Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]2.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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.O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]3)=[CH:19][CH:18]=1
Reactant: COC(=O)c1cnc2ccc(Br)cc2c1
Reactant: OB(O)c1ccc(Cl)cc1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cnc2ccc(-c3ccc(Cl)cc3)cc2c1
Temperature: 150 °C

Procedure:
To a 2-5 mL microwave vial fitted with a stirbar was added methyl 6-bromoquinoline-3-carboxylate (Int-1, 0.15 g, 0.564 mmol), 4-chlorophenylboronic acid (0.114 g, 0.733 mmol), sodium carbonate (0.179 g, 1.69 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0651 g, 0.056 mmol). The vial was capped and 1,4-dioxane (1.6 mL) and water (0.47 mL) were added by syringe. The mixture was purged with argon for 5 min. The contents of the vial were heated in a microwave at 150° C. for 30 min. The reaction mixture was cooled to room temperature and the vial was opened. The mixture was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted twice with water. The extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was used as obtained in the following step. LC-MS: (FA) ES+ 298.
Reaction SMILES: N1C=CC=CC=1.O[CH2:8][C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[CH:11]=[CH:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S(Cl)([Cl:27])=O>C(Cl)(Cl)Cl>[Cl:27][CH2:8][C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[CH:11]=[CH:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccccc1C=CCOc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: ClCc1ccccc1C=CCOc1ccccc1
Reaction time: 1 h

Procedure:
47.4 g (0.6 mol) of pyridine was added to a solution which had been obtained by adding 500 ml of chloroform to 120 g (0.5 mol) of o-hydroxymethylphenoxy methylstyrene. 71.4 g (0.6 mol) of thionyl chloride was dropwise added to the mixture with stirring while keeping the temperature at 3° to 4° C. in an ice bath. The mixture was stirred at the same temperature for 1 hour and then at a temperature of 30° C. for 1 hour. After being washed with water, the mixture was dried by sodium sulfate. The chloroform was removed from by distillation under reduced pressure to obtain a yellow liquid as the desired product.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.N1(C2C=C[C:24]([CH:25]=[O:26])=CC=2)C=CC=N1>>[F:1][C:2]1[CH:9]=[C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:24][CH:25]=[O:26]
Reactant: O=Cc1ccc(-c2ncccn2)cc1F
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1ccc(-c2ncccn2)cc1F

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 2-fluoro-4-(2-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 15) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 229 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[CH:2]1.[C:9]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[C:9]1(=[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C:7]#[N:8])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: N#CCc1ccsc1
Reactant: O=C1CCCCC1
Product: N#CC(=C1CCCCC1)c1ccsc1

Procedure:
The expected intermediate is obtained in the manner described in General Protocol A starting from 3-thienylacetonitrile and cyclohexanone.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:34])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([OH:30])[C:22]=3[CH2:31][CH2:32][CH3:33])[CH:14]=2)[CH:7]=1.O.Cl>O1CCCC1>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:15]2[CH:14]=[C:13]([NH:12][C:8]3[CH:7]=[C:6]([CH:11]=[CH:10][N:9]=3)[C:5]([OH:34])=[O:4])[CH:18]=[CH:17][CH:16]=2)=[C:22]([CH2:31][CH2:32][CH3:33])[C:23]=1[OH:30])(=[O:29])[CH3:28]
Reactant: CCCc1c(OCc2cccc(Nc3cc(C(=O)OC)ccn3)c2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCc2cccc(Nc3cc(C(=O)O)ccn3)c2)ccc(C(C)=O)c1O
Temperature: 80 °C
Reaction time: 1 h
Yield: 21.6 %

Procedure:
Add 1M aqueous lithium hydroxide (2.14 mL, 2.14 mmol) to a solution of 2-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-isonicotinic acid methyl ester (282 mg, 0.649 mmol) in tetrahydrofuran (20 mL):water (20 mL) and stir. Heat to 80° C. After 1 hour, pour reaction into 1N aqueous hydrochloric acid (50 mL) and filter the resulting precipitate to yield the title compound as a yellow solid (59 mg, 22%): 1H NMR (DMSO-d6) δ 0.86 (t, 3H), 1.52 (sextet, 2H), 2.57 (s, 3H), 2.63 (t, 2H), 5.25 (s, 2H), 6.72 (d, 1H), 6.99 (d, 1H), 7.13 (d, 1H), 7.30 (t, 1H), 7.37 (s, 1H), 7.56 (d, 1H), 7.80 (d, 1H), 7.91 (s, 1H), 8.28 (d, 1H), 9.37 (s, 1H), 12.85 (s, 1H), 13.44 (bs, 1H); MS (esi negative) m/z (rel intensity) 419 (100).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:7].[N:20]1([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:9]([NH:8][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:23]2[CH2:24][CH2:25][N:20]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=3)[CH2:21][CH2:22]2)[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: COC(=O)c1c(Cl)cccc1NC(=O)CCCCBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1c(Cl)cccc1NC(=O)CCCCN1CCN(c2ccc3ccccc3n2)CC1
Yield: 63.5 %

Procedure:
A mixture of 1.29 g of methyl 2-(5-bromopentanoylamino)-6-chloro-benzoate as synthesized in above Step 7-18-B, 800 mg of 2-piperazin-1-ylquinoline as synthesized in Step 7-1-A, 400 mg of triethylamine and 20 ml of toluene was heated under reflux for 3 hours. After cooling, the solution was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified on silica gel column chromatography (ethyl acetate:methanol=15:1) to provide 1.13 g (64%) of methyl 2-chloro-6-[5-(4-quinolin-2-ylpiperazin-1-yl)pentanoylamino]benzoate.
Reaction SMILES: [N:1]1([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:15](OC(=O)C)(=[O:17])[CH3:16].N1C=CC=CC=1>ClCCl>[C:15]([N:4]1[CH2:3][CH2:2][N:1]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:5]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NN1CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCN(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(1-piperazinyl)-tert-butoxycarboxamide (15 g) in dichloromethane (200 ml) was added acetic anhydride (7.74 ml) and pyridine (6.63 ml). The mixture was stirred at ambient temperature for 1 hour. The solution was washed with saturated aqueous solution of sodium hydrogen carbonate and brine. The organic layer was collected, dried over magnesium sulfate, and concentrated. The residue was triturated with n-hexane to give N-(4-acetyl-1-piperazinyl)-tert-butoxycarboxamide (16.4 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:24][O:25][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][O:19]1)[C:9]3=[O:23].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>CC(=O)CC>[CH3:37][O:36][C:34](=[O:35])[CH2:33][O:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:24][O:25][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][O:19]1)[C:9]3=[O:23]
Reactant: COC(=O)CBr
Reactant: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)COc1ccc2c(c1)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21
Yield: 101.3 %

Procedure:
The mixture of 6-hydroxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.42 g, 1.23 mmol), potassium carbonate (0.22 g, 1.60 mmol) and methyl bromoacetate (0.15 mL, 1.60 mmol) in 2-butanone (10 mL) was refluxed for 15 h. The reaction mixture was concentrated in vacuo to dryness. The residue was purified by flash chromatography with 25% ethyl acetate in hexanes to afford methyl({2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl}oxy)acetate (0.51 g, 87%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.33-7.26 (m, 1H), 7.15-7.00 (m, 3H), 6.64-6.59 (m, 1H), 6.51 (d, J=2.4 Hz, 1H), 6.36 (dd, J=8.4, 2.4 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.72 (d, J=9.0 Hz, 1H), 4.59 (s, 2H), 4.32-4.24 (m, 1H), 3.99-3.66 (m, 7H), 2.07-1.84 (m, 3H), 1.78-1.64 (m, 1H); MS (ES+) m/z 409.9 (M+1), 447.9 (M+39).
Reaction SMILES: N1C=CC([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][N:8]2[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=CC=1.[H-].[Na+].Cl[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:24]=1>CN(C=O)C>[N:24]1[CH:25]=[CH:26][C:31]([N:11]2[CH2:12][CH2:7][N:8]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:23]4[N:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=4)=[CH:17][CH:18]=3)[CH2:9][CH2:10]2)=[CH:32][CH:23]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc(N2CCNCC2c2ccncc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc(N3CCN(c4ccncc4)CC3)cc2)nc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 94.5 %

Procedure:
To a suspension of 4-((4-pyridyl)piperazin-1-yl)phenol (1.13 g) in DMF (10 ml) was added a 60% dispersion of sodium hydride in oil (195 mg) and the resulting mixture was stirred for 20 minutes. A solution of methyl 6-chloronicotinate (758 mg) in DMF (2 ml) was added and the mixture was heated at 60° C. for 2 hours. The mixture was partitioned between ethyl acetate(100 ml) and water(20 ml). The organic layer was dried (MgSO4) and evaporated to give an oil which was purified by flash column chromatography on silica, eluting with methanol/dichloromethane (5:95 v/v) to give the title compound as a solid (815 mg): mp 143°-144° C. ; NMR (d6DMSO) δ3.2-3.35 (4H,m) 3.45-3.55 (4H,m), 3.85 (3H,s), 6.9 (2H,dd), 7.05-7.1 (4H,m), 8.15-8.3 (3H,m), 8.7 (2H,d); m/e 391 (M+H)+ ; calculated for C22H22N4O3.0.25H2O: C,66.9; H,5.7; N,14.2. Found: C,66.9; H,5.7; N,14.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:21]([CH3:22])=[C:20]([C:23]#[N:24])[C:11]3[N:12]=[C:13]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[O:14][C:10]=3[C:9]=2F)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:33][NH:34][C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:21]([CH3:22])=[C:20]([C:23]#[N:24])[C:11]3[N:12]=[C:13]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[O:14][C:10]=3[C:9]=2[N:37]2[CH2:38][CH2:39][C@H:35]([NH:34][CH3:33])[CH2:36]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@H]1CCNC1
Reactant: Cc1c(-c2cccc(Cl)c2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN[C@H]1CCN(c2c(-c3cccc(Cl)c3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
6-(3-Chlorophenyl)-4-cyano-7-fluoro-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide (I-311) (500 mg, 1.40 mmol) was dissolved in dimethyl sulfoxide (20 ml), and at room temperature, triethylamine (215 μl, 1.54 mmol) was added. The solution was gradually heated from room temperature up to 150° C., and a solution of (3S)-3-(methylamino)pyrrolidine (164 μl, 1.54 mmol) dissolved in dimethyl sulfoxide (3 ml) was added all at a time. After stirred at the same temperature for 30 minutes, this was cooled to room temperature. The solvent was evaporated away under reduced pressure, and the resulting residue was fractionated with chloroform and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was first roughly purified by middle-pressure liquid chromatography using an eluent of chloroform:methanol=95:5 (v/v), and then the roughly-purified product was purified by preparative TLC (eluent, chloroform:7 N ammonia/methanol solution=95:5, v/v), and further the obtained solid was purified in slurry with diisopropyl ether to obtain the entitled compound (250 mg, 41%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]([CH3:28])=O>>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH:26]([CH3:28])[CH3:25])[CH2:16][CH2:17]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)NC(CCCC1CCNCC1)c1ccccc1
Product: CC(C)N1CCC(CCCC(NC(=O)OC(C)(C)C)c2ccccc2)CC1

Procedure:
Using alkylation method A, crude N-[1-phenyl-4-(piperidine-4-yl)butyl]carbamic acid tert-butyl ester (0.70 mmol) and acetone (1.5 mL, 20 mmol) afforded the title compound as a crude residue that was used without further purification.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[C:37]1[S:38][CH:39]=[C:40]([C:42](O)=[O:43])[N:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:42]([C:40]3[N:41]=[C:37]([C:31]4[C:30]([F:29])=[CH:35][CH:34]=[CH:33][C:32]=4[F:36])[S:38][CH:39]=3)=[O:43])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1csc(-c3c(F)cccc3F)n1)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
3-Amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (7.0 mg, 0.018 mmol), 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (5.2 mg, 0.022 mmol), HATU (17 mg, 0.045 mmol), DMF (0.042 mL) and DIPEA (7.0 mg, 0.054 mmol) were mixed together and the mixture was stirred at room temperature for 1 h. The mixture was filtered, concentrated and purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give pure sub-title compound as light yellow powder (3.7 mg, 34%). LCMS calc. for C30H34F2N5O5S (M+H)+: m/z=614.2. Found: 614.1.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[NH2:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13](F)[N:12]=2)[N:9]=[CH:8][C:7]=1[C:23]#[N:24].Cl>C(OC)(C)(C)C>[NH2:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13]([O:2][CH3:1])[N:12]=2)[N:9]=[CH:8][C:7]=1[C:23]#[N:24]
Reactant: N#Cc1cnn(-c2nc(F)c(C(F)(F)F)cc2Cl)c1N
Reactant: CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: COc1nc(-n2ncc(C#N)c2N)c(Cl)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
5 ml of methanol were added in the course of 10 minutes at 20° C. to a suspension of 0.23 g (0.0092 mol) of 95% sodium hydride in 75 ml of methyl tert-butyl ether and the mixture was stirred for 25 minutes until a clear solution was obtained. 3 g (0.0098 mol) of 5-amino-4-cyano-1-(3-chloro-6-fluoro-5-trifluoromethylpyrid-2-yl)pyrazole (Example IV.1.) in 50 ml of methyl tert-butyl ether were subsequently added with stirring and the mixture was stirred for 2 hours at 25° C. Approximately 50 g of ice and 100 ml of hydrochloric acid were added and the phases were separated. The organic phase was washed using saturated sodium chloride solution, dried and filtered through silica gel. After concentration, stirring with ether/pentane, filtration with suction and drying, 2.4 g (77% of theory) of the title compound of m.p. 135°-139° C. were obtained (active ingredient example No. 5.003).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.CO.[BH4-].[Na+]>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:15]1
Reactant: CCOC(=O)N1CCC(=Nc2c(Cl)cccc2Cl)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Product: CCOC(=O)N1CCC(Nc2c(Cl)cccc2Cl)CC1
Reaction time: 1 h

Procedure:
To a stirred and refluxing mixture of 250 parts of ethyl 4-[(2,6-dichlorophenyl)imino]-1-piperidinecarboxylate in 160 parts of methanol and 160 parts of 2-propanol are added portionwise 30 parts of sodium borohydride. Upon completion, stirring at reflux temperature is continued for one hour. The warm reaction mixture is poured onto water and the product is extracted with methylbenzene. The extract is dried and evaporated. The residue is crystallized from a mixture of 160 parts of 2,2'-oxybispropane and 160 parts of petroleumether, yielding 96 parts of ethyl 4-[(2,6-dichlorophenyl)-amino]-1-piperidinecarboxylate; mp. 107.2°-116.6° C.
Reaction SMILES: [O:1]=[C:2]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:3][CH2:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C@H:8]1[CH:9]=O)=[O:6].Cl.[NH2:24][OH:25].N1C=CC=CC=1>CN(C=O)C>[O:1]=[C:2]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:3][CH2:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C@H:8]1[CH:9]=[N:24][OH:25])=[O:6]
Reactant: NO
Reactant: O=C[C@@H]1CCCN1C(=O)CCC(=O)NCc1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(CCC(=O)N1CCC[C@H]1C=NO)NCc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of N-[4-oxo-4-(4-chlorobenzylamino)butanoyl]-L-prolinal (304 mg) in DMF (2.5 ml) were added hydroxylamine hydrochloride (75 mg) and pyridine (90 μl), and the mixture was stirred at 70° C. for 2 hours. To a solution of crude (2S)-1-[4-oxo-4-(4-chlorobenzylamino)butanoyl]-2-pyrrolidinecarboxaldehyde oxime as obtained by subjecting the reaction mixture to concentration under reduced pressure, in methylene chloride (4 ml) were added pyridine (0.16 ml) and acetic anhydride (0.19 ml), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was treated in the same manner as in Example 15 to give 249 mg of (2S)-1-[4-oxo-4-(4-chlorobenzylamino)butanoyl]-2-pyrrolidinecarboxaldehyde O-acetyloxime.
Reaction SMILES: [K].[OH:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6].[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CN(C=O)C>[CH3:16][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1O
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc([N+](=O)[O-])c(C=O)c1OC
Reaction time: 8 h

Procedure:
Potassium salt from Procedure 5 (396 g) was slurried with DMF (8 l) and added to a 1 l flask containing 800 g potassium carbonate. Dimethyl sulfate (420 ml) was added in portions at 60° over 1 hour and the reaction was stirred at 60° overnight. The K2CO3 was washed with acetone and the washings were added to the distillation residue and again solvent was removed in vacuo. The dry residue was treated with water (1 l) and extracted with CH2Cl2. The extracts were dried, evaporated, and the product was crystallized from methanol to afford the product, (335 g, 94%) mp 109°-111° C.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C@H:8](N)[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.N([O-])=[O:14].[Na+]>OS(O)(=O)=O>[OH:14][C@@H:8]([CH2:7][CH:4]1[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1)[C:9]([OH:11])=[O:10]
Reactant: O=N[O-]
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)[C@@H](O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To a stirring suspension of L-cyclohexylalanine (4.00 g,23.4 mmol) in 0.5M H2SO4 (120 mL) at 0° C. was slowly added dropwise an aqueous solution of NaNO2 (12.1 g in 40 mL H2O). Addition was complete after approximately 1 h, at which point the solution was allowed to warm to room temperature. After 16 h, the reaction mixture was extracted with ether (3×100 mL), and the combined organic extracts were washed with 1M NaHSO4 (1×200 mL) and brine (1×100 mL) and then dried over anhydrous Na2SO4. The solvent was removed in vacuo, and the crude product was recrystallized from Et2O/pentane (10 mL/100 mL) to afford 2.1 g (52% yield) of (S)-2-hydroxy-3-cyclohexylpropionic acid as fine white needles.
Reaction SMILES: Br[C:2]1[C:7]2=[N:8][S:9][N:10]=[C:6]2[C:5](Br)=[C:4]([F:12])[C:3]=1[F:13].[CH2:14]([C:26]1[CH:27]=[C:28]([Sn](C)(C)C)[S:29][CH:30]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>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.C1(C)C=CC=CC=1>[CH2:14]([C:26]1[CH:27]=[C:28]([C:2]2[C:7]3=[N:8][S:9][N:10]=[C:6]3[C:5]([C:28]3[S:29][CH:30]=[C:26]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:27]=3)=[C:4]([F:12])[C:3]=2[F:13])[S:29][CH:30]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Fc1c(F)c(Br)c2nsnc2c1Br
Reactant: CCCCCCCCCCCCc1csc([Sn](C)(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCc1csc(-c2c(F)c(F)c(-c3cc(CCCCCCCCCCCC)cs3)c3nsnc23)c1
Temperature: 105 °C
Yield: 89.1 %

Procedure:
4,7-Dibromo-5,6-difluoro-benzo[1,2,5]thiadiazole (0.33 g, 1 mmol), (4-dodecyl-thiophen-2-yl)-trimethyl-stannane (1.04 g, 2.5 mmol), and Pd(PPh3)4 (20 mg) were combined in a 50-mL Schlenk flask. The system was vacuumed and backfilled with argon for three cycles before 20 mL of anhydrous toluene was added. The mixture was heated at 105° C. for 3 days. After the reaction was cooled down, the solvent was removed by rotary evaporation. The product was further purified by silica gel column with toluene/hexane (v/v, 1/4) as the eluent and recrystallization from a hexane/iso-propoanol mixture. The final product (0.60 g, 89.5% yield) was obtained as red needle crystals after drying in vacuo. 1H NMR (CDCl3, 500 MHz): δ 8.15 (d, 2H, J=1.0 Hz), δ 7.23 (d, 2H, J=1.0 Hz), δ 2.74 (t, 4H, J=7.5 Hz), δ 1.73 (m, 4H), δ 1.29 (m, 18H), δ 0.90 (t, 6H, 7.0 Hz). 13C NMR (CDCl3, 500 MHz): δ 150.8, 148.9, 143.7, 132.3, 131.2, 124.0, 111.7, 31.97, 30.60. 30.52, 29.74, 29.72, 29.70, 29.67, 29.53, 29.42, 29.39, 22.75, 14.19.