Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][CH:16]=[N:15][CH:14]=2)=[CH:9][CH:8]=1.CN([CH:21]=[O:22])C.Cl>C1COCC1.CCOCC>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:17][C:16]([CH:21]=[O:22])=[N:15][CH:14]=2)=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(-c2cnco2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1ncc(-c2ccc(F)cc2)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
A solution of nBuLi (1.6 M in hexane, 3.45 ml, 5.53 mmol) was added dropwise at −78° C. to a stirred solution of 5-(4-fluorophenyl)-1,3-oxazole (0.82 g, 5.03 mmol) in THF (10 ml) (Organic Letters (2001),(3)2, 271-273). The mixture was stirred at −78° C. for 30 minutes and then quenched with DMF (0.43 ml, 5.53 mmol). It was gradually warmed to room temperature, stirred for further 30 minutes, diluted with Et2O (30 ml), then neutralised with 1N HCl. The organic layer was separated, washed with brine (20 ml), dried over MgSO4 and concentrated in vacuo. Purification by chromatography on silica gel eluting with DCM afforded 5-(4-fluorophenyl)-1,3-oxazole-2-carbaldehyde (0.58 g, 60%): δH (360 MHz, CDCl3) 7.18 (2H, t, J 8.6 ), 7.58 (1H, s), 7.77-7.81 (2H, m), 9.76 (1H, s); m/z (ES+) 192 (MH+).
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:12])[CH2:4]/[CH:5]=[CH:6]\[CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9].C1COCC1.[OH-].[K+]>O>[CH3:9][Si:8]([CH3:11])([CH3:10])[CH2:7]/[CH:6]=[CH:5]\[CH2:4][C@@H:3]1[CH2:2][O:12]1
Reactant: C[Si](C)(C)C/C=C\C[C@@H](O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)C/C=C\C[C@@H]1CO1
Yield: 98.3 %

Procedure:
12.97 g (62.7 mmol) of (Z)-(R)-1-Chloro-6-trimethylsilanyl-hex-4-en-2-ol was dissolved in 215 ml of abs. THF. A solution of 60.34 g (1.08 mol) of KOH in 61 g of water was added ant the heterogeneous mixture stirred at 30° for 24h, until GC analysis indicated the disappearance of the starting chlorohydrine. The reaction mixture was then poured onto crushed ice/NH4Cl, extracted with ether, dried over sodium sulfate, and the solvents removed i.V. Thereby, 10.5 g of (Z)-(R)-trimethyl-(4-oxiranyl-but-2-enyl)-silane was isolated, 93% pure according to GC, which was used as such for the next step.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:24])[C:7]([C:19]([O:21]CC)=[O:20])=[CH:8][N:9]3[CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:4][C:3]=2[O:2]1.Cl>>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:24])[C:7]([C:19]([OH:21])=[O:20])=[CH:8][N:9]3[CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)c1cn(CC(F)(F)F)c2cc3c(cc2c1=O)OCO3
Agent: Cl
Product: O=C(O)c1cn(CC(F)(F)F)c2cc3c(cc2c1=O)OCO3

Procedure:
A mixture of 1 g. of the ethyl ester obtained from Example 3 and 40 ml. of 6N. hydrochloric acid was heated under reflux for 11/2 hours. The mixture was cooled and the solid product was collected by filtration and washed with water and dried under reduced pressure, m.p. 323°-5° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]2)=[CH:3][C:4]=1[O:9][CH3:10]
Reactant: COC(=O)C1CCNCC1
Reactant: COc1cc(Br)ccc1Cl
Product: COC(=O)C1CCN(c2ccc(Cl)c(OC)c2)CC1

Procedure:
Methyl 1-(4-chloro-3-methoxyphenyl)piperidine-4-carboxylate was synthesized from 4-bromo-1-chloro-2-methoxybenzene and methyl piperidine-4-carboxylate analogous to the preparation described in Example 1a, Step 1. 1H-NMR (500 MHz, CDCl3) δ ppm 7.19 (1 H, d, J=8.57 Hz), 6.51 (1 H, s), 6.44 (1 H, s), 5.82 (1 H,), 3.85-3.88 (3 H, m), 3.70-3.72 (3 H, m), 3.33 (2 H, d, J=11.55 Hz), 2.67-2.74 (2 H, m), 2.46 (1 H, ddd, J=15.05, 10.52, 4.40 Hz), 1.94-2.04 (4 H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([F:31])[CH:22]=2)([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH2:9][C:10]([O:12]C)=O)=[N:6][CH:7]=1.[NH3:32]>C(O)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([F:31])[CH:22]=2)([NH:14][S@@:15]([C:17]([CH3:18])([CH3:19])[CH3:20])=[O:16])[CH2:9][C:10]([NH2:32])=[O:12])=[N:6][CH:7]=1
Reactant: N
Reactant: COC(=O)C[C@](N[S@](=O)C(C)(C)C)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Solvent: OCCO
Product: CC(C)(C)[S@@](=O)N[C@@](CC(N)=O)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: 180 °C

Procedure:
(S)-methyl 3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-3-((R)-2-methylpropan-2-ylsulfinamido)propanoate (0.10 g, 0.20 mmol) was dissolved in 8N NH3 solution in ethylene glycol (1 mL) in a microwave vial. The reaction mixture was heated to 180° C. for 300 sec, the pressure was cautiously vented and the reaction mixture purified directly by prep HPLC (YMC ODSA30×100 mm, 0-100% over 10 min, MeOH/H2O/0.1% TFA). (S)-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-3-((R)-2-methylpropan-2-ylsulfinamido)propanamide was isolated as a white solid (0.041 g, 41% yield) LCMS: 1.85 min [M+1] 466.1 (2 min gradient, MeOH/H2O 0.1% TFA). Starting material was also recovered (0.055 g, 55% recovered yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH:19](Br)Br)[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.S(=O)(=O)(O)[OH:23]>>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH:19]=[O:23])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: FC(F)(F)c1cnc(-c2ccc(Cl)c(C(Br)Br)c2)c(Cl)c1
Reactant: O=S(=O)(O)O
Product: O=Cc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Temperature: 0 °C

Procedure:
6.99 g (15.1 mmol) of 3-chloro-2-(4-chloro-3-dibromomethylphenyl)-5-trifluoromethylpyridine in 100 ml of 96% strength sulfuric acid were stirred at 100° C. for one hour during which a vigorous stream of nitrogen was passed through the reaction mixture. The mixture was cooled and then poured into ice-water. The solid product was separated off, washed with water and dried under reduced pressure. Yield: 4.2 g (87%) of colorless crystals of melting point 94° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[C:10]1([C:20]2[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(#N)C>[CH3:8][C:7]1[C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][CH:11]=3)=[CH:21][CH:22]=2)=[N:3][CH:4]=[C:5]([CH3:9])[N:6]=1
Reactant: Cc1cnc(Cl)c(C)n1
Reactant: OB(O)c1ccc(-c2cccc3ccccc23)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cnc(-c2ccc(-c3cccc4ccccc34)cc2)c(C)n1
Yield: 50 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were placed 0.74 g of 2-chloro-3,5-dimethylpyrazine, 1.29 g of 4-(1-naphthyl)phenylboronic acid, 0.55 g of sodium carbonate, 0.024 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation: Pd(PPh3)2Cl2), 10 mL of water, and 10 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was irradiated with microwaves (2.45 GHz, 100 W) for 15 minutes, so that heating was performed. Then, the reaction container was cooled to 50° C. or less. Water was added to the reaction solution, and the organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and dried with magnesium sulfate. The solution which had been dried was filtered. The solvent of this solution was distilled, and recrystallized using ethyl acetate, whereby Hdm1nppr, which is the pyrazine derivative to be produced, was obtained (as a white powder in 50% yield). Note that the microwave irradiation was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). The synthesis scheme of Step 1 is illustrated in the following (a-1).
Reaction SMILES: C[C:2]1[S:3][C:4]([C:8]([NH:10][NH2:11])=O)=[C:5]([CH3:7])[N:6]=1.Cl.[CH3:13][NH:14][C:15](=NC)[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>>[CH3:13][N:14]1[C:15]([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])=[N:11][N:10]=[C:8]1[C:4]1[S:3][CH:2]=[N:6][C:5]=1[CH3:7]
Reactant: Cc1nc(C)c(C(=O)NN)s1
Reactant: C=CCCCC(=NC)NC
Agent: Cl
Product: C=CCCCc1nnc(-c2scnc2C)n1C

Procedure:
The title compound was prepared in analogy to Preparation 11 in 0.31 g yield starting from 2,4-dimethyl-thiazole-5-carboxylic acid hydrazide (0.52 g) and N,N′-dimethyl-5-hexenimidamide hydrochloride (0.58 g). MS (m/z): 249 [MH]+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[CH:24]4)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[CH:24]4)[CH:13]=[N:12]2)[C:8]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc3cnccc23)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cccc4cnccc34)cc2=O)n1

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(isoquinolin-5-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 56) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(isoquinolin-5-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionamide an off-white solid (0.56 g, 44%); ES+-HRMS m/e calcd for C28H32N6O4 [M+H+] 517.2558 found 517.2557. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.04 (s, 3H), 1.06 (s, 3H), 1.10 (m, 1H), 1.22-1.80 (m, 8H), 1.92 (m, 1H), 2.29 (m, 1H), 3.89 (s, 2H), 4.68 (s, 1H), 5.46 (dd, J=4.2, J=10.6 Hz, 1H), 5.76 (d, J=2.8 Hz, 1H), 6.40 (d, J=2.2 Hz, 1H), 7.52 (d, J=2.2 Hz, 1H), 7.73-7.85 (m, 3H), 8.16 (m, 1H), 8.30 (d, J=2.8 Hz, 1H), 8.58 (d, J=5.7 Hz, 1H), 9.47 (s, 1H), 10.86 (s, 1H).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:13]([OH:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].CN.C(Cl)Cl.CO>C(O)C>[NH2:3][C@@H:12]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C@H:13]([OH:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)[C@@H](O)[C@@H](N)Cc1ccccc1
Yield: 82 %

Procedure:
Analogously to Example 23, by reacting a solution of 10.42 g of a 95:5 mixture of the (2S,3S) and (2R,3S) isomers of ethyl 3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-hydroxy-4-phenylbutyrate (Example 20) in 10 ml of ethanol with 5.9 ml of a 33% solution of methylamine in ethanol there are obtained 5.39 g (82%) of ethyl (2S,3S)-3-amino-2-hydroxy-4-phenylbutyrate, TLC (SiO2, CH2Cl2 /methanol 10:1, UV254):Rf =0.34.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[N+:13]([O-])([O-:15])=[O:14].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:13]([C:12]1[C:2]([OH:1])=[C:3]([CH:9]=[CH:10][CH:11]=1)[CH:4]=[CH:5][C:6]([OH:8])=[O:7])([O-:15])=[O:14]
Reactant: O=C(O)C=Cc1ccccc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)C=Cc1cccc([N+](=O)[O-])c1O
Reaction time: 24 h
Yield: 52.3 %

Procedure:
2-Hydroxycinnamic acid (3.00 g, 18.3 mmol) was dissolved in methylene chloride (40 mL) followed by the addition of sodium nitrate (2.21 g, 26.1 mmol). The addition of sulfuric acid (30 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product (2.0 g, 52%). 1H NMR (CD3COCD3): d 8.21 (d, 1H), 8.16 (d, 1H), 8.05 (d, 1H), 7.19 (t, 1H), 6.72 (d, 1H)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=O)[CH3:2].[Cl-].[Cl-].[Cl-].[Al+3].[C:24]1([O:30]C)C=CC=CC=1.C(N1CCC(C(Cl)=O)CC1)(=O)C>C(=S)=S>[OH:30][CH2:24][CH2:2][CH2:1][N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1
Reactant: COc1ccc(C(=O)C2CCN(C(C)=O)CC2)cc1
Reactant: COc1ccccc1
Agent: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(=O)C2CCN(CCCO)CC2)cc1
Yield: 60 %

Procedure:
1-Acetyl-4-(4-methoxybenzoyl)piperidine. To a suspension of aluminum trichloride (3.40 g, 25.7 mmol) in CS2 (15 mL) were added anisole (1.90 mL, 17.6 mmol) and, portionwise, N-acetylisonipecotoyl chloride (2.40 g, 11.7 mmol). After the addition was complete, the mixture was refluxed for 1 h. The solvent was decanted and the red residue was dissolved in 5% HCl (50 mL) and was extracted with EtOAc (4×30 mL). The combined organic phase was dried and was concentrated under reduced pressure to afford the title compound as a colorless solid (1.8 g, 60%):mp 102-105° C.; 1H NMR (CDCl3) d 1.50-1.75 (m, 1H), 1.70-2.00 (m, 3H), 2.10 (s, 3H), 2.70-2.90 (m, 1H), 3.15-3.30 (m, 1H), 3.40-3.53 (m, 1H), 3.86 (s, 3H), 3.85-4.00 (m, 1H), 4.56 (d, J=13.2 Hz, 1H), 6.94 (d, J=8.7 Hz, 2H), 7.92 (d, J=9.0 Hz, 2H).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH2:2][CH3:3].Cl[C:12]1[N:13]=[N+:14]([O-:25])[C:15]2[C:24]3[CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=[CH:18][C:16]=2[N:17]=1>COCCOC>[O-:25][N+:14]1[C:15]2[C:24]3[CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=[CH:18][C:16]=2[N:17]=[C:12]([NH:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][CH3:10])[CH2:1][CH2:2][CH3:3])[N:13]=1
Reactant: [O-][n+]1nc(Cl)nc2ccc3c(c21)CCC3
Reactant: CCCN(CCC)CCN
Solvent: COCCOC
Product: CCCN(CCC)CCNc1nc2ccc3c(c2[n+]([O-])n1)CCC3
Yield: 91.9 %

Procedure:
N,N-Dipropyl-1,2-ethanediamine (297) (0.53 g, 3.7 mmol) was added to a stirred solution of chloride 5 (325 mg, 1.5 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue was partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 10 (454 mg, 94%) as a pale yellow solid: mp (MeOH) 148-151° C.; 1H NMR δ 7.54 (d, J=8.4 Hz, 1H, H-6), 7.40 (d, J=8.4 Hz, 1H, H-5), 5.77 (br s, 1H, NH), 3.63-3.68 (m, 2H, H-9), 3.48-3.52 (m, 2H, CH2N), 2.95-3.00 (m, 2H, H-7), 2.68 (dd, J=6.0, 5.8 Hz, 2H, CH2N), 2.40-2.45 (m, 4H, 2×CH2N), 2.16-2.23 (m, 2H, H-8), 1.43-1.52 (m, 4H, 2×CH2), 0.90 (t, J=7.3 Hz, 6H, 2×CH3); 13C NMR δ 158.5, 149.0, 142.0, 137.3, 132.2, 129.2, 124.7, 55.9 (2), 52.6, 38.9, 35.3, 32.9, 24.8, 20.3 (2), 11.9 (2). Anal. calcd for C18H27N5O: C, 65.6; H, 8.3; N, 21.3. Found: C, 65.7; H, 8.6; N, 21.5%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:7][O:8][C:9]=1[C:10]([OH:12])=O)=[O:4].O[N:20]=[C:21]([C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)[NH2:22].N1C=CC=CC=1C1C(C(F)(F)F)=C(C2ON=C(C3C=CC(CN4CC(C(O)=O)C4)=CC=3)N=2)ON=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>CN(C)C=O>[C:35]([O:34][C:32]([CH:30]1[CH2:31][N:28]([CH2:27][C:26]2[CH:39]=[CH:40][C:23]([C:21]3[N:22]=[C:10]([C:9]4[O:8][N:7]=[C:6]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=5)[C:5]=4[C:3]([O:2][CH3:1])=[O:4])[O:12][N:20]=3)=[CH:24][CH:25]=2)[CH2:29]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(C(N)=NO)cc2)C1
Reactant: COC(=O)c1c(-c2ccccn2)noc1C(=O)O
Agent: O=C(O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccccn2)noc1-c1nc(-c2ccc(CN3CC(C(=O)OC(C)(C)C)C3)cc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
To a mixture of 4-(methoxycarbonyl)-3-(pyridin-2-yl)isoxazole-5-carboxylic acid (79 mg, 0.318 mmol), tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int. 1 (97 mg, 0.318 mmol), and BOP—Cl (97 mg, 0.382 mmol) in dimethylformamide (1.5 mL) at room temperature was added triethylamine (0.133 mL, 0.955 mmol). The reaction mixture was allowed to stir at room temperature overnight. Some uncyclized material remained, so stirring was continued for an additional 24 hrs. At this time, the reaction mixture was partitioned between ethyl acetate (30 mL) and a saturated aqueous solution of sodium bicarbonate (30 mL). The organic layer was washed with water (2×30 mL), washed with brine (30 mL), and dried over anhydrous magnesium sulfate. Concentration afforded a brown oil that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-70% EtOAc/Hex gradient. The essentially pure fractions containing product were concentrated to afford methyl 5-(3-(4-((3-(tert-butoxycarbonyl)azetidin-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-(pyridin-2-yl)isoxazole-4-carboxylate (80 mg, 0.155 mmol, 48.6% yield) as a light purple solid. HPLC retention time=2.91 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=518.20.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[CH3:12].[BH4-].[Li+]>O1CCCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CO)ccc1Br
Temperature: 0 °C
Yield: 82.1 %

Procedure:
A solution of methyl 4-bromo-3-methylbenzoate (50.0 g, 218 mmol), lithium tetrahydroborate (5.70 g, 262 mmol) and tetrahydrofuran (500 mL) was stirred at 25° C. for 2 d. The reaction was cooled to 0° C., quenched with saturated NH4Cl solution and diluted with ethyl acetate. The aqueous layers were extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (36.0 g, 82%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:9]([C:13]([F:16])([F:15])[F:14])=[N:10][NH:11][CH:12]=1)=[O:7])[CH3:4].Br[CH2:18][C:19]([NH:21][C:22]1[S:26][C:25]2[CH2:27][CH2:28][CH2:29][CH2:30][C:24]=2[C:23]=1[C:31]([NH2:33])=[O:32])=[O:20].O>CN(C=O)C>[C:31]([C:23]1[C:24]2[CH2:30][CH2:29][CH2:28][CH2:27][C:25]=2[S:26][C:22]=1[NH:21][C:19](=[O:20])[CH2:18][N:11]1[CH:12]=[C:8]([C:6]([O:5][CH2:3][CH3:4])=[O:7])[C:9]([C:13]([F:15])([F:16])[F:14])=[N:10]1)(=[O:32])[NH2:33]
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reactant: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Temperature: 120 °C
Yield: 19 %

Procedure:
NaH (60% [w/w] suspension in oil, 10 mg, 0.25 mmol) was added to a solution of ethyl-3-(trifluoromethyl)pyrazole-4-carboxylate (25 mg, 0.056 mmol) in DMF (2 mL). The reaction mixture was stirred at RT for 60 min before the addition of 2-(2-bromoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide. The reaction mixture was heated at 120° C. for 10 min in the microwave. Water (5 μL) was added and the reaction mixture extracted with EtOAc (3×10 mL). The combined EtOAc layers were washed with water (5×5 mL), brine (5 mL), dried over MgSO4, filtered and the solvent removed under reduced pressure to give the crude reaction mixture as a yellow solid (44 mg, 0.01 mmol). Purification by preparative reverse phase HPLC gave the desired product (10 mg, 0.024 mmol, 19%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[C:7]([CH2:12][N:13]=[N+]=[N-])=[CH:6][C:5]=1[N:16]([CH3:18])[CH3:17]>CO.[C].[Pd]>[CH3:1][NH:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][C:5]=1[N:16]([CH3:18])[CH3:17])[CH2:12][NH:13][C:10]2=[NH:11])=[O:19]
Reactant: CNC(=O)c1cc(C#N)c(CN=[N+]=[N-])cc1N(C)C
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1cc2c(cc1N(C)C)CNC2=N
Reaction time: 0.5 h
Yield: 42 %

Procedure:
After dissolving N1-methyl-4-(azidomethyl)-5-cyano-2-(dimethylamino)benzamide (755 mg, 2.9 mmol) in methanol (50 ml), 10% palladium-carbon (50% wet) (0.2 g) was added prior to catalytic reduction for 30 minutes at room temperature and normal pressure. The catalyst was separated off, the solvent was distilled off under reduced pressure and ethyl acetate was added to the residue for crystallization. This was filtered off to yield the title compound (283 mg) as a faint yellow powder. (42% yield)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10](=[O:27])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@@H:13]2[CH2:25][OH:26])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[BH4-].[Na+].O>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]([OH:27])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][C@@H:13]2[CH2:25][OH:26])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccc(F)c(C#N)c2)[C@@H](CO)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc(F)c(C#N)c2)[C@@H](CO)C1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (3R)-4-[2-(3-cyano-4-fluorophenyl)-2-oxoethyl]-3-(hydroxymethyl)piperazine-1-carboxylate (20 g, 0.053 mol) in MeOH (400 mL) was added partionwise NaBH4 (15.6 g, 0.424 mol) at 0° C. and the mixture was stirred at r.t overnight. The reaction mixture was added water, extracted with EtOAc. The organic layer was combined, washed with brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified with silica gel column chromatography to give the title compound.
Reaction SMILES: O.[OH-].[Na+].C(=O)CCCC.C1(=O)CCCC1.O[CH:17]([CH:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27])[CH2:18][CH2:19][CH2:20][CH3:21]>>[CH:17](=[C:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(O)C1CCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC=O
Solvent: O
Solvent: O=C1CCCC1
Product: CCCCC=C1CCCC1=O
Temperature: 15 °C
Yield: 2.2 %

Procedure:
A 100 mL four-necked flask was charged with 16.6 g (0.92 mol) of water and 0.16 g (0.004 mol) of sodium hydroxide. After cooling the contents of the flask to 15° C. under stirring, a mixed solution containing 61.3 g (0.71 mol) of valeraldehyde (acid value: 1.5 mg-KOH/g) and 237.8 g (2.83 mol) of cyclopentanone, and 36.0 g of a sodium hydroxide aqueous solution (concentration of sodium hydroxide: 0.36% by mass) were added dropwise into the flask over 6 h. While dropping, the resulting reaction mixture was withdrawn from the flask at a rate 1.4 times the dropping rate, and introduced into a dropping funnel (separator) to separate the reaction mixture into an organic layer and a water layer. The water layer separated as a lower layer of the reaction mixture was returned to the flask. Whereas, the organic layer separated as an upper layer of the reaction mixture was collected every one hour, and each part of the organic layer collected every one hour was subjected to gas chromatography. After completion of the dropping, the reaction mixture in the flask was separated into the respective layers, and each of the thus separated organic and water layers was analyzed by gas chromatography. As a result, it was confirmed that the organic layer contained 3.06 g (0.036 mol) of valeraldehyde, 106.5 g (0.63 mol) of 2-(1-hydroxy-n-pentyl)cyclopentanone and 2.13 g (0.014 mol) of pentylidene cyclopentanone (conversion rate of valeraldehyde: 95.0%; yield: 89.9%).