Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[O:16]1[CH:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17]1.[C:27](N1C=CN=C1)([N:29]1C=CN=C1)=[O:28].[OH-].[NH4+]>C(O)(C)C.C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:17][CH:18]([O:16][C:27](=[O:28])[NH2:29])[CH2:19][O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:14][CH:15]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)OC(COc1ccccc1)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-(4-fluorobenzoyl)piperidine (5 mmol) and 1,2-epoxy-3-phenoxypropane (5 mmol) was refluxed in 30 ml of isopropanol for 4 h. This solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was then washed with brine, the resulting organic layer was dried and concentrated in vacuo to give a solid. This was recrystallized in a solution mixture of n-hexane and ethyl acetate to give a white solid. This was dissolved in THF (50 ml) and was added with 1,1′-carbonyl diimidazole (10 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 h, followed by the addition of excess ammonium hydroxide (10 ml) at 0° C. After 5 h stirring at room temperature, water was added to terminate the reaction. The organic layer was extracted 3 times with dichloromethane, dried and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:hexane=1:2). The resulting carbamic acid 1-[4-(4-fluoro-benzoyl)-piperidin-1-ylmethyl]-2-phenoxy-ethyl ester was dissolved in THF and the solution was treated with a solution of HCl in ethyl ether. The resulting precipitate was filtered to give carbamic acid 1-[4-(4-fluoro-benzoyl)-piperidin-1-ylmethyl]-2-phenoxy-ethyl ester; hydrochloride.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[NH:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][CH:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]#[N:43])[CH2:37][CH2:36]1>ClCCl>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([N:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[N:27]=[C:26]2[NH:34][CH:35]2[CH2:36][CH2:37][N:38]([CH2:41][C:42]#[N:43])[CH2:39][CH2:40]2)=[O:8])=[CH:2]1
Reactant: N#CCN1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: O=C(O)c1ccoc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCN1CCC(Nc2nc3ccccc3n2C(=O)c2ccoc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
To a stirred mixture of 3.14 parts of 3-furancarboxylic acid, 6 parts of N,N-diethylethanamine and 390 parts of dichloromethane were added 7.2 parts of 2-chloro-1-methylpyridinium iodide. After stirring for 10 minutes at room temperature, 7 parts of 4-[(1H-benzimidazol-2-yl)amino]-1-piperidineacetonitrile were added and the whole was stirred for 1 hour at room temperature. The reaction mixture was washed with water. The organic phase was dried, filtered and evaporated. The residue was crystallized from acetonitrile, yielding 7 parts (74%) of 4-[[1-(3-furanylcarbonyl)-1H-benzimidazol-2-yl]amino]-1-piperidineacetonitrile (intermediate 101).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:14])[N:9]([CH2:11][CH2:12][CH3:13])[CH2:10][C:6]=2[N:5]=[C:4]2[N:15]([CH:18]=[CH2:19])[N:16]=[CH:17][C:3]=12.Cl.[C:21](=O)([O-])[O-].[Na+].[Na+].[C:27](#N)[CH3:28]>>[NH2:1][C:2]1[C:7]2[C:8](=[O:14])[N:9]([CH2:11][CH2:12][CH3:13])[CH2:10][C:6]=2[N:5]=[C:4]2[N:15]([CH2:18][CH2:19][C:21]#[C:27][CH3:28])[N:16]=[CH:17][C:3]=12
Reactant: CC#N
Reactant: O=C([O-])[O-]
Reactant: C=Cn1ncc2c(N)c3c(nc21)CN(CCC)C3=O
Agent: Cl
Agent: [Na+]
Product: CC#CCCn1ncc2c(N)c3c(nc21)CN(CCC)C3=O

Procedure:
A mixture of 4-amino-6,7-dihydro-6-(n-propyl)-1-vinylpyrazolo[3,4-b]pyrrolo[3,4-e]pyridin5-(1H)-one (9.9 g.) and acetonitrile (250 ml.) was stirred while 6N aqueous hydrochloric acid (100 ml.) was added. The mixture was heated under reflux for 3.5 hours under nitrogen. The cooled suspension was neutralized by the cautious addition of saturated aqueous sodium carbonate and the acetonitrile was removed at reduced pressure. The aqueous suspension of product was chilled to 4° overnight. The precipitated white solid was collected by filtration, washed with water, and dried in vacuo. There was thus obtained 8.0 g. of 4-amino-6,7-dihydro-1H-6-n-propylpyrazolo[3,4-b]pyrrolo[3,4-e]pyridin-5-(1H)-one. Recrystallization from acetonitrile gave a sample: m.p. 278°-281 °.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[CH:7]=[O:8].CC1(C)C(C)(C)[O:21][B:20](B2OC(C)(C)C(C)(C)O2)[O:19]1.C([O-])(=O)C.[K+]>COCCOC>[CH:7]([C:6]1[N:5]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:4]=[CH:3][C:2]=1[B:20]([OH:21])[OH:19])=[O:8]
Reactant: C[Si](C)(C)CCOCn1ncc(Br)c1C=O
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: COCCOC
Product: C[Si](C)(C)CCOCn1ncc(B(O)O)c1C=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
A mixture of 4-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-5-carbaldehyde (2.00 g, 6.55 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (1.75 g, 6.88 mmol), potassium acetate (1.93 g, 19.7 mmol) and 1,2-dimethoxyethane (40 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (0.535 g, 0.655 mmol) was added, and the mixture was purged with argon again. The mixture was stirred at 90° C. overnight. After cooled to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, hexane to 70:30 hexane/EtOAc) to afford the title compound (571 mg, 25%) as a colorless oil:
Reaction SMILES: C([Li])CCC.[C:6]([OH:10])(C)([CH3:8])[CH3:7].C([O:18][C:19](=O)[NH:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[C:23]([F:28])[CH:22]=1)C1C=CC=CC=1.C1C[O:33]CC1>>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([N:20]2[CH2:7][CH:6]([CH2:8][OH:33])[O:10][C:19]2=[O:18])=[CH:22][C:23]=1[F:28]
Reactant: C1CCOC1
Reactant: CC(C)(C)O
Reactant: O=C(Nc1ccc(Br)c(F)c1)OCc1ccccc1
Agent: [Li]CCCC
Product: O=C1OC(CO)CN1c1ccc(Br)c(F)c1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
Butyl lithium (2.3M in n-hexanes, 118.3 ml, 0.272 mol, 1.06 eq) was added at −30° C. to anhydrous tert-butanol (25.0 g, 0.53 mol, 2.07 eq) in anhydrous THF (170 ml), under nitrogen. The mixture was stirred for 30 min at −30° C., and was then allowed to warm slowly to 0° C. After 30 min at 0° C., the (4-bromo-3-fluoro-phenyl)-carbamic acid benzyl ester (83 g, 0.256 mol, 1 eq) was added portionwise, keeping the temperature cold, and the mixture was stirred for an additional 30 min at 0° C. To this ice cold mixture, R(−)-glycidyl butyrate (39.7 ml, 0.288 mol, 1.12 eq) were added and the mixture allowed to come gradually to room temperature. The mixture was extracted with saturated sodium chloride solution and the organic phase was dried over MgSO4, filtrated and evaporated. The product was obtained after recrystallisation of the crude product with ethyl acetate, to give (64.1 g, 86.4%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.[CH:15](N(C(C)C)CC)(C)C.O1CCOCC1.[F:30][C:31]([F:68])([F:67])[C:32]1[CH:33]=[C:34]([CH:60]=[C:61]([C:63]([F:66])([F:65])[F:64])[CH:62]=1)[CH2:35][N:36]1[CH2:43][CH2:42][CH2:41][NH:40][C:39]2[N:44]=[C:45](S(C)(=O)=O)[N:46]=[C:47]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[CH3:54])[C:38]=2[C:37]1=[O:59]>C(OCC)(=O)C>[C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:45]2[N:46]=[C:47]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[CH3:54])[C:38]3[C:37](=[O:59])[N:36]([CH2:35][C:34]4[CH:60]=[C:61]([C:63]([F:66])([F:65])[F:64])[CH:62]=[C:32]([C:31]([F:30])([F:68])[F:67])[CH:33]=4)[CH2:43][CH2:42][CH2:41][NH:40][C:39]=3[N:44]=2)[CH2:10][CH2:9]1)(=[O:7])[CH3:15]
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)N1CCCN(c2nc3c(c(-c4ccccc4C)n2)C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCN3)CC1
Reaction time: 0.5 h
Yield: 74 %

Procedure:
1-(t-butoxycarbonyl)homopiperazine (36.1 mg), diisopropylethylamine (0.1 mL) and 1,4-dioxane (1 mL) were added to 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg). While heated, the mixture was refluxed for 5 hours. The reaction mixture was then diluted with ethyl acetate, was washed with water, and was then dried over anhydrous sodium sulfate. The solvent was removed and 3 mol/L hydrogen chloride/ethyl acetate (1 mL) was added while the residue was chilled on an ice bath. The mixture was stirred for 30 min and then additional 1 hour at room temperature. Following removal of the solvent, the residue was dissolved in tetrahydrofuran (1 mL). While the residue was chilled on an ice bath, triethylamine (0.1 mL) and anhydrous acetic acid (0.05 mL) were added and the mixture was stirred at room temperature for 30 min. Subsequently, the reaction mixture was diluted with ethyl acetate, was washed with water, and was then dried over anhydrous sodium sulfate. Following removal of the solvent, the residue was purified on a silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain 2-(4-acetylhomopiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine (70.7 mg, 74%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[C:17]3[O:16][CH:15]=[CH:14][C:13]=3[CH:12]=[C:11]([N+:18]([O-])=O)[CH:10]=2)[C@H:5]([CH3:21])[CH2:4][N:3]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O.NN>C1COCC1.CCO.[Ni]>[NH2:18][C:11]1[CH:10]=[C:9]([CH2:8][N:6]2[C@H:5]([CH3:21])[CH2:4][N:3]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C@@H:2]([CH3:1])[CH2:7]2)[C:17]2[O:16][CH:15]=[CH:14][C:13]=2[CH:12]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1Cc1cc([N+](=O)[O-])cc2ccoc12
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1Cc1cc(N)cc2ccoc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
tert-Butyl trans-2,5-dimethyl-4-[(5-nitro-1-benzofuran-7-yl)methyl]piperazine-1-carboxylate (0.14 g, 0.35 mmol; obtained in Step 2) was dissolved in THF/EtOH (4:1; 5 mL). Excess Raney-Ni (slurry in EtOH) was added followed by hydrazine hydrate (0.07 g, 1.39 mmol). The reaction mixture was stirred overnight at ambient temperature. After filtration and evaporation of solvent, a crude oil (0.11 g, 87%) was obtained that was used in the next step without further purification. HPLC 86% RT=1.15 min (System B; 10-97% MeCN over 3 min). MS (ESI+) m/z 360.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:19][C:18]([C:20](OCC)=[O:21])=[N:17][C:16]=2[CH3:25])=[CH:11][CH:10]=1.C(O)C>C(OCC)(=O)C>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[S:19][C:18]([C:20]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:21])=[N:17][C:16]=2[CH3:25])=[CH:13][CH:14]=1
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1nc(C)c(-c2ccc(OC)cc2)s1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-c2sc(C(=O)N3CCCCC3)nc2C)cc1
Temperature: 92.5 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
Piperidine (1.84 g, 21.63 mmol) was added to a stirred solution of ethyl 5-(4-methoxyphenyl)-4-methylthiazole-2-carboxylate (prepared according to the procedure reported in WO 2006/089076, 0.6 g, 2.16 mmol) in a ethanol (10 ml) in a tube at 25° C. under nitrogen atmosphere. The tube was agitated for about 15 minutes under nitrogen and was sealed. The reaction mixture was heated at 90-95° C. for 15 hr with stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and was concentrated under reduced pressure. The residue obtained was dissolved in ethyl acetate (50 ml). The mixture was washed with saturated sodium bicarbonate solution (20 ml). The separated organic layer was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.50 g, 73.0%).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[OH:14])([CH3:6])([CH3:5])[CH3:4].[CH2:15]([N:27]1[C:31](=[O:32])[CH:30]=[CH:29][C:28]1=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(O)(C)(C)C>[C:3]([C:7]1[CH:12]=[C:11]([CH:30]2[CH2:29][C:28](=[O:33])[N:27]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:31]2=[O:32])[CH:10]=[C:9]([CH3:13])[C:8]=1[OH:14])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCCCCCCCCCCCN1C(=O)C=CC1=O
Reactant: Cc1cccc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCN1C(=O)CC(c2cc(C)c(O)c(C(C)(C)C)c2)C1=O

Procedure:
This compound is prepared by the procedure of Example 1 from 1.20 g (50 mmol) of sodium hydride, 8.21 g (50 mmol) of 2-tert-butyl-6-methylphenol, and 13.27 g (50 mmol) of N-n-dodecylmaleimide in tert-butyl alcohol. The residue is purified by preparative HPLC (8:2 heptane:ethyl acetate eluent) to give 4.70 g (22%) of a yellow wax.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])[C:3]#[N:4].[C:14]([Si:18]([CH3:28])([CH3:27])[O:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22](O)=[O:23])([CH3:17])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[Si:18]([O:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([NH:1][CH:2]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])[C:3]#[N:4])=[O:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:28])[CH3:27]
Reactant: COc1ccc(Cl)cc1C(N)C#N
Reactant: CC(C)(CC(=O)O)O[Si](C)(C)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1C(C#N)NC(=O)CC(C)(C)O[Si](C)(C)C(C)(C)C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
2-amino-2-(5-chloro-2-methoxyphenyl)acetonitrile (500 mg, 2.54 mmol) in DMF (2 mL) was added to a solution of 3-(tert-butyl-dimethyl-silanyloxy)-3-methyl-butyric acid (prepared according to patent EP2025667) (590 mg, 2.54 mmol), diisopropylethylamine (0.87 mL, 5.08 mmol) and HATU (966 mg, 2.54 mmol) in DMF (5 mL) and stirred for 18 hours. Ethyl acetate was added, the organics washed with sodium hydrogen carbonate (sat. aq.) and brine, then evaporated to dryness. The residues were purified by flash chromatography on silica gel (0 to 5% ethyl acetate in dichloromethane) to yield 740 mg (73%) of 3-(tert-butyldimethylsilyloxy)-N-((5-chloro-2-methoxyphenyl)(cyano)methyl)-3-methylbutanamide. LCMS (ESI) m+H=411.4.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH2:8][CH3:9])[CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17]1[CH:22]=[CH:21][C:20]([CH2:23][SH:24])=[CH:19][CH:18]=1.O>C1COCC1>[CH2:23]([S:24][C:2]1[C:3](=[O:10])[N:4]([CH2:8][CH3:9])[CH:5]=[CH:6][N:7]=1)[C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: CCn1ccnc(Br)c1=O
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCn1ccnc(SCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To 250 mg (1.23 mM) of 3-bromo-1-ethylpyrazin-2(1H)-one and 340.3 mg (2.46 mM) of potassium carbonate in 4 ml of THF were added 159 μl (1.35 mM) of benzylthiol. The reaction mixture was then stirred at room temperature for 16 h. Water was added and the organic phase was extracted with ethyle acetate. The combined organic layer was washed with water, dried on anhydrous sodium sulfate and the solvent was removed under vacuum, to give a solid, which was triturated in diisopropyle oxide, filtrated and dried under vacuum, to give 250 mg of 3-(benzylthio)-1-ethylpyrazin-2(1H)-one. Yield: 82%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][N:6]1[C:13]([NH:14][NH2:15])=[CH:12][C:10](=[O:11])[N:9]([CH2:16][CH2:17][CH3:18])[C:7]1=[O:8].[CH3:22][N:23]=[C:24]=S.CO>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][N:6]1[C:13]2[NH:14][N:15]=[C:22]([NH:23][CH3:24])[C:12]=2[C:10](=[O:11])[N:9]([CH2:16][CH2:17][CH3:18])[C:7]1=[O:8]
Reactant: CCCn1c(=O)cc(NN)n(Cc2cccc(Cl)c2)c1=O
Reactant: CN=C=S
Solvent: CN(C)C=O
Solvent: CO
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2cccc(Cl)c2)c1=O

Procedure:
A solution of 1-(3-chlorobenzyl)-6-hydrazino-3-propyluracil (3.0 g, 9.6 mM) and methyl isothiocyanate (2.2 ml, 32 mM) in DMF (30 ml) was heated at 120° C. for 27 hours. To the solution was added 50% methanol (10 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol afforded colorless crystals (1.22 g, 36%), m.p. 263°-265° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Br:12]Br>O>[Br:12][C:9]1[CH:10]=[N:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1ncccc1C(=O)O
Reactant: BrBr
Solvent: O
Product: COc1ncc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of 2-methoxynicotinic acid (20 g, 130.60 mmol) in H2O (1500 mL), Br2 (20 mL, 375.45 mmol) was added at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was filtered, washed with water and dried to provide 5-bromo-2-methoxynicotinic acid (25 g, yield: 82%). 1H-NMR (DMSO, 400 MHz) δ 13.33 (br s, 1H), 8.47 (d, J=2.4 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H), 3.90 (s, 3H). MS (M+H)+: 232/234.
Reaction SMILES: Br.Br[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[C:9]([Cl:21])[CH:8]=1)=[O:5].[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[NH2:33]>CN(C=O)C.O>[Cl:21][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][NH:33][C:24]2[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[CH:28][C:23]=2[Cl:22])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18]
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)CCOc1ccc(NC(=O)CBr)cc1Cl
Agent: Br
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1ccc(NC(=O)CNc2ccc(C(F)(F)F)cc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 0.228 g (0.511 mmol) of 2-bromo-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide-hydrobromide (intermediate product Z1c) and 0.200 g (1.023 mmol) of 2-chloro-4-trifluoromethyl-phenylamine in 5 mL DMF was stirred for 16 hours at 90° C. and then for 24 hours at 120° C. The reaction mixture was cooled to RT, diluted with water and exhaustively extracted with EtOAc. The combined org. extracts were dried over magnesium sulphate and evaporated down i. vac. The residue was dissolved in DMF and purified by HPLC-MS (Stable Bond C18; 3.5 μm; water:acetonitrile:formic acid 9:1:0.01→1:9:0.01 over 9 min).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([N:9]=[N+:10]=[N-:11])[CH2:7][OH:8])(=[O:3])[CH3:2].[C:12]([N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[N+:20]([O-:22])=[O:21])#[C:13][CH3:14]>>[C:1]([O:4][CH2:5][CH:6]([N:9]1[CH:14]=[C:13]([CH2:12][N:15]2[CH:19]=[CH:18][N:17]=[C:16]2[N+:20]([O-:22])=[O:21])[N:11]=[N:10]1)[CH2:7][OH:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(CO)N=[N+]=[N-]
Reactant: CC#Cn1ccnc1[N+](=O)[O-]
Product: CC(=O)OCC(CO)n1cc(Cn2ccnc2[N+](=O)[O-])nn1
Temperature: 60 °C
Yield: 51.7 %

Procedure:
A vial containing Compound 24 (500 mg, 3.14 mmol) and 1-propynyl-2-nitroimidazole (475 mg, 3.14 mmol) was heated at 60° C. overnight. The resultant solid was purified on a silica gel cartridge using EtOAc:Hex as the eluent to afford 504 mg (52% yield) of a white solid.
Reaction SMILES: [NH:1]([C:3]([C@@H:5]1[CH2:9][C:8](=[N:10][O:11][CH3:12])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4])[NH2:2].C(N(CC)CC)C.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28]>C1COCC1>[CH3:12][O:11]/[N:10]=[C:8]1\[CH2:9][C@@H:5]([C:3]2[O:4][C:27](=[O:28])[NH:2][N:1]=2)[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]\1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CON=C1C[C@@H](C(=O)NN)N(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CO/N=C1\C[C@@H](c2n[nH]c(=O)o2)N(C(=O)OC(C)(C)C)C1
Reaction time: 5 h

Procedure:
To a stirring solution of tert-butyl (2S,4EZ)-2-(hydrazinocarbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate (Intermediate 9, 1.84 mmoles; 500 mg) and triethylamine (2.76 mmoles; 27 mg) in THF (25 mL) at 0° C. was added 1,1′-carbonyldiimidazole (2.76 mmoles, 448 mg). The stirring was continued for 5 hours. Another portion of triethylamine and 1,1′-carbonyldiimidazole were added and stirring was continued at room temperature overnight. The solvent was evaporated and the residue was dissolved in EtOAc and washed with NH4Clsat., and 10% NaHCO3, and brine. The organic layer was dried over Na2SO4 and evaporated to dryness to give the desired N-protected intermediate, tert-butyl (2S,4E)-4-(methoxyimino)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1-pyrrolidinecarboxylate, as a white foam (460 mg, 84%).
Reaction SMILES: C[O:2][C:3](=[O:10])[CH2:4]CCCC#N.[CH3:11][O:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([OH:18])=[O:17]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH3:11][O:12][C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:4][C:3]([OH:10])=[O:2].[C:3]([OH:10])(=[O:2])[CH2:4][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: COC(=O)CCC(=O)O
Reactant: COC(=O)CCCCC#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COC(=O)CCCCC(=O)O
Product: O=C(O)CCCCC(=O)O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Into a 10-mL volumetric flask was added 1.425 g (10.0 mmol, 1.00 M) of 5-cyanopentanoic acid methyl ester, 8.38 mL of potassium phosphate buffer (50 mM, pH 7.0), and 0.20 mL of a 50 wt % cell suspension (0.10 g wet cell weight, 0.024 g dry cell weight) of Acidovorax facilis 72W (ATCC 55746) cells in 0.35 M potassium phosphate buffer (pH 7.0, previously heat-treated at 50° C. for 1 h), and the resulting 10 mL suspension stirred at 25° C. Samples (0.100 mL) were withdrawn and mixed with 0.900 mL of distilled water, centrifuged, then 0.180 mL of the 1:10 diluted supernatant was mixed with 0.020 mL of 0.750 M N-methylpropionamide (HPLC external standard solution). The resulting solution was analyzed by HPLC. After 120 h, the conversion of 5-cyanopentanoic acid methyl ester was complete, and the yield (determined by HPLC) of hexanedioic acid monomethyl ester and hexanedioic acid were 97%, and 3%, respectively, with no production of 5-cyanopentanoic acid.
Reaction SMILES: [ClH:1].Cl.Cl.[Cl:4][C:5]1[CH:14]=[CH:13][C:12](Cl)=[C:11]2[C:6]=1[CH:7]=[C:8]([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)[N:9]=[CH:10]2.[CH3:34][O:35]C1C=C2C(=CC=1)C=NC(OS(C(F)(F)F)(=O)=O)=C2>>[ClH:4].[ClH:1].[ClH:4].[CH3:34][O:35][C:14]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][C:8]([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)=[CH:7]2
Reactant: COc1ccc2cnc(OS(=O)(=O)C(F)(F)F)cc2c1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)ccc(Cl)c2cn1
Agent: Cl
Product: COc1ccc2cnc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)cc2c1

Procedure:
The procedure for the preparation of 3-(5,8-dichloroisoquinolin-3-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine trihydrochloride was followed, except using trifluoromethanesulfonic acid 6-methoxyisoquinolin-3-yl ester in place of trifluoromethanesulfonic acid 5,8-dichloroisoquinolin-3-yl ester. This afforded the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.16-2.29 (m, 4H), 3.05-3.17 (m, 2H), 3.38 (d, J=12.6 Hz, 2H), 4.00 (s, 3H), 4.48-4.59 (m, 1H), 7.46-7.54 (m, 2H), 8.13 (s, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.48-8.51 (m, 2H), 8.59 (s, 1H), 8.80 (d, J=2.3 Hz, 1H), 9.19 (br. s., 1H), 9.28 (br. s., 1H), 9.45 (s, 1H). MS (ES+): m/z=318.16 [MH+]. HPLC: tR=1.70 min (ZQ2, polar—5 min).