Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][CH2:10][CH:11]([CH3:23])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].N1C=CC=CC=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl>[CH3:1][CH:2]([CH2:8][CH2:9][CH2:10][CH:11]([CH3:23])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][S:36]([C:33]1[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=1)(=[O:38])=[O:37]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCC(C)CCCC(C)CCCC(C)CCCC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
Under a nitrogen atmosphere, a solution of 30 g (0.09 mol) of 5,9,13,17-tetramethyl-1-octadecanol and 8.72 g (0.11 mol) of pyridine in 200 ml of dry methylene chloride was added dropwise to a solution of 19.3 g (0.10 mol) of p-toluenesulfonyl chloride in 100 ml of dry methylene chloride under ice cooling. After the dropwise addition, the mixture was agitated at room temperature overnight, the resulting reaction solution was successively washed with 200 ml of water, 200 ml of 2N hydrochloric acid, and 200 ml of a saturated sodium bicarbonate water, and it was dried over anhydrous magnesium sulfate. After the filtration, the resultant was concentrated under reduced pressure to obtain 42 g of (5,9,13,17-tetramethyloctadecyl)tosylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2O[C:12]([CH2:15][CH2:16][OH:17])=[N:13][N:14]=2)[CH:5]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.O.C1(C)C=CC([S:32](O)(=O)=O)=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:32][C:12]([CH2:15][CH2:16][O:17][CH:24]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[N:13][N:14]=2)[CH:5]=1
Reactant: C1=COCCC1
Reactant: COC(=O)c1cccc(-c2nnc(CCO)o2)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2nnc(CCOC3CCCCO3)s2)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A mixture of 3-[5-(2-hydroxy-ethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acid methyl ester (7.45 g), dihydropyrane (4.1 mL) and p-toluenesulfonic acid hydrate (0.57 g) in AcOEt (80 mL) was stirred at 20° C. for 2 h. The solution was diluted with AcOEt, washed with 5% NaHCO3 solution and with brine, dried and evaporated in vacuum. The residual oil was purified by chromatography on silica gel using AcOEt/hexane (1:2) as eluent to give 3-{5-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-[1,3,4]thiadiazol-2-yl}-benzoic acid methyl ester (8.2 g) as a pale-yellow oil.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([O:18][C:19](=[O:21])[CH3:20])=[C:10]([O:22][CH3:23])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>[Cl-].[Zn+2].[Cl-]>[C:24]([N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19](=[O:21])[CH3:20])=[C:10]([O:22][CH3:23])[CH:9]=1)(=[O:26])[CH3:25]
Reactant: COc1cc(NC2CCCCC2)c2ccccc2c1OC(C)=O
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: COc1cc(N(C(C)=O)C2CCCCC2)c2ccccc2c1OC(C)=O

Procedure:
A solution 5.0 g of 4-(cyclohexylamino)-1-acetoxy-2-methoxynaphthalene in 75 ml of acetic anhydride is stirred with 500 mg of zinc chloride in at 160°-170° C. for 2 hours. The reaction is cooled, filtered and evaporated under reduced pressure. The residue is taken up in 300 ml of diethyl ether and washed with 100 ml of water and then with 100 ml of brine. The organic solvent is dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is crystallized from 120 ml of 2:1 diethyl ether-hexane to yield 4-(N-acetylcyclohexylamino)-1-acetoxy-2-methoxynaphthalene, m.p. 137°-139° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([O:16][C:17]1[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][C:18]=1[C:19]([OH:21])=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[C:3]1([N:2]([CH3:1])[C:19](=[O:21])[C:18]2[CH:22]=[C:23]([CH:26]=[O:27])[CH:24]=[CH:25][C:17]=2[O:16][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc(C=O)ccc1OCc1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 93.1 %

Procedure:
N-Methylaniline (0.18 mL, 1.68 mmol, 2 eq) was added to a solution of 2-benzyloxy-5-formylbenzoic acid (200 mg, 0.84 mmol, 1 eq), 1-hydroxy-7-azabenzotriazole (230 mg, 1.68 mmol, 2 eq), and N-methylmorpholine (0.25 mL, 2.29 mmol, 2.73 eq) in N,N-dimethylformamide (4 mL). To this was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (320 mg, 1.68 mmol, 2 eq) and the reaction mixture stirred overnight. The reaction mixture was diluted with ethyl acetate (20 mL) and washed sequentially with 10% HCl (3×20 mL), brine (20 mL), saturated aqueous sodium bicarbonate (2×20 mL) and brine (20 mL). The organic solution was dried over sodium sulfate and evaporated in vacuo to give a yellow oil (270 mg, 99%). RF (petroleum ether:ethyl acetate 1:1) 0.73. 1H NMR (CDCl3) δ9.79 (s, 1H, O═C—H), 5.01 (s, 2H, CH2Ph), 3.47 (s, 3H, CH3).
Reaction SMILES: [CH3:1][C:2]([S@:5](/[N:7]=[CH:8]/[C:9]1[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=1)=[O:6])([CH3:4])[CH3:3].C1COCC1.[F:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>O>[CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[F:20][C:21]1[CH:22]=[C:23]([C@@H:8]([C:9]2[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=2)[NH:7][S@@:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[O:6])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc([Mg]Br)cc1F
Reactant: Cn1cncc1/C=N/[S@](=O)C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)S(N)=O
Product: COc1ccc([C@H](N[S@](=O)C(C)(C)C)c2cncn2C)cc1F
Temperature: -10 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
A solution of 128 (1.444 g, 6.770 mmol) and THF (20 mL) was cooled to −10° C., and (3-fluoro-4-methoxyphenyl)magnesium bromide (2.717 g, 11.85 mmol) was added via addition funnel. The reaction was stirred at −10° C. for 1 h. Water was added, and the mixture was extracted with EtOAc. The organic layer was concentrated, and the resulting residue was purified by reverse phase chromatography (eluting with 0-65% MeCN/water) to afford 0.203 g (8.83%) of (R)—N#R)-(3-fluoro-4-methoxyphenyl)(1-methyl-1H-imidazol-5-yl)methyl)-2-methylpropane-2-sulfinamide (130a) and 315 mg (13.71%) of (R)—N—((S)-(3-fluoro-4-methoxyphenyl)(1-methyl-1H-imidazol-5-yl)methyl)-2-methylpropane-2-sulfinamide (1306).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([Cl:31])[C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:32]([O:34][C:35](=[O:46])[CH:36]=[C:37]([CH3:45])[CH:38]=[CH:39][CH:40]=[C:41]([CH:43]=O)[CH3:42])[CH3:33].C1OC1CC>>[CH2:32]([O:34][C:35](=[O:46])[CH:36]=[C:37]([CH3:45])[CH:38]=[CH:39][CH:40]=[C:41]([CH3:43])[CH:42]=[CH:5][C:4]1[C:25]([Cl:31])=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:3]=1[Cl:2])[CH3:33]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Reactant: COc1cc(Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Agent: CCC1CO1
Agent: [Cl-]
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(Cl)cc(OC)cc1Cl
Reaction time: 2 h

Procedure:
39 g. of 2,6-dichloro-4-methoxy-benzyl-triphenylphosphonium chloride and 16 g. of 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester are heated at 82°-85° C. under reflux conditions while stirring for 2 hours after the addition of 40 g. of 1,2-butylene oxide. The mixture is then thoroughly extracted with hexane. The hexane extract is washed several times with methanol/water (60:40 parts by volume), dried over sodium sulphate and evaporated under reduced pressure. The residue is purified by absorption on silica gel using hexane for the elution. The 9-(2,6-dichloro-4-methoxyphenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester obtained from the eluate melts at 117°-118° C. after recrystallization from hexane.
Reaction SMILES: [N:1]#[C:2]Br.[O:4]=[C:5]1[NH:14][C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([O:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:22][CH2:21]1>>[O:4]=[C:5]1[N:14]([C:2]#[N:1])[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([O:26][CH:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:22][CH2:21]1
Reactant: O=c1[nH]c(=O)n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c2ccccc12
Reactant: N#CBr
Product: N#Cn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Yield: 64.3 %

Procedure:
Using the method similar to that in Example 61 and cyanogen bromide (657 mg, 6.20 mmol) instead of benzyl bromide and starting from 2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline (2.50 g, 5.17 mmol) obtained in Example 2, the title compound (1.69 g, 64%) was synthesized. Recrystallization from ethyl acetate yielded a colorless crystal having a melting point of 106 to 107° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](Br)=[CH:4][N:3]=1.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:16]2[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=[C:14]([C:13]([F:12])([F:28])[F:27])[CH:15]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1c(Br)cnc(N)c1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cnc(N)c1C#N

Procedure:
A stirred solution of 1.7 grams (0.008 mole) of 2-amino-5-bromo-3-cyano-4-methylpyridine, 3.2 grams (0.012 mole) of 3,5-di(trifluoromethyl)phenylboronic acid (commercially available), 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene is heated at 90° C. for about 20 hours. After this time, the reaction mixture is stirred with 100 mL of water, and the organic layer is separated. The organic layer is concentrated under reduced pressure, yielding 2-amino-3-cyano-4-methyl-5-[3,5-di(trifluoromethyl)phenyl]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:34]=[CH:33][C:27]([O:28]CC(O)=O)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl.C([O:40][C:41](=[O:50])[C@@H:42]([CH2:44][O:45]C(C)(C)C)[NH2:43])(C)(C)C.CN1CC[O:55][CH2:54][CH2:53]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:53][C:54]([NH:43][C@@H:42]([C:41]([OH:40])=[O:50])[CH2:44][OH:45])=[O:55])=[CH:33][CH:34]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC[C@@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)N[C@H](CO)C(=O)O
Reaction time: 3 h
Yield: 35.6 %

Procedure:
A solution of [4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid (0.050 g, 0.103 mmol), O-(tert-butyl)-D-Serine tert-butyl ester hydrochloride (0.032 g, 0.147 mmol) and N-Methylmorpholine (0.035 ml, 0.318 mmol) in DCM (4 ml) was stirred at RT for 5 min, after which TBTU (0.044 g, 0.137 mmol) was added. After 3 h, the conversion to the ester (m/z: 683.1) was completed and the solution was added TFA (2 ml). After 22 h, the solvent was removed under reduced pressure and the residue (m/z: 571.1) was dissolved in MeOH (4 ml). To the solution were successively added small portions of NaBH4 (totally 0.130 g, 3.44 mmol) until the reduction was completed. The reaction mixture was added a 0.1M ammonium acetate buffer (3 ml) and the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC using a gradient of 20-60% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.021 g (36% yield) of the desired product (as a mixture of diastereomers) was obtained as a white solid. M/z: 573.1. 1H NMR (DMSO, 400 MHz): δ 2.84-2.96 (m, 2H), 3.47 (dd, 1H), 3.69 (dd, 1H), 3.97-4.06 (m, 1H), 4.27-4.32 (m, 1H), 4.52 (ABq, 2H), 4.68-4.77 (m, 1H), 5.04-5.09 (m, 1H), 5.65 (bs, 1H), 6.99 (d, 2H), 7.07-7.41 (m, 10H), 7.89 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:29][CH3:30])=[C:19]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C1CCN2C(=NCCC2)CC1.[C:42]([O:46]CC)(=[O:45])[CH:43]=[CH2:44].[OH-].[Na+].Cl>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:29][CH3:30])=[C:19]([CH:23]4[CH2:28][CH2:27][N:26]([CH2:44][CH2:43][C:42]([OH:46])=[O:45])[CH2:25][CH2:24]4)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: C=CC(=O)OCC
Reactant: CCc1c(-c2nnc(-c3ccc(OC(C)C)c(Cl)c3)s2)cccc1C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1c(-c2nnc(-c3ccc(OC(C)C)c(Cl)c3)s2)cccc1C1CCN(CCC(=O)O)CC1
Temperature: 60 °C
Yield: 5.2 %

Procedure:
To a solution of 4-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]piperidine (D120) (200 mg, 0.452 mmol) in Acetonitrile (10 mL) was added DBU (0.205 mL, 1.357 mmol) and ethyl 2-propenoate (136 mg, 1.357 mmol). The reaction solution was heated to 60° C. for 2 h. The reaction solution was concentrated and the residue was hydrolized with a solution of NaOH (4.52 mL, 2.262 mmol) in water. The reaction mixture was neutralized with 2N HCl till pH ˜6.0. The mixture was extracted with EA/THF for 3 times. The combined organic layers were concentrated and purified by Mass Directed AutoPrep to afford 3-{4-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]-1-piperidinyl}propanoic acid (E95) (12 mg) as a TFA salt.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[N:31]1([CH2:36][CH2:37][CH2:38][NH2:39])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:36][CH2:37][CH2:38][NH:39][C:8](=[O:7])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27]([NH2:28])=[O:29])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: NCCCN1CCCC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCN3CCCC3)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 3-pyrrolidin-1-yl-propylamine by the procedure analogous to Example 1. MS (APCI, m/z): 472 [M+H]+.
Reaction SMILES: [Cl:1][CH:2]([Cl:37])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([NH:27]C(=O)OC(C)(C)C)([CH3:26])[CH3:25])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7]C1(C)C)=[O:4].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1(C)C=CC=CC=1>[NH2:27][C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([C@@H:8]([OH:7])[C@H:9]([NH:5][C:3](=[O:4])[CH:2]([Cl:37])[Cl:1])[CH2:10][F:11])=[CH:13][CH:14]=2)=[CH:19][CH:20]=1)([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(Cl)Cl)[C@@H]3CF)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(N)c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.1 %

Procedure:
To a solution of the product of Step 1 (50 mg. 0.09 mmol) in DCM (1 mL) is added TFA (0.25 mL) and stirred at room temperature for 1 hour. Reaction is diluted with toluene (5 mL) and concentrated. Crude product is dissolved in DCM (0.5 mL) and DIPEA (200 μL), adsorbed on celite and purified on silica gel column eluting from 5 to 20% MeOH/DCM. The combined fractions are concentrated to give an oil, which is basified using saturated aqueous NaHCO3 (0.5 mL), and extracted with ethyl acetate (3×2 mL). The combined extracts are dried over Na2SO4 and concentrated to give the title compound (3 mg). 1H NMR (400 MHz, CD3OD) δ 1.52 (s, 6H), 4.2-4.29 (m, 1.5H), 4.32-4.38 (m, 0.5H) 4.4-4.51 m, 1.5H), 4.55-4.61 (m, 0.5H), 4.89 (d, 1H, J=4.0 Hz) 6.19 (s, 1H), 7.38 (d, 2H, J=8.0 Hz), 7.45-7.50 (m, 3H), 7.51-7.56 (m, 3H). m/z (Cl) 396 [M-OH].
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH:7]([CH:10]1[CH2:12][CH2:11]1)[CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].C([O:16][C:17]([C:19]1[N:20]=[C:21](C#N)[C:22]2[C:27]([C:28]=1[OH:29])=[CH:26][CH:25]=[C:24]([O:30][C:31]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=1[F:38])[CH:23]=2)=O)C.C1CCN2[C:44](=[N:45]CCC2)CC1>CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:13])[CH:7]([CH:10]1[CH2:12][CH2:11]1)[CH2:8][NH:9][C:17]([C:19]1[N:20]=[CH:21][C:22]2[C:27]([C:28]=1[OH:29])=[CH:26][CH2:25][C:24]([C:44]#[N:45])([O:30][C:31]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=1[F:38])[CH:23]=2)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOC(=O)c1nc(C#N)c2cc(Oc3c(F)cccc3F)ccc2c1O
Reactant: CC(C)(C)OC(=O)C(CN)C1CC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)C(CNC(=O)c1ncc2c(c1O)=CCC(C#N)(Oc1c(F)cccc1F)C=2)C1CC1
Temperature: 150 °C
Yield: 45.2 %

Procedure:
A mixture of 3-amino-2-cyclopropyl-propionic acid tert-butyl ester (20 mg), 1-cyano-7-(2,6-difluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (16 mg) and DBU (10 mg) in DMA (0.3 mL) was heated in an oil bath (150° C.) for 1 h. The reaction mixture was then partitioned between EtOAc and diluted HCl solution, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulfate solution, filtered, concentrated and silica gel column purified to give desired product as brown solid (10 mg). LC-MS ESI+: 510 (M+1)+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4].[CH3:23][NH2:24].C1COCC1>CO.C(OCC)(=O)C>[F:19][C:13]1[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=1[NH:11][C:10]1[N:9]2[CH:20]=[N:21][CH:22]=[C:8]2[CH:7]=[N:6][C:5]=1[C:3]([NH:24][CH3:23])=[O:4]
Reactant: CN
Reactant: COC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.8 %

Procedure:
To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid methyl ester (108 mg, 0.26 mmol) in anhydrous methanol (0.5 mL) was added 2M methylamine in THF (1.3 mL, 2.6 mmol, 10 eq), and the reaction mixture was stirred at room temperature under N2 for 3 days. The reaction mixture was diluted with ethyl acetate (50 mL). The organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to reverse-phase preparative HPLC [Gemini-NX (100×30 mm, 10 micron), 0.1% FA in water/acetonitrile, 5-85%, ramp time in 10 minutes, flow at 60 ml/min] to afford the title compound as a white solid (48.3 mg, 44.8%). 1H NMR (DMSO-d6, 400 MHz) δ ppm 10.89 (s, 1H), 8.95 to 8.91 (m, 1H), 8.86 (s, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 7.76 (dd, J=8.4 Hz, 1.2 Hz, 1H), 7.44 (d, J=6.8 Hz, 1H), 6.51 (t, J=6.8 Hz, 1H), 2.81 (d, 4.0 Hz, 3H); LCMS (method E2): RT=12.23 min, [M+H]+=412.
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10]([OH:12])=O)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(OCCC)(=O)C.C(OC(=O)C)(=O)C.[O-2].[Mg+2]>C(O)(=O)C>[C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:15][C:10](=[O:12])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: [Mg+2]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CCCOC(C)=O
Product: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Temperature: 10 °C
Reaction time: 1.25 h

Procedure:
N-acetoacetyl-L-aspartic acid, 80.4 parts, was mixed with 111 parts by volume of dry n-propyl acetate and 39.6 parts of acetic anhydride. A solution of 0.207 parts magnesium oxide in 7.4 parts by volume glacial acetic acid was added and the mixture was stirred at 45°-50° C. for 75 minutes. The resulting slurry was cooled to 10° C. and the solid was collected on a filter under nitrogen. The solid was rinsed with n-propyl acetate and dried at 0.1 mm to afford 70.3 parts of N-acetoacetyl-L-aspartic anhydride.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[N:4]1)[CH3:2].S(Cl)([Cl:12])=O>O1CCCC1>[ClH:12].[Cl:12][CH2:8][C:6]1[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CCn1cc(CO)cn1
Solvent: C1CCOC1
Product: CCn1cc(CCl)cn1
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
To a solution (400 mL) of (1-ethyl-1H-pyrazol-4-yl)methanol (16.80 g) in tetrahydrofuran was added thionyl chloride (40.0 g), and the mixture was stirred at room temperature for 4 hr. The mixture liquid was concentrated under reduced pressure to obtain 4-chloromethyl-1-ethyl-1H-pyrazole hydrochloride as a colorless oil (24.15 g, yield 100%).
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[OH:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:14]=1[C:23]([O:25][CH3:26])=[O:24]>C(#N)C.O>[OH:12][C:13]1[C:22]([N+:8]([O-:11])=[O:9])=[CH:21][CH:20]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:14]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC#N
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(O)c1C(=O)OC
Reaction time: 0.67 h
Yield: 94.5 %

Procedure:
Acetyl nitrate obtained by mixing acetic anhydride (3.6 g, 36 mmol) with fuming nitric acid (2.16 g, 36 mmol) at 0° C. was dropped into a solution of dimethyl 3-hydroxyphthalate (3.8 g, 18 mmol) in acetonitrile (60 ml) at 0° C. followed by stirring for 40 minutes. The reaction solution was diluted with water and extracted with ether. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom. A 3:2 mixture (4.34 g; yield 94%) of dimethyl 3-hydroxy-4-nitrophthalate and dimethyl 3-hydroxy-6-nitrophthalatewas obtained as a yellow solid. This was used in the next reaction without separation and purification.