Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>>[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:12]1[N:13]([CH2:18][CH3:19])[N:14]=[C:15]2[C:11]=1[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]2
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: OB(O)c1ccccc1Cl
Product: CCn1nc2c(c1-c1ccccc1Cl)CCNCC2
Yield: 48.2 %

Procedure:
The title compound (73 mg) was prepared according to Example 263 using 227 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 120 mg of 2-chlorophenylboronic acid. MS (ESI): exact mass calculated for C15H18ClN3, 275.12; found, m/z 276.4 [M+H]+, 278.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.64-7.62 (m, 1H), 7.58-7.48 (m, 2H), 7.41-7.39 (m, 1H), 3.97-3.86 (m, 2H), 3.44-3.42 (m, 2H), 3.20-3.17 (m, 2H), 2.70-2.63 (m, 2H), 1.26 (t, J=7.2 Hz, 3H).
Reaction SMILES: C1(C[O:8][C:9](=[O:46])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:13]=[C:12]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:11]=2)C=CC=CC=1.[H][H]>[Pd].C1COCC1.C(OCC)(=O)C>[CH2:28]([O:27][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:13]=1)[C:9]([OH:46])=[O:8])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccccc2)cc(C(=O)O)c1
Yield: 94.3 %

Procedure:
A mixture of 14.6 g of 3-(octadecyloxy)-5-(3-phenoxypropoxy) benzoic acid phenylmethyl ester and 3 g of 10% palladium on carbon in 200 ml THF and 20 ml ethyl acetate was shaken in a hydrogen atmosphere at room temperature for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated to a solid which was recrystallized from ether-hexane to give 11.8 g (95% yield, mp 79°-81°) of 3-(octadecyloxy) -5-(3-phenoxypropoxy)benzoic acid.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:13][CH:14]([CH3:35])[CH2:15][C:16]1([CH2:31][C:32](O)=[O:33])[CH2:20][C:19](=[O:21])[N:18]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:17]1=[O:30].Cl.[CH2:37]([O:44][NH2:45])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CN1CCOCC1>C(Cl)Cl>[CH2:37]([O:44][NH:45][C:32](=[O:33])[CH2:31][C:16]1([CH2:15][CH:14]([CH3:13])[CH3:35])[CH2:20][C:19](=[O:21])[N:18]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:17]1=[O:30])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)CC1(CC(=O)O)CC(=O)N(CCc2ccccc2)C1=O
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)CC1(CC(=O)NOCc2ccccc2)CC(=O)N(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.5 %

Procedure:
CDI (153 mg, 0.945 mmol) is added to a mixture of 3-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-3-pyrrolidineacetic acid (300 mg, 0.945 mmol) and CH2Cl2 (7.5 mL) at room temperature. Afar stirring at room temperature for 1 hour, O-benzylhydroxylamine hydrochloride (181 mg, 1.13 mmol) and 4-methylmorpholine (124 μL, 1.13 mmol) are added to the solution. The mixture is allowed to stir overnight at room temperature. Basic workup (CH2Cl2, NaHCO3, MgSO4) and purification by column chromatography (1.5% MeOH/CHCl3) affordes 70 mg (18%) of the title compound as a white solid (mp 115°-117° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(Cl)(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2](/[CH:14]=[CH:13]/[C:12]([O:16][CH3:17])=[O:15])[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1cnc2ccccc2c1
Reaction time: 0.5 h

Procedure:
In an amount of 10.2 g of 3-bromoquinoline was stirred together with 7 ml of methyl acrylate, 110 mg of palladium(II) acetate, 599 mg of tri-o-tolylphosphine, and 29 ml of triethylamine at 100° C. for 17 hours in a sealed tube. The reaction mixture was diluted with 300 ml of chloroform, and successively washed with 250 ml of saturated brine, and 250 ml of saturated aqueous ammonium chloride. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 80 ml of chloroform, added with 200 ml of hexane under ice cooling, and stirred for 30 minutes. The precipitates were taken by filtration, washed with hexane, and then dried under reduced pressure to obtain 8.0 g of methyl (E)-3-(quinolin-3-yl)acrylate. Physicochemical Properties of this Compound
Reaction SMILES: [NH2:1][C@H:2]([C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:24])[C:22]=1[NH2:23])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.[C:32]([O:36][C:37]([NH:39][CH2:40][CH2:41][C:42](ON1C(=O)CCC1=O)=[O:43])=[O:38])([CH3:35])([CH3:34])[CH3:33]>C(Cl)(Cl)Cl>[NH2:23][C:22]1[N:21]([CH3:24])[N:20]=[CH:19][C:18]=1[NH:17][C:15](=[O:16])[C@@H:2]([NH:1][C:42](=[O:43])[CH2:41][CH2:40][NH:39][C:37]([O:36][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:38])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: Cn1ncc(NC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C)c1N
Reactant: CC(C)(C)OC(=O)NCCC(=O)ON1C(=O)CCC1=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.3 %

Procedure:
To a solution of tert-butyl (5S)-5-amino-6-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-6-oxohexylcarbamate (1.60 g) and triethylamine (0.47 g) in chloroform (100 ml) was added N-[3-(tert-butoxycarbonylamino)propionyloxy]succinimide (1.34 g). The mixture was stirred at room temperature for 15 hours. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a crude product of tert-butyl (5S)-6-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-5-{[3-(tert-butoxycarbonylamino)propionyl]amino}-6-oxohexylcarbamate (2.09 g) as an oil. The crude product was used directly in the next step without further purification.
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)Cl.[CH2:13]=[CH:14][C:15]([Cl:17])=[CH2:16]>O>[Cl:17][C:15]1[CH2:14][CH2:13][CH:1]([C:3](=[O:4])[CH3:5])[CH2:2][CH:16]=1
Reactant: C=CC(=C)Cl
Reactant: C=CC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)C1CC=C(Cl)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 98.1 parts of methyl vinyl ketone, 187 parts of anhydrous aluminum chloride and 1980 parts of methylene chloride was added 123 parts of chloroprene and the mixture was stirred at 25° C. for three hours and left standing for another 16 hours. Water was added to the reaction mixture and the organic layer was washed with 5% hydrochloric acid. Distillation gave a center cut of 61 parts of 1-chloro-4-acetyl-cyclohexene (125°-6° C./20 mm Hg). Reference: A. A. Petrov and N. P. Sopov, CA 42, 1910h (1948).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(OCC)(=O)C>[Cl:19][CH2:20][C:21]([CH:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:7][NH:8]1)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: O=[N+]([O-])c1ccc2c(c1)CNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C(CCl)C1NCc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a suspension in which 42.8 g of 5-nitroisoindoline had been added to an aqueous potassium carbonate solution (108 g of potassium carbonate, 200 ml of water) was added dropwise 200 ml of an ethyl acetate solution containing 31.2 ml of chloroacetyl chloride at 0° C. over 1 hour. The mixture was further stirred at 0° C. for 45 minutes and precipitates were collected by filtration. The obtained solid-was treated with activated carbon in ethyl acetate and recrystallized to obtain 2-chloroacetyl-5-nitroisoindoline.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:10][S:11]SC.O>O1CCCC1.C([Li])CCC>[CH3:10][S:11][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[CH:1][N:2]=1
Reactant: CSSC
Reactant: c1ccn2cncc2c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CSc1ncc2ccccn12
Yield: 104.6 %

Procedure:
To a solution of 1.63 g of imidazo[1,5-a]pyridine in 20 ml of tetrahydrofuran, 11 ml of n-butyl lithium (1.6N-hexane solution) is added below 70° C. during 15 minutes under nitrogen gas atmosphere. After stirring the mixture for an hour at the same temperature, a solution of 1.7 g of dimethyldisulfide in 10 ml of tetrahydrofuran is dropwise added during 30 minutes and continued to stir for 30 minutes. The mixture added with water is extracted with ether. The extract is dried over anhydrous magnesium sulfate and distilled to remove ether. The residue is purified by silica gel chromatography (eluent: chlooform-ethylacetate) to give 2.37 g of the oily title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9]([C@@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:10].C(N(CC)CC)C.[C:39]1([C:45](Cl)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)(Cl)Cl>[CH3:7][N:6]1[C:2]([NH:1][C:45]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[C:3]([NH:8][C:9]([C@@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:10])[CH:4]=[N:5]1
Reactant: Cn1ncc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1ncc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the crude product of di-tert-butyl (1S)-{1-[(5-amino-1-methyl-1H-pyrazol-4-yl)carbamoyl]pentamethylene}biscarbamate and triethylamine (0.91 g) in chloroform (30 ml) was added triphenylmethyl chloride (2.51 g), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was washed successively with 0.10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 3% methanol/chloroform to give di-tert-butyl (1S)-(1-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]carbamoyl}pentamethylene)biscarbamate (4.23 g) as an oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16]>>[C:12]([C:13]1[CH:14]=[C:15]([NH2:16])[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[Cl:2])[N:10]=1)([CH3:19])([CH3:18])[CH3:11]
Reactant: NNc1ccccc1Cl
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Product: CC(C)(C)c1cc(N)n(-c2ccccc2Cl)n1
Yield: 65.3 %

Procedure:
Following the procedure in Example 161A Step 3, 2-chlorophenylhydrazine hydrochloride (1.43 g, 8.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) were reacted to give 3-tert-butyl-1-(2-chlorophenyl)-1H-pyrazol-5-amine (1.30 g, 5.22 mmol, 65%). 1H NMR (300 MHz, DMSO-d6) δ 7.60 (d, 1H), 7.48-7.42 (m, 3H), 5.28 (s, 1H), 4.94 (s, 2H), 1.19 (s, 9H); LC-MS (ESI) m/z 250 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]1[C:9]([O-:11])=[O:10].[Na+].[F:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=1)[O:18][C:19]1[CH:20]=[C:21]([C:24]([F:27])=[CH:25][CH:26]=1)[CH2:22]Br>CN(C)C=O>[CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]1[C:9]([O:11][CH2:22][C:21]1[C:24]([F:27])=[CH:25][CH:26]=[C:19]([O:18][C:17]2[CH:28]=[CH:29][CH:30]=[C:15]([F:14])[CH:16]=2)[CH:20]=1)=[O:10]
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)[O-]
Reactant: Fc1cccc(Oc2ccc(F)c(CBr)c2)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OCc1cc(Oc2cccc(F)c2)ccc1F
Yield: 69.3 %

Procedure:
6.9 g (0.03 mol) of sodium 2,2-dimethyl-3-(2,2-dichlorovinyl)-cyclopropanecarboxylate were dissolved in 150 ml of dimethylformamide and heated, with 8.0 g (0.027 mol) of 3-(3-fluorophenoxy)-6-fluorobenzyl bromide, for 4 hours at 120° C. After completion of the reaction, the dimethylformamide was distilled off in vacuo and the residue was taken up in 200 ml of methylene chloride. This solution was then extracted by shaking twice with 150 ml of water, the organic phase was dried over sodium sulphate and the solvent was stripped off in vacuo. The last remnants of solvent were removed by brief incipient distillation at 70° C. (bath temperature)/1 mm Hg. 8.0 g (71% of theory) of 3-(3-fluorophenoxy)-6-fluorobenzyl 2,2-dimethyl-3-(2,2-dichlorovinyl)-cyclopropanecarboxylate were obtained as a yellow oil having a refractive index nD24 of 1.5395.
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[CH2:5][NH:4][C:3]1=[O:6].C=O.[C:10](=O)([O-])[O-:11].[K+].[K+]>>[OH:11][CH2:10][N:4]1[CH2:5][C:2]([CH3:7])([CH3:1])[C:3]1=[O:6]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)CNC1=O
Agent: C=O
Agent: [K+]
Product: CC1(C)CN(CO)C1=O
Reaction time: 0.25 h

Procedure:
A flask is charged with 3,3-dimethyl-azetidin-2-one (0.159 g, 1.524 mmol), aqueous formaldehyde (37% wt., 0.124 g, 1.524 mmol) and crushed potassium carbonate (0.009 g, 0.061 mmol). The flask is lowered in a pre-heated oil bath (75° C.). After 15 min, the flask is removed from the oil bath and allowed to stand at room temperature. After 2 h, the mixture is taken up in acetone, dried over magnesium sulfate and filtered through a plug of silica gel. Concentration in vacuo (30° C., 40 Torr) gives 1-hydroxymethyl-3,3-dimethyl-azetidin-2-one, which is used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 1.32 (s, 6H), 3.23 (s, 2H), 4.69 (d, J=7.5 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][OH:11])=[C:4]([C:12]#[C:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.CC([O-])(C)C.[K+]>CN(C=O)C>[C:14]([C:13]1[N:8]([CH2:9][CH2:10][OH:11])[C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:12]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)C#Cc1cc(Cl)ncc1NCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2cc(Cl)ncc2n1CCO
Temperature: 80 °C
Yield: 44.3 %

Procedure:
To a solution of 2-(6-chloro-4-(3,3-dimethylbut-1-ynyl)pyridin-3-ylamino)ethanol (3.6 g, 14.3 mmol) in DMF (100 mL) was added t-BuOK (3.1 g, 28 mol) under N2 atmosphere. The mixture was heated at 80° C. for 12 h and then was quenched with H2O (200 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (150 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and purified by chromatography on silica gel (3% ethyl acetate in petroleum ether as eluant) to afford 2-(2-tert-butyl-5-chloro-1H-pyrrolo[2,3-c]pyridin-1-yl)ethanol (1.6 g, 44%). 1H-NMR (CDCl3, 300 MHz) δ 8.50 (s, 1H), 7.39 (s, 1H), 6.28 (s, 1H), 4.55 (t, J=6.6, 2H), 4.05 (t, J=6.6, 2H), 1.49 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=S)[C@H:10]2[F:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>O1CCCC1.[Ni]>[CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:15])[CH2:11][C@H:10]2[F:23])[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=S)[C@H]2F)CC1
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C[C@H]2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
4-(S)-(1-Ethoxycarbonylcyclopropyl)-3-(S)-fluoro-1-[1-(S)-phenylethyl]-2-pyrrolidinthione (6.49 g, 19.35 mmol) was dissolved in dry tetrahydrofuran (150 ml). After adding Raney nickel catalyst (15 ml), the mixture was stirred at room temperature for 30 minutes. After eliminating the catalyst by filtering through celite (washed with tetrahydrofuran), the filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether (200 ml) and the thus obtained solution was washed with a 10% aqueous solution of ammonia (200 ml×2) and a saturated aqueous solution of sodium chloride (150 ml) and dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure to obtain 5.08 g (86.0%) of the title compound as a colorless oily substance.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][NH:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([O:17][CH3:18])[CH:9]=1)=O.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[Cl:1][CH2:2][C:3]1[O:19][C:7]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([O:17][CH3:18])[CH:9]=2)=[N:6][N:5]=1
Reactant: COc1cc(C(=O)NNC(=O)CCl)ccc1[N+](=O)[O-]
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: COc1cc(-c2nnc(CCl)o2)ccc1[N+](=O)[O-]
Yield: 84.2 %

Procedure:
N′-(Chloroacetyl)-3-(methyloxy)-4-nitrobenzohydrazide (1.00 g, 3.48 mmol) and Burgess' reagent (0.994 g, 4.17 mmol) in THF (15 mL) was heated to 120° C. for 20 minutes in the microwave. The reaction was complete by TLC. Purification by flash chromatography provided the title compound (0.802 g, 2.93 mmol, 85%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.04 (s, 3H), 5.16 (s, 2H), 7.72 (dd, J=8.4, 1.8 Hz, 1H), 7.84 (d, J=1.8 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=O)=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].NN.[OH-].[K+].O>C(O)CO>[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[CH:10][N:11]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNc1ccc(C(=O)c2c[nH]c3ncccc23)cn1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CC(C)CNc1ccc(Cc2c[nH]c3ncccc23)cn1
Temperature: 180 °C

Procedure:
To (6-Isobutylamino-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-0025, 60.0 mg, 0.20 mmol, prepared as described in Example 5) in 1,2-ethanediol (5.0 mL) was added hydrazine (1.0 mL, 0.032 mol) and potassium hydroxide (200.0 mg, 3.56 mmol). The reaction mixture was heated to 180° C. overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give compound (P-0028, 10 mg, 16.7%). MS (ESI) [M+H+]+=281.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:42])([F:41])[F:40])[CH:33]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:41])([F:42])[F:40])[CH:33]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(OC(F)(F)F)c1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(OC(F)(F)F)c2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 22.6 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (556 mg, 0.003 mol) in N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (1.75 g, 0.014 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(3-trifluoromethoxy-phenoxy)-but-2-enoic acid ethyl ester (1.00 g, 0.003 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[2-oxo-4-(3-trifluoromethoxy-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (290 mg, 23%) as a yellow oil.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[C:17]([OH:19])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:20][C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][CH:34]=1)[O:24][CH2:25][C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH2:1]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[C:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][CH:34]=1)[O:24][CH2:25][C:26]([O:28][CH:29]([CH3:30])[CH3:31])=[O:27])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cnc2c(C(=O)O)cccc2c1
Reactant: CC(C)OC(=O)COc1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCCCCc1cnc2c(C(=O)Nc3cccc(OCC(=O)OC(C)C)c3)cccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
To a solution of 3-hexylquinoline-8-carboxylic acid (170 mg, 0.66 mmol), isopropyl 2-(3-aminophenoxy)acetate (207 mg, 0.99 mmol) and N-methylmorpholine (0.18 mL, 1.65 mmol) in DMF (2.0 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (380 mg, 1.0 mmol) and the solution was stirred at room temperature for 16 h. The DMF was removed in vacuo and the residue was partitioned between EtOAc and water. The organic phase was washed with saturated aqueous NaHCO3 (2×) then dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified on 12 g silica gel eluting (17:3 hexanes/EtOAc) to afford 259 mg (87%) of isopropyl 2-(3-(3-hexylquinoline-8-carboxamido)phenoxy)acetate.
Reaction SMILES: [CH:1]1([C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.[Br:22]N1C(=O)CCC1=O.O>C(OCC)(=O)C>[Br:22][CH:5]([C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:10])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CC(=O)C1CC1
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(Br)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 106.8 %

Procedure:
Methyl 3-cyclopropyl-3-oxopropanoate (2.0 g) and magnesium perchlorate (940 mg) were dissolved in ethyl acetate (20 ml), followed by stirring at room temperature for 5 minutes, and N-bromosuccinimide (2.76 g) was added thereto, followed by stirring at room temperature for 4 hours. Water was added thereto, followed by extraction with ethyl acetate, the organic layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain, as a colorless oily product, methyl 2-bromo-3-cyclopropyl-3-oxopropanoate (3.32 g).