorophenyl)-N-(4-methyl-2-(2-methylpyridin-4-yl)thiazol-5-yl)propanamide (0.0500 g, 0.13 mmol), thiazole-4-carbaldehyde (0.015 g, 0.13 mmol), reactant 3 (0.10 g, 0.47 mmol), N,N-dimethylformamide (0.50 ml, 0.13 mmol) and 1,2-dichloroethane (1.50 ml, 0.13 mmol) was allowed to stir at rt overnight. The mixture was directly subjected to HPLC purification to give 35.6 mg of (2S)-3-(4-Fluorophenyl)-N-(4-methyl-2-(2-methylpyridin-4-yl)thiazol-5-yl)-2-(thiazol-4-ylmethylamino)propanamide 22. 400 MHz 1H NMR (CD3OD) δ: 9.12 (d, 1H), 8.64 (d, J=4.0 Hz, 1H), 8.28 (d, 1H), 8.22 (dd, J=8.0, 4.0 Hz, 1H), 7.82 (d, 1H), 7.26 (dd, 1H), 7.06 (dd, J=8.0, 8.0 Hz, 2H), 4.56 (dd, J=12.0, 8.0 Hz, 1H), 3.50 (dd, J=16.0, 8.0 Hz, 1H), 3.23 (dd, J=12.0, 8.0 Hz, 1H), 2.80 (s, 3H), 2.31 (s, 3H). LCMS (ES+) m/z 468.
Reaction SMILES: C(=O)([O-])[O-].[NH4+:5].[NH4+].ClC1C=C(C=CC=1)C(O[CH:14]1[C:19](=[O:20])[NH:18][C:17]([CH3:21])=[C:16]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[S:15]1)=O>C(#N)C>[NH2:5][CH:14]1[C:19](=[O:20])[NH:18][C:17]([CH3:21])=[C:16]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[S:15]1
Reactant: CC1=C(c2ccncc2)SC(OC(=O)c2cccc(Cl)c2)C(=O)N1
Reactant: [NH4+]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC1=C(c2ccncc2)SC(N)C(=O)N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.8 %

Procedure:
Ammonium carbonate (0.6 g) was added to a solution of 2-(3-chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (0.4 g) in acetonitrile (20 ml). The mixture was stirred at ambient temperature for 3 days, was filtered and the filtrate was evaporated to dryness. The residue was chromatographed on silica gel (Wakogel C-200) column, using chloroform-methanol (=20:1) as an eluant to give the titled compound (0.1 g, yield 40.7%).
Reaction SMILES: [CH:1]1([CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH:9]2[CH2:13][O:12]C(C)(C)[O:10]2)[CH2:3][CH2:2]1>CC(O)=O>[CH:1]1([CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH:9]([OH:10])[CH2:13][OH:12])[CH2:2][CH2:3]1
Reactant: CC1(C)OCC(CCC=CCC2CC2)O1
Solvent: CC(=O)O
Product: OCC(O)CCC=CCC1CC1

Procedure:
Stirred 4-(5-Cyclopropyl-pent-3-enyl)-2,2-dimethyl-[1,3]dioxolane (0.30 g, 1.4 mmol) in 80% AcOH (5 mL) overnight at room temperature. Concentrated and purified by silica gel chromatography (70˜90% EtOAc in hexanes) to collect 7-Cyclopropyl-hept-5-ene-1,2-diol as a clear oil. 1H NMR (400 MHz, CDCl3): δ 5.52–5.47 (m, 1H), 5.41–5.35 (m, 1H), 3.77–3.71 (m, 1H), 3.66 (d, 1H, J=11.2 Hz), 3.46 (dd, 1H, J1=11.2 Hz, J2=7.7 Hz), 2.19–2.10 (m, 2H), 1.97 (t, 2H, J=7.1 Hz), 1.53–1.46 (m, 2H), 0.74–0.68 (m, 1H), 0.44–0.39 (m, 2H), 0.08–0.04(m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.[NH2:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:7]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: N[C@H](CO)Cc1ccccc1
Product: Cc1cc(C(=O)N[C@H](CO)Cc2ccccc2)ccc1[N+](=O)[O-]
Yield: 81.8 %

Procedure:
5 g (27.6 mmol) of 3-methyl-4-nitrobenzoic acid were reacted with 4.2 g (27.6 mmol) of (S)-2-amino-3-phenyl-1-propanol by the method of procedure 3c. 7.1 g (82%) of the product were obtained.