Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([NH:24][C@H:25]1[CH2:28][CH2:27][C@H:26]1[C:29](O)=[O:30])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][N:11]([C:29]([C@H:26]3[CH2:27][CH2:28][C@H:25]3[NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:30])[CH2:10][C:9]2([CH3:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H]1C(=O)O
Reactant: CC1(C)CNCC[C@]1(O)c1ccc(Cl)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H]1C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
A mixture of (S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (91 mg, 0.381 mmol), (±)-(cis)-2-(tert-butoxycarbonylamino)cyclobutanecarboxylic acid (82 mg, 0.381 mmol), and triethylamine (0.186 mL, 1.333 mmol) in methylene chloride (5 mL) was treated with BOP (168 mg, 0.381 mmol), and the mixture was stirred overnight at room temperature. At the conclusion of this period, the solvent was evaporated with a stream of nitrogen, and the resulting residue was taken up in ethyl acetate. The resulting mixture was washed 3× with saturated sodium carbonate, 3× with 1 N HCl, once with water, and once with brine, then the organic phase was concentrated in vacuo to yield the title compound (160 mg, 96% yield) as a colorless glass. The material was used as-is without further purification. MS (ESI+)=437.4 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].C[Si](C#N)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CS(O[CH2:29][C:30]1[CH:31]=[N:32][C:33]([Cl:36])=[CH:34][CH:35]=1)(=O)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C.[I-].[Zn+2].[I-]>[Cl:36][C:33]1[N:32]=[CH:31][C:30]([CH2:29][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])=[CH:35][CH:34]=1
Reactant: CS(=O)(=O)OCc1ccc(Cl)nc1
Reactant: O=Cc1ccco1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)nc1)c1ccco1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
To a mixture of 2-furaldehyde (7.9 g, 82.2 mmol) and zinc (II) iodide (110 mg, 0.345 mmol) was dropwise added trimethylsilyl cyanide (11.0 ml, 82.5 mmol) over 10 minutes at 0° C. under an atmosphere of nitrogen gas, followed by stirring as it was. After 30 minutes, the reaction mixture was diluted with tetrahydrofuran (200 ml) and then cooled to −78° C. A 1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (86 ml, 86 mmol) was added dropwise thereto over 1 hour and then a solution of (6-chloro-3-pyridyl)methyl methanesulfonate (18.1 g, 81.7 mmol) in tetrahydrofuran (50 ml) was added dropwise over 1.5 hours thereto, followed by stirring while gradually elevated to room temperature. After 12.5 hours, a 1.0M solution of tetrabutylammonium fluoride in tetrahydrofuran (86 ml, 86 mmol) was added thereto, followed by stirring as it was. After further 30 minutes, the reaction mixture was diluted with a saturated aqueous ammonium chloride solution and ethyl acetate. The resulting organic layer was washed with a saturated aqueous ammonium chloride solution twice, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography (elution solvent; hexane, hexane:ethyl acetate=10:1, 4:1, 3:1, and 2:1) and then suspended in hexane. Subsequently, the resulting precipitates were collected by filtration, to give the title compound (11.9 g, 54%) as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16].Cl>O.C(Cl)Cl>[OH:9][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]
Reactant: COc1cccc(O)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)Oc2ccccc2)c(O)c1
Reaction time: 24 h

Procedure:
To a 1,000-mL, three-neck, nitrogen-purged flask was added 26.5 g (0.21 mole) of 3-methoxyphenol, 215 mL of methylene chloride, 32 g (0.24 mole) of aluminum chloride and 32 mL (0.26 mole) of phenyl chloroformate. This mixture was heated to reflux. After 24 hours, the mixture was cooled to 20°-30° C. and 400 mL of water and 32 mL of 37% hydrochloric acid were added. The layers were separated and the organic layer washed with two 100-mL portions of 5N hydrochloric acid. The organic layer was dried with anhydrous magnesium sulfate, filtered, then the solvent stripped off under vacuum. The crude product was recrystallized from heptane. The yield of phenyl 2-hydroxy-4-methoxybenzoate (white, m.p. 61.5°-62.5° C.) obtained was 49%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:13]2[CH:12]=[CH:11][C:10]3[CH:14]=[CH:15][CH:16]=[C:17]([I:18])[C:9]=3[CH:8]([OH:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(Cl)Cl.CN(C)C1C=CN=CC=1.O1CCCC1>[C:20]([O:1][CH2:2][C:3]1[C:13]2[CH:12]=[CH:11][C:10]3[CH:14]=[CH:15][CH:16]=[C:17]([I:18])[C:9]=3[CH:8]([OH:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1)(=[O:22])[CH3:21]
Reactant: OCc1cccc2c1C=Cc1cccc(I)c1C2O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)OCc1cccc2c1C=Cc1cccc(I)c1C2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
310 mg of the mixture of 1-(hydroxymethyl)-6-iodo-5H-dibenzo[a,d]cyclohepten-5-ol with its 4-iodo form prepared in Example 6-e was dissolved in 15 ml of methylene chloride, and 100 mg of 4-(dimethylamino)pyridine and 0.8 ml of 1M solution of acetic anhydride in tetrahydrofuran were added under ice-cooling, followed by stirring at room temperature for 2 hours. The solvent was evaporated, and the residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=3:17), to give 230 mg of a mixture of the title compound with its 4-iodo form as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[CH:38][N:37]=[N:36]2)[CH:30]=1)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[CH:38][N:37]=[N:36]2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Yield: 74.1 %

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) (152 mg, 0.5 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example H2) (200 mg, 0.77 mmol) according to the general procedure K. Obtained as a yellow oil (191 mg).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2cccc(Cl)c2)cc1
Yield: 57.9 %

Procedure:
[2-(4-Bromophenoxy)propyl][(methylethyl)sulfonyl]amine (300 mg, 0.892 mmol, prepared in example 1), 3-chlorobenzeneboronic acid (170 mg, 1.09 mmol), dichlorobis(triphenylphosphine)palladium(II) (25 mg, 0.036 mmol), 2 M sodium carbonate (320 mg in 1.5 mL water) and 1,2-dimethoxyethane (6.0 mL) were combined in a 15 ml round bottom flask, fitted with a condenser, stirbar, and in a temperature regulated oil bath, and heated at reflux 85 C. in a nitrogen system overnight. The reaction mixture was quenched with water and extracted three times with 25 mL of methylene chloride. The organic extracts were combined, dried over anyhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, yielding 190 mg brown viscous oil. This material was purified via silica gel chromatography, utilizing a Chromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solvent system, yielding the title compound (175 mg, 53%) as a yellow foam. Electrospray-MS 369.0 (M*+1).
Reaction SMILES: C(OC([NH:11][C@@H:12]1[C:18](=[O:19])[N:17]2[C@@H:13]1[S:14][C:15]([CH3:25])([CH3:24])[C@@H:16]2[C:20]([O:22][CH3:23])=[O:21])=O)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:11][C@@H:12]1[C:18](=[O:19])[N:17]2[C@@H:13]1[S:14][C:15]([CH3:25])([CH3:24])[C@@H:16]2[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)[C@@H]1N2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2SC1(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1N2C(=O)[C@@H](N)[C@H]2SC1(C)C

Procedure:
Methyl (2S,5R,6R)-6-benzyloxycarbonylamino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3,2,0] heptane-2-carboxylate (364 mg, 1 mmol) was hydrogenated with about 1.5 g of 10% palladium on activated carbon in 25 ml of ethyl acetate at 50 psi hydrogen pressure at room temperature for 10 hrs. After removal of catalyst by filtration, deprotected methyl (2S,5R,6R)-6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3,2,0] heptane-2-carboxylate in ethyl acetate was obtained.
Reaction SMILES: [Na].[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1C=CC(C=O)=CC=1>>[CH:10](=[O:9])[C:3]1[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=1)[OH:8]
Reactant: Oc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: [Na]
Product: O=Cc1ccccc1O
Yield: 32 %

Procedure:
The phenol aldehyde mixture is in a form combined with sodium. It is neutralized and acidified to a pH of 5. Thereupon the salicylaldehyde is recovered by the conventional carrier vapor distillation of the aqueous phases (following methanol recovery). A yield of 32% (3.9 g) of salicylaldehyde and of 27% (3.2 g) in p-hydroxybenzaldehyde relative to the initial phenol are obtained.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Br:23][C:24]1[CH:25]=[CH:26][C:27]2[N:28]([CH2:38][CH:39]([OH:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:29]3[C:34]([C:35]=2[CH:36]=1)=[CH:33][C:32]([Br:37])=[CH:31][CH:30]=3>ClCCl.CCOC(C)=O>[Br:23][C:24]1[CH:25]=[CH:26][C:27]2[N:28]([CH2:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:29]3[C:34]([C:35]=2[CH:36]=1)=[CH:33][C:32]([Br:37])=[CH:31][CH:30]=3
Reactant: OC(COc1ccccc1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(COc1ccccc1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Yield: 74 %

Procedure:
Dess-Martin periodinane (58.2 mg, 0.137 mmol) was charged to a solution of the title compound of Example 3b (45.0 mg, 0.095 mmol) in dichloromethane (1.0 ml, 0.095 M). After two hours the reaction mixture was diluted with EtOAc and washed with saturated sodium thiosulfate solution, water and brine. The organic layer was dried over Na2SO4, filtered and condensed. The crude product was used without additional purification. Yield=74%
Reaction SMILES: ClC1C=C2C(=CC=1)NC(C(N[C@@H]1CC3C(=CC=CC=3)NC1=O)=O)=C2.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30]([C:35]([NH:37][C@@H:38]1[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]([CH3:48])[C:39]1=[O:49])=[O:36])=[CH:29]2.C(OC(N[C@@H]1CC2C(=CC=CC=2)NC1=O)=O)(C)(C)C>>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30]([C:35]([NH:37][C@H:38]1[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]([CH3:48])[C:39]1=[O:49])=[O:36])=[CH:29]2
Reactant: CN1C(=O)[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Agent: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2NC1=O
Agent: O=C(N[C@@H]1Cc2ccccc2NC1=O)c1cc2cc(Cl)ccc2[nH]1
Product: CN1C(=O)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21

Procedure:
The title compound was prepared from (S)-3-t-butyloxycarbonylamino-3,4-dihydrocarbostyril (prepared in Example 5) by the procedures described for the preparation of (R)-3-(5-chloroindole-2-carbonylamino)-1-methyl-3,4-dihydrocarbostyril (Example 14) from (R)-3-t-butyloxycarbonylamino-3,4-dihydrocarbostyril. HPLC/MS [M+H]+, 354.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:7])=[O:6].Cl.[N:17]([O-])=O.[Na+]>O>[CH2:12]([N:11]1[C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=[N:17]1)[CH2:13][CH2:14][CH3:15]
Reactant: O=N[O-]
Reactant: CCCCNc1ccc(C(=O)O)cc1N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCn1nnc2cc(C(=O)O)ccc21
Yield: 72.6 %

Procedure:
To a stirred and cooled mixture of 43.7 parts of 3-amino-4-(butylamino)benzoic acid and 200 parts of a hydrochloric acid solutin 6N was added dropwise a solution of 22 parts of sodium nitrite in a small amount of water. Upon complete addition, the reaction mixture was stirred for 4 hours at 10°-20° C. The product was filtered off, washed with 30 parts of water and crystallized from a mixture of 2-propanone and ethyl acetate. The product was filtered off and dried, yielding 33.3 parts (72.6%) of 1-butyl-1H-benzotriazole-5-carboxylic acid; mp. 192.5° C. (int. 9).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][CH:28]=[CH:27][C:9]=3[N:10]([CH2:19][C:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:11](=[O:18])[N:12]([CH2:14][C:15](O)=[O:16])[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)Cl.Cl.[NH2:36][C:37]1[CH:38]=[C:39]([C:43]2[NH:47][C:46](=[O:48])[O:45][N:44]=2)[CH:40]=[CH:41][CH:42]=1.CCN(C(C)C)C(C)C>CC#N>[CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][CH:28]=[CH:27][C:9]=3[N:10]([CH2:19][C:20]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[O:21])[C:11](=[O:18])[N:12]([CH2:14][C:15]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]4[NH:47][C:46](=[O:48])[O:45][N:44]=4)[CH:38]=3)=[O:16])[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cccc(-c2noc(=O)[nH]2)c1
Reactant: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O)Nc1cccc(-c2noc(=O)[nH]2)c1
Temperature: -10 °C
Reaction time: 8 h

Procedure:
A 2L three-necked-reaction flask was charged with [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetic acid (100 g, 243 mmol) and MeCN (600 mL). At room temperature SOCl2 (19.5 mL, 267.3 mmol) was added via addition funnel. In a 3L three-necked-flask a slurry of 3-(3-amino-phenyl)-4H-[1,2,4]oxadiazol-5-one hydrochloride salt (53.47 g, 250.3 mmol) in MeCN (300 mL) was treated with DIPEA (148 mL, 851 mmol) at room temperature, then cooled to −10° C. The solution of the acid chloride was then added to the amine solution to maintain the temperature below −5° C. Upon consumption of starting material (30 minutes) the reaction mixture was quenched by addition of 1N HCl (650 mL) followed by addition of water (300 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. The resulting suspension was then cooled in an ice bath (1 h) and the solid collected by vacuum filtration and washed with MeCN (50 mL) to yield the title compound as an off white solid.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:3]([C:1]([NH2:2])=[O:35])=[N:4][CH:5]=1)[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C[C@@H](Nc1cnc(C#N)c(Nc2ccc3ncccc3c2)n1)C(N)=O
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CC(C)C[C@@H](Nc1cnc(C(N)=O)c(Nc2ccc3ncccc3c2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-4-methylpentanamide (80 mg, 0.299 mmol), 6-aminoquinoline (60 mg, 0.416 mmol), K2CO3 (65 mg, 0.471 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 100 C for 20 h. Water and EtOAc were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-4-methylpentanamide as a crude residue (151 mg). The crude (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-4-methylpentanamide (151 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 60 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (21 mg). MS 394.2 (M+H); UV 201.1, 265.8, 297.2, 358.5 nm; t 0.451 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.Br[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1>>[N:4]1([CH2:3][CH2:2][O:1][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: OCCN1CCCC1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(OCCN2CCCC2)nc1
Temperature: 23 °C
Reaction time: 2.25 h

Procedure:
A solution of 8.00 g (69.6 mmol) of N-(2-hydroxyethyl)pyrrolidine in 150 mL of xylenes was treated with 534 mg (23.2 mmol) of Na and the mixture was heated to 80° C. until all the Na had disappeared. The reaction was cooled to 23° C. and 5.50 g (23.2 mmol) of 2,5-dibromopyridine was added. The mixture was stirred at room temperature for 2.25 h and was concentrated in vacuo. Purification by flash chromatography (SiO2; gradient of 50-70% EtOAc in hexanes) afforded 3.53 g (13.0 mmol; 56%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([C:14]#[N:15])[N:11]=[CH:10]1.NO.Cl.CC[N:23](CC)CC>CCO>[F:17][C:2]([F:16])([F:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([C:14](=[NH:23])[NH2:15])[N:11]=[CH:10]1
Reactant: N#Cc1cn(-c2ccccc2C(F)(F)F)cn1
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Solvent: CCO
Product: N=C(N)c1cn(-c2ccccc2C(F)(F)F)cn1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
A mixture of give 1-(3′-methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl-1H-imidazole-4-carbonitrile (694 mg, 1.485 mmol), NH2OH.HCl (258 mg, 3.71 mmol), Et3N (0.6 mL, 4.3 mmol), and dry EtOH (15 mL) was stirred at 55° C. for 5 h under N2. The solvent was removed in vacuo to give N′-hydroxy-1-(3′-methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl-1H-imidazole-4-carboximidamide as a white solid, which was used in the next reaction without further purification. MS (ESI) 501 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([O:18][CH2:19][CH2:20][OH:21])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:5]([N:12]1[CH2:13][CH2:14][CH:15]([O:18][CH2:19][C:20]([O:3][CH2:1][CH3:2])=[O:21])[CH2:16][CH2:17]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: OCCOC1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)COC1CCN(Cc2ccccc2)CC1
Reaction time: 48 h
Yield: 65.8 %

Procedure:
15.6 g (0.2 mole) of acetyl chloride were added dropwise while cooling at 20° C with an ice bath to a solution of 47 g (0.2 mole) of 2-(1-benzyl-4-piperidyloxy)-ethanol, prepared according to the step B of Example I, and 20.2 g (0.2 mole) of triethylamine in 300 ml of benzene and after standing for 48 hours at room temperature, the precipitate was removed by vacuum filtration. The benzene filtrate was washed with aqueous sodium bicarbonate solution, then water, dried and the benzene distilled off. The residue was distilled to obtain 36.5 g (66% yield) of ethyl 2-(1-benzyl-4-piperidyloxy)-acetate as a clear oil boiling at 160°-170° C at 0.1 mm Hg and having a refractive index nD20 = 1.512.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16].O>CN(C)C=O>[F:16][C:15]([F:18])([F:17])[CH2:14][CH2:13][CH:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: FC(F)(F)CCBr
Reactant: N#CCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
27.6 g of malononitrile was dissolved in 50 ml of N,N-dimethylformamide, 27.6 g of potassium carbonate was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, a mixture of 17.7 g of 1-bromo-3,3,3-trifluoropropane and 20 ml of N,N-dimethylformamide was added thereto and the mixture was further stirred for 1 hour. Thereafter, the reaction mixture was poured to water and then extracted with diethyl ether. The organic layer was washed successively with water and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 11.3 g of 2-(3,3,3-trifluoropropyl)malononitrile.
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]([C:7]1[S:8][C:9]([Br:14])=[C:10]([Br:13])[C:11]=1[Br:12])=[O:6])C.Cl>CC(C)=O.O>[Br:12][C:11]1[C:10]([Br:13])=[C:9]([Br:14])[S:8][C:7]=1[C:5](=[O:6])[C:4]([OH:15])=[O:3]
Reactant: CCOC(=O)C(=O)c1sc(Br)c(Br)c1Br
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)C(=O)c1sc(Br)c(Br)c1Br
Temperature: 25 °C

Procedure:
A solution of (3,4,5-tribromothiophen-2-yl)-oxo-acetic acid ethyl ester (0.4 g, 0.95 mmol) in acetone (10 ml), water (2 ml), and conc. HCl (8 ml) was stirred under reflux for 1.5 hours. The reaction mixture was allowed to cool to ambient temperature and concentrated in vacuo to remove acetone which gave rise to solids which were collected, washed with water and dried. (3,4,5-tribromothiophen-2-yl)-oxo-acetic acid was thus obtained as a light yellow solid (0.17 g, 49%). MS (M−H)−: 392.75; 13C NMR (75 MHz, CDCl3) δ124.19, 117.80, 113.26, 111.72. IR (KBr) cm−1 3477.9, 3107.1, 2922.5, 1715.9, 1681.5, 1666.0, 1484.5, 1306.5, 1268.9.