Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][O:17][CH2:18][C@H:19]([O:34][CH2:35][C:36]([CH3:38])=[CH2:37])[C@@H:20]([O:29][CH2:30][C:31]([CH3:33])=[CH2:32])[C@H:21]([OH:28])[CH2:22][O:23][CH2:24][C:25]([CH3:27])=[CH2:26])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC=C([N+]([O-])=O)C=1C(OC(C1C([N+]([O-])=O)=CC=CC=1C)=O)=O>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:38][C:36](=[CH2:37])[CH2:35][O:34][C@@H:19]1[C@@H:20]([O:29][CH2:30][C:31]([CH3:33])=[CH2:32])[C@@H:21]([CH2:22][O:23][CH2:24][C:25]([CH3:27])=[CH2:26])[O:28][C:13](=[O:15])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][O:17][CH2:18]1.[CH3:38][C:36](=[CH2:37])[CH2:35][O:34][C@@H:19]1[C@@H:20]([O:29][CH2:30][C:31]([CH3:33])=[CH2:32])[C@@H:21]([CH2:22][O:23][CH2:24][C:25]([CH3:27])=[CH2:26])[O:28][C:13](=[O:14])[C@H:12]([NH:11][C:9](=[O:10])[O-:8])[CH2:16][O:17][CH2:18]1
Reactant: C=C(C)COC[C@@H](O)[C@H](OCC(=C)C)[C@H](COC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCC(=C)C
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: C=C(C)COC[C@H]1OC(=O)[C@@H](NC(=O)OCc2ccccc2)COC[C@H](OCC(=C)C)[C@H]1OCC(=C)C
Product: C=C(C)COC[C@H]1OC(=O)[C@H](NC(=O)[O-])COC[C@H](OCC(=C)C)[C@H]1OCC(=C)C
Reaction time: 1 h
Yield: 36 %
Yield: 36 %

Procedure:
A solution of (S)-2-(benzyloxycarbonylamino)-3-((2S,3S,4R)-4-hydroxy-2,3,5-tris(2-methylallyloxy)pentyloxy)propanoic acid (400 mg, 0.747 mmol) in anhydrous toluene (400 mL) was added to a solution of MNBA (411 mg, 1.195 mmol) and DMAP (547 mg, 4.48 mmol) in toluene (1600 mL) over the course of 3 h via syringe pump. After the addition was complete, the reaction mixture was stirred for 1 h, concentrated, and the residue purified by flash chromatography (SiO2, 20% EtOAc/hexanes) to furnish benzyl (3S,7S,8R,9R)-7,8-bis(2-methylallyloxy)-9-((2-methylallyloxy)methyl)-2-oxo-1,5-dioxonan-3-ylcarbamate (140 mg, 36%) and (3R,7S,8R,9R)-7,8-bis(2-methylallyloxy)-9-((2-methylallyloxy)methyl)-2-oxo-1,5-dioxonan-3-ylcarbamate as white foams (140 mg, 36%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH2:16]([NH:19][C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[S:21])[CH:17]=[CH2:18]>>[BrH:1].[CH2:16]([N:19]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=2)([OH:4])[CH2:2][S:21][C:20]1=[N:22][CH:23]([CH3:25])[CH3:24])[CH:17]=[CH2:18]
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Reactant: C=CCNC(=S)NC(C)C
Product: Br
Product: C=CCN1C(=NC(C)C)SCC1(O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
6.2 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone and 3.16 g of 1-allyl-3-isopropylthiourea were reacted according to the prescription given in Example 23 and the colorless crystalline end product was filtered off.
Reaction SMILES: [C:1]([C:3]([C:12]#[N:13])=[C:4]([NH:6][C:7](=[O:11])[N:8]([CH3:10])[CH3:9])[SH:5])#[N:2].[OH:14]O>O>[C:1]([C:3]1[C:12]([OH:14])=[N:13][S:5][C:4]=1[NH:6][C:7](=[O:11])[N:8]([CH3:10])[CH3:9])#[N:2]
Reactant: OO
Reactant: CN(C)C(=O)NC(S)=C(C#N)C#N
Solvent: O
Product: CN(C)C(=O)Nc1snc(O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-(2,2-Dicyano-1-mercapto-vinyl)-1,1-dimethyl-urea (sodium salt) (30 g, 137 mmol) in water (300 mL) was treated at ambient temperature with hydrogen peroxide (14 mL of a 10 M solution). The reaction warmed and thickened with solid formation and so was treated with additional water (100 mL). The mixture was heated to reflux for 15 minutes, effecting complete dissolution and then cooled to ambient temperature. After 1 hour at ambient temperature, the mixture was concentrated to a constant weight (35 g,>100% due to water content) and was used immediately in the next step
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=1.[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[Li+].CO[C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>C1COCC1>[CH3:13][C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([CH2:14][C:26]1[CH:33]=[CH:32][C:29]([CH3:30])=[CH:28][CH:27]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C(C)c1cccnc1
Reactant: COc1ccc(CCl)cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(Cc1ccc(C)cc1)c1cccnc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of the product of STEP 1 (7.5 g, 42.1 mmol) was dissolved in 50 ml THF and a solution of lithium bis(trimethylsilyl)amide (45 ml, 45 mmol, 1.0 M in THF) was added dropwise at −70° C. The reaction was stirred at −70° C. for 1 h and a solution of 4-methoxybenzyl chloride (7.8 g, 50 mmol) in 25 ml THF was added. The reaction was allowed to warm to room temperature and quenched with 5%Na2SO3 solution (200 ml). The product was extracted with ethyl acetate (3×100 ml). The organic layer was washed with H2O, brine, dried with MgSO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=1/1) to give a brown liquid in 11.7 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([CH:46]([CH3:48])[CH3:47])=[N:43][C:42]=2[C:49]2[CH:50]=[CH:51][C:52]([F:56])=[C:53]([CH:55]=2)[NH2:54])[CH:38]=[CH:37][N:36]=1.[F:57][C:58]1[CH:59]=[C:60]([S:64](Cl)(=[O:66])=[O:65])[CH:61]=[CH:62][CH:63]=1>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([CH:46]([CH3:48])[CH3:47])=[N:43][C:42]=2[C:49]2[CH:50]=[CH:51][C:52]([F:56])=[C:53]([NH:54][S:64]([C:60]3[CH:61]=[CH:62][CH:63]=[C:58]([F:57])[CH:59]=3)(=[O:66])=[O:65])[CH:55]=2)[CH:38]=[CH:37][N:36]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC(C)c1nc(-c2ccc(F)c(N)c2)c(-c2ccnc(Cl)n2)s1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(Cl)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline (12 g, 34.5 mmol) and 3-fluorobenzenesulfonyl chloride (8.72 g, 44.8 mmol) the title compound of Step A was obtained (9.3 g, 53.4%). 1H NMR (400 MHz, CDCl3) δ ppm 8.35 (d, J=5.3 Hz, 1H), 7.65-7.73 (m, 1H), 7.52-7.60 (m, 1H), 7.41-7.50 (m, 2H), 7.20-7.37 (m, 1H), 7.04-7.12 (m, 1H), 6.83-7.00 (m, 2H), 3.30-3.40 (m, 1H), 1.46 (d, J=6.8 Hz, 6H). MS (ES+): 507 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O-:7])=[O:6].[CH2:12](Br)[CH:13]=[CH2:14].[C:16](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:11][C:3]1[C:2]([O:1][CH2:12][CH:13]=[CH2:14])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH3:16])=[O:6]
Reactant: Cc1c(O)cccc1C(=O)[O-]
Reactant: C=CCBr
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc(C(=O)OC)c1C
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 100.6 %

Procedure:
A mixture of 3-hydroxy-2-methylbenzoate (5.46 g, 33 mmol), allyl bromide (4.33 mL, 50 mmol) and cesium carbonate (21.5 g, 66 mmol) in dimethylformamide (60 mL) was stirred at 60° C. for 2.5 hours. The reaction mixture was allowed to cool to room temperature and was then partitioned between water and ethyl acetate. The aqueous portion was extracted twice using ethyl acetate, and the combined organic portion was washed with 5% aqueous lithium chloride, 1N aqueous sodium hydroxide, brine, and then was dried over sodium sulfate, filtered and concentrated in vacuo to afford (6.85 g, 100%) of methyl 2-methyl-3-(prop-2-en-1-yloxy)benzoate as a colorless oil. 1H NMR (400 MHz, DMSO-d6): 7.33-7.30 (m, 1H), 7.27-7.23 (m, 1H), 7.18-7.15 (m, 1H), 6.13-6.02 (m, 1H), 5.35 (dd, 2H), 4.61 (d, 2H), 3.82 (s, 3H), 2.35 (s, 3H). MS (EI) for C12H14O3: 207 (MH+).
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:40][O:41][CH2:42][C:43]1[S:44][CH:45]=[C:46]([CH2:48][N:49]2[N:53]=[C:52]([NH2:54])[CH:51]=[N:50]2)[N:47]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:40][O:41][CH2:42][C:43]1[S:44][CH:45]=[C:46]([CH2:48][N:49]2[N:53]=[C:52]([NH:54][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:16])[CH:51]=[N:50]2)[N:47]=1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: COCc1nc(Cn2ncc(N)n2)cs1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCc1nc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)cs1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 5-phenyloxazole-4-carboxylic acid (42 mg, 0.21 mmol) in CH2Cl2 (3.0 mL) was treated at rt with DMAP (6.6 mg, 0.05 mmol), HOBt (36 mg, 0.26 mmol), EDC (102 mg, 0.53 mmol) and DIPEA (0.16 mL, 0.96 mmol) and the resulting mixture was stirred for 45 min at rt. A solution of 2-((2-(methoxymethyl)thiazol-4-yl)methyl)-2H-1,2,3-triazol-4-amine (48 mg, 0.21 mmol) in CH2Cl2 (3.0 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (15.0 mL), the layers were separated and the org. phase was washed with 1N HCl (10.0 mL), water (5.0 mL), followed by brine (10.0 mL) and dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (60:40 hept-EA) gave the title compound as a white solid. TLC: rf (7:3 hept-EA)=0.15. LC-MS-conditions 07: tR=0.83 min, [M+H]+=397.23.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=[CH:6][CH:5]=1>ClCCl>[CH3:6][CH2:5][CH2:4][CH2:9][CH3:8].[Br:1][CH:11]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])[C:10]([C:7]1[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=1)=[O:20]
Reactant: O=C(Cc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClCCl
Product: CCCCC
Product: O=C(c1ccc(Cl)cc1)C(Br)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
2.5 ml of bromine are added dropwise to a solution of 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)ethanone in dichloromethane (200 ml). The mixture is stirred for 4 hours at room temperature. The reaction medium is washed with water, with saturated aqueous NaHCO3 solution and then with aqueous NH4Cl solution. The organic phase is dried over Na2SO4, filtered and evaporated to dryness. The expected product is precipitated from pentane (yield=94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[O:5][CH2:6][CH:7]([OH:27])[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:18][C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])=[O:17])[CH2:11][CH2:10]1.[C:32](OC(=O)C)(=[O:34])[CH3:33].O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[O:5][CH2:6][CH:7]([O:27][C:32](=[O:34])[CH3:33])[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:18][C:19]2[C:20]([CH3:26])=[CH:21][CH:22]=[CH:23][C:24]=2[CH3:25])=[O:17])[CH2:11][CH2:10]1
Reactant: COc1ccccc1OCC(O)CN1CCN(CC(=O)Nc2c(C)cccc2C)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COc1ccccc1OCC(CN1CCN(CC(=O)Nc2c(C)cccc2C)CC1)OC(C)=O
Reaction time: 2 h

Procedure:
One g of 1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine is dissolved in 25 ml of pyridine and cooled in an ice bath to 0°-5° C. Acetic anhydride (0.6 g) is slowly added and the reaction is stirred for 2 hours. After the addition of 100 ml of water, the reaction mixture is extracted twice with 100 ml portions of diethylether. After combining, the ether extract is washed twice with 100 ml of water and evaporated to dryness to produce 1-[3-(2-methoxyphenoxy)-2-acetoxypropyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine as an oil.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([C:21](O)=[O:22])[S:19][CH:20]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC[N:26]=C=NCCCN(C)C.Cl.C(N(CC)CC)C.O>CN(C=O)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([C:21]([NH2:26])=[O:22])[S:19][CH:20]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Yield: 54.1 %

Procedure:
A solution of 4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylic acid (89 mg), HOBt ammonium salt (49 mg), EDCI hydrochloride (62 mg) and triethylamine (33 mg) in DMF (10 mL) was stirred at room temperature for 24 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (48 mg).
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2)[CH2:3][CH2:4][CH2:5][N:6]([CH2:10][CH2:11]Cl)[CH2:7][CH2:8]Cl.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:1][CH:2]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:11][N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:7]1
Reactant: Nc1ccccc1
Reactant: O=C1CCc2cc(C(O)CCCN(CCCl)CCCl)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1CCc2cc(C(O)CCCN3CCN(c4ccccc4)CC3)ccc2N1

Procedure:
2.5 Grams of 6-{1-hydroxy-4-[bis-chloroethyl-amino]butyl}-3,4-dihydrocarbostyril, 1.5 g of aniline and 2.2 g of potassium carbonate were mixed in 150 ml of ethanol and the mixture was refluxed by heating for 24 hours. The reaction mixture was concentrated under a reduced pressure and the residue thus obtained was extracted with chloroform. The chloroform layer was washed with water, dried and chloroform was removed by distillation. The residue thus obtained was separated and purified by a preparative thin layer chromatography and recrystallized from isopropanol to obtain 0.2 g of 6-[1-hydroxy-4-(4-phenyl-1-piperazinyl)butyl]-3,4-dihydrocarbostyril in colorless needle-like crystals.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[C@@H:18]3[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:12][CH2:11][CH2:10]2)=[O:8])[CH:3]=1.[NH:19]1[CH:23]=[CH:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.[Cu](I)I>[N:9]1([C:7]([C:4]2[CH:3]=[C:2]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)[S:6][CH:5]=2)=[O:8])[CH:18]2[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11][CH2:10]1
Reactant: O=C(c1csc(Br)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reactant: c1cn[nH]c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=C(c1csc(-n2cccn2)c1)N1CCCC2CCCCC21
Temperature: 120 °C
Yield: 21.9 %

Procedure:
To a solution of cis-(5-bromo-thiophen-3-yl)-(octahydro-quinolin-1-yl)-methanone (0.095 g, 0.29 mmol) in DME (2 mL) was added N′N′-dimethylethylenediamine (0.005 g), pyrazole (0.039 g, 0.58 mmol), copper iodide (0.011 g) and potassium carbonate (0.040 g, 0.29 mmol). The reaction mixture was placed under nitrogen then sealed in a vial and heated at 120° C. for 79 hours. The solution was partitioned between DCM and water and the phases separated using a hydrophobic frit. The organic phase was evaporated and the compound was purified by chromatography on a silica cartridge eluting 0-10% methanol in DCM then re-purified on a larger cartridge using 0-3% methanol in DCM. The compound was further purified by HPLC on a C6 phenyl column, eluting with 50%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were evaporated to give the title compound as a colourless oil (0.02 g). LCMS m/z 316.19 [M+H]+ R.T.=10.74 min (Analytical Method 2).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:11]([CH2:21][CH2:22][CH3:23])[C:12]([CH2:14][O:15][C:16](=[O:20])[CH2:17][CH2:18][NH2:19])=[O:13])[CH2:9][CH3:10].Cl[S:25]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([OH:33])=[O:32])(=[O:27])=[O:26].O.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:21]([N:11]([CH2:8][CH2:9][CH3:10])[C:12]([CH2:14][O:15][C:16]([CH2:17][CH2:18][NH:19][S:25]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([OH:33])=[O:32])(=[O:27])=[O:26])=[O:20])=[O:13])[CH2:22][CH3:23]
Reactant: CCCN(CCC)C(=O)COC(=O)CCN
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCN(CCC)C(=O)COC(=O)CCNS(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-amino-propionic acid dipropylcarbamoylmethyl ester (step 2) (20.1 g, 75 mmol) in DCM (240 ml) at 0° C. under N2 was added DMAP (0.46 g, 3.76 mmol) followed by TEA (38.8 ml, 278 mmol). The reaction mixture was treated with a solution of 3-chlorosulfonylbenzoic acid (16.6 g, 75 mmol) in DCM (200 ml). The mixture was allowed to stir at 0° C. for 1 h and then warmed up to RT for 1 h. Water (200 ml) was added and the pH adjusted with 1N HCl (100 ml). The organic layer was separated, dried over MgSO4 and concentrated in vacuo. Purification by C18 reverse phase chromatography, eluting with MeCN/water (1% HCl) afforded the title product; LC-MS Rt 1.01 mins; 415.2 [M+H]+, Method 2minLC_v003.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1([CH2:12][C:13]([OH:15])=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.[F:16][C:17]([F:38])([F:37])[C:18]1[CH:19]=[C:20]([S:24]([CH2:27][CH2:28][S:29][C:30]2[C:35]([NH2:36])=[CH:34][CH:33]=[CH:32][N:31]=2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.O1CCOCC1.CCCCCC>[CH:7]1([CH2:12][C:13]([NH:36][C:35]2[C:30]([S:29][CH2:28][CH2:27][S:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:37])([F:38])[F:16])[CH:19]=3)(=[O:26])=[O:25])=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=C(O)CC1CCCC1
Reactant: Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(CC1CCCC1)Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
254 μl (3.0 mmol) oxalylchloride were added to a solution of 192 mg (1.5 mmol) 2-cyclopentyl acetic acid in DCM (10 ml) and the mixture was stirred for 3 h at RT. Then the mixture was concentrated to small volume under vacuum and the residue was taken up with dioxane (6 ml). This solution was added at 0° C. to a solution of 362 mg (1.0 mmol) [2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]amine (VPF-001) in dioxane (5 ml). Then the reaction solution was mixed with 420 mg (5.0 mmol) NaHCO3 and stirred for 16 h at RT. Then the mixture was concentrated to small volume under vacuum and the residue was taken up with water. Then it was extracted with EE and the organic phase was washed with a saturated aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 3:1) of the residue yielded 231 mg (0.5 mmol, 54%) 2-cyclopentyl-N-[2-[2-[[3-(trifluoromethyl)-phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]acetamide. MS: m/z 473.1 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]#[N:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.[NH2:24][NH2:25]>CCO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=[N:24][NH2:25])[NH2:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: N#Cc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Solvent: O
Solvent: CCO
Product: NN=C(N)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 60 °C

Procedure:
To a solution of 1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine-6-carbonitrile (80 mg, 0.278 mmol) in EtOH (3 mL), was added hydrazine hydrate (18.12 mg, 0.362 mmol). The reaction was heated to 60° C. overnight. The mixture was filtered and washed with EtOH, H2O, and EtOH to give a yellow solid. 1H-NMR (400 MHz, DMSO-d6+D2O) δ ppm 9.29 (s, 1H), 8.88 (s, 1H), 8.34 (d, 1H), 8.01 (m, 2H), 7.83 (d, 1H), 7.52 (m, 1H), 6.16 (s, 2H). LCMS (method B): [MH]+=320, tR=1.03 min.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:14]=[O:15])C1C=CC=CC=1.[CH3:16][C:17]1[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][C:18]=1[OH:19]>CCOCC>[OH:19][C:18]1[C:17]([CH3:16])=[C:23]([OH:24])[CH:22]=[CH:21][C:20]=1[CH:14]=[O:15]
Reactant: CN(C=O)c1ccccc1
Reactant: Cc1c(O)cccc1O
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(O)ccc(C=O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
Phosphorus oxychloride (80 mL, 0.86 mol) was added to a stirred mixture of N-methylformanilide (102 mL, 0.82 mol) in ether (250 mL). The mixture was stirred for 1 hour at room temperature and then cooled in ice. 2-Methyl resorcinol (Aldrich, 100 g, 0.81 mol) was added and the mixture was allowed to warm to room temperature while stirring overnight. The precipitated intermediate product was collected by filtration and rinsed with ether (3×). The intermediate was hydrolyzed by dissolving in a mixture of acetone (250 mL) and water (250 mL) and stirring for 30 minutes. Water (2 L) was added, the mixture was brought to a boil, and then allowed to cool and deposit crystalline product. This was recrystallized a second time from water (4 L) to afford pure product (70 g, 57%). M.p. 150° C. (Lit. 152°-3° C. [W. Baker et al., J. Chem. Soc. 2834-5 (1949)⟧
Reaction SMILES: C(O[CH:5]([C:12]1[CH:13]=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:15]=[N:16][C:17]=1[O:18][CH3:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.C(N(CC)CC)C.[H][H]>[C].[Pd].C(O)C>[C:20]1([C:14]2[N:15]=[N:16][C:17]([O:18][CH3:19])=[C:12]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:13]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1nnc(-c2ccccc2)cc1C(OC(C)=O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1nnc(-c2ccccc2)cc1Cc1ccccc1
Yield: 100.3 %

Procedure:
600 mg of 10% palladium carbon was added to a mixture of 1.58 g of 5-(α-acetoxybenzyl)-3-phenyl-6-methoxypyridazine, 2.0 ml of triethylamine and 10 ml of ethanol, and the mixture was subjected to hydrocracking in a hydrogen atmosphere. The catalyst was filtered off, and the solvent was removed. Then, the residue was subjected to NH-silica gel (Fuji Silicia) and eluted with ethyl acetate, to give 1.31 g of the target compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[C:6]([C:18]([O:20]CCC#N)=[O:19])=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[OH-].[K+]>CC(C)=O>[C:1]([C:4]1[CH:5]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[C:6]([C:18]([OH:20])=[O:19])=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)NC(CCCCN=[N+]=[N-])=C(C(=O)OCCC#N)C1c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(=O)C1=C(C)NC(CCCCN=[N+]=[N-])=C(C(=O)O)C1c1ccc([N+](=O)[O-])cc1
Yield: 64.8 %

Procedure:
A solution of 5-acetyl-2-(4-azidobutyl)-3-(2-cyanoethoxy)carbonyl-1,4-dihydro-6-methyl-4-(4-nitrophenyl)pyridine (1.05 g, 2.32 mmol) in 10 ml of acetone was treated with 20 ml of 1N aqueous KOH solution at 0° C. for 1 hr. The acetone was removed in vacuo and the aqueous layer was acidified to pH=3 by 2N hydrochloric acid, the resulting yellow precipitate was collected by filtration, washed with 10 ml of cold water and dried in vacuo to yield 0.60 g (60% yield) of 5-acetyl-2-(4-azidobutyl)-1,4-dihydro-6-methyl-4-(4-nitrophenyl)pyridine-3-carboxylic acid as a yellow powder.