Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]([F:16])([F:15])[CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([F:15])([F:16])[C@H:8]2[CH2:9][CH2:10][C@H:11]([OH:14])[CH2:12][CH2:13]2)=[CH:17][CH:18]=1
Reactant: O=C1CCC(C(F)(F)Oc2ccc(Br)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O[C@H]1CC[C@H](C(F)(F)Oc2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 4-[(4-bromo-phenoxy)-difluoro-methyl]-cyclohexanone (1050 mg, 3.290 mmoles) in ethanol (16.4 mL, 0.2M) was added NaBH4 (249 mg, 6.58 mmoles) 0° C. The solution was stirred at 0° C. for 20 minutes and then warmed to room temperature for 20 minutes. The reaction was quenched with 1 N HCl to a pH of ˜7, and extracted three times with ethyl acetate. The organics where combined, dried over magnesium sulfate, filtered and concentrated. Cis/trans isomers were then separated by chiral purification. Isolated 260 mg of trans isomer (24%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.39 (s, 2H) 1.51-1.65 (m, 2H) 1.83-1.96 (m, 2H) 2.01-2.21 (m, 2H) 2.38-2.47 (m, 1H) 7.03-7.14 (m, 2H) 7.41-7.58 (m, 2H)
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32][C:33]1[CH:34]=[N:35][NH:36][CH:37]=1.[C:38]([O:42][C:43](=[O:49])[N:44]([CH2:46][CH2:47]O)[CH3:45])([CH3:41])([CH3:40])[CH3:39]>C1COCC1>[C:38]([O:42][C:43](=[O:49])[N:44]([CH2:46][CH2:47][N:35]1[CH:34]=[C:33]([Br:32])[CH:37]=[N:36]1)[CH3:45])([CH3:41])([CH3:40])[CH3:39]
Reactant: Brc1cn[nH]c1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(CCn1cc(Br)cn1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.9 %

Procedure:
Diethylazodicarboxylate (0.48 mL, 3.1 mmol) was added to a 0° C. solution of triphenylphosphine (0.80 g, 3.1 mmol) in THF (20 mL). After stirring for 5 minutes, 4-bromopyrazole (0.30 mg, 2.0 mmol) was added. After another 5 minutes of stirring, (2-hydroxyethyl)-methyl-carbamic acid tert-butyl ester (0.45 g, 2.6 mmol) was added. The reaction was allowed to warm to room temperature and stir overnight. The reaction was cooled to 0° C. and filtered. The filtrate was concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution of dichloromethane, ethyl acetate to afford [2-(4-bromo-pyrazol-1-yl)-ethyl]-methyl-carbamic acid tert-butyl ester (541 mg, 87%).
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17]C)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.CO.[CH3:21][NH2:22]>>[NH2:1][C@H:2]([C:15]([NH:22][CH3:21])=[O:17])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1
Reactant: CN
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Solvent: CO
Product: CNC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1

Procedure:
A mixture of Tyr(3-tBu)-OMe (12 g, 48 mmol) and a 40% methylamine methanol solution (80 ml) was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, giving Tyr(3-tBu)-NHMe (T2) (12 g) as a crude product.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[N:12][N:13]=[CH:14]3)O1.[NH2:20][C:21]1[N:22]=[CH:23][C:24]([C:31]2[CH:32]=[N:33][N:34]([CH:36]3[CH2:41][CH2:40][N:39]([C:42](=[O:44])[CH3:43])[CH2:38][CH2:37]3)[CH:35]=2)=[C:25]2[CH:29]=[C:28](Cl)[O:27][C:26]=12>>[NH2:20][C:21]1[N:22]=[CH:23][C:24]([C:31]2[CH:32]=[N:33][N:34]([CH:36]3[CH2:37][CH2:38][N:39]([C:42](=[O:44])[CH3:43])[CH2:40][CH2:41]3)[CH:35]=2)=[C:25]2[CH:29]=[C:28]([C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[CH:11]=[N:12][N:13]=[CH:14]4)[O:27][C:26]=12
Reactant: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Reactant: CC1(C)OB(c2cccc3cnncc23)OC1(C)C
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5cccc6cnncc56)cc34)cn2)CC1
Yield: 3 %

Procedure:
The title compound was prepared in 3% yield from 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phthalazine and 1-{4-[4-(7-amino-2-chlorofuro[2,3-c]pyridin-4-yl)-1H-pyrazol-1-yl]piperidin-1-yl}ethanone, by a procedure analogous to Example 223, Step D. The sample underwent both mass-directed purification and preparative TLC during purification. 1H NMR (400 MHz, CD3OD): δ 10.32 (s, 1H), 9.73 (s, 1H), 8.63 (dd, J=0.76, 7.58 Hz, 1H), 8.32 (d, J=8.08 Hz, 1H), 8.18-8.25 (m, 2H), 7.96-8.03 (m, 2H), 7.76 (s, 1H), 4.67-4.76 (m, 1H), 4.55-4.61 (m, 1H), 3.35-3.42 (m, 1H), 2.88 (dt, J=2.65, 12.95 Hz, 1H), 2.21-2.31 (m, 2H), 2.19 (s, 3H), 1.98-2.18 (m, 3H); MS (ESI): 454.19 [M+H]+; HPLC tR=0.85 min (TOF: polar—3 min).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:45]=[CH:44][C:35]([C:36]([NH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:37])=[CH:34][CH:33]=1>>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:37])=[CH:44][CH:45]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Nc1ccc(C(=O)NCCC(=O)O)cc1
Product: O=C(O)CCNC(=O)c1ccc(NCc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and 3-(4-amino-benzoylamino)-propionic acid according to the procedure of Example 66. MS (ES) m/z 595.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:17](Br)[CH:18]=[CH2:19]>CC(C)=O.[Ag]=O>[CH2:19]([N:13]1[CH2:14][CH2:15][CH2:16][CH:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:12]1)[CH:18]=[CH2:17]
Reactant: COc1ccc(C2CCCNC2)cc1OC
Reactant: C=CCBr
Agent: O=[Ag]
Solvent: CC(C)=O
Product: C=CCN1CCCC(c2ccc(OC)c(OC)c2)C1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
2.8 g of silver oxide were added to a solution of 5.6 g of 3-(3',4'-dimethoxyphenyl)-piperidine in 28 ml of acetone and then 2.3 ml of allyl bromide were added dropwise thereto with slow cooling. The mixture was stirred at 20° C for 30 minutes and was then filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 6-3-1 cyclohexane-chloroform-triethylamine mixture yielded 5.55 g of N-allyl-3-(3',4'-dimethoxyphenyl)-piperidine.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13]1([C:19]#[C:20][C:21]2[CH:39]=[CH:38][C:24]([C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[O:26])=[CH:23][CH:22]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:13]1([C:19]#[C:20][C:21]2[CH:39]=[CH:38][C:24]([C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34]([NH:35][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:37])=[O:36])=[O:26])=[CH:23][CH:22]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Reactant: CCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
In a stream of nitrogen, 0.30 ml (1.46 mmol) of decanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 500 mg (1.30 mmol) of 4-phenylethynyl-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 10 and 320 mg (2.60 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 540 mg (yield: 76.4%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21]>ClCCl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][Si:23]([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24])=[CH:6][CH:7]=1
Reactant: OCCCc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCCc1ccc(Br)cc1
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of the product of step (i) (32.25 g, 0.15 mol) in anhydrous dichloromethane (400 mL) was added triethylamine (45 g, 0.45 mol), DMAP (915 mg, 7.5 mmol) and TBSCl (33 g, 0.215 mol) sequentially. The resulting solution was stirred overnight. The reaction mixture was extracted with dichloromethane and washed with water (×3). The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography with PE to afford the subtitle compound (ii) as a pale brown oil (40 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][C:22]([F:24])=[CH:21][CH:20]=3)[NH:14][C:12]2=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Nc1cc(F)ccc1C(=O)O
Product: O=c1[nH]c2cc(F)ccc2c(=O)n1S(=O)(=O)c1ccc(Cl)cc1
Yield: 83.7 %

Procedure:
2.31 g (10.6 mmol) of 4-chlorobenzenesulfonylisocyanate and 1.50 g (9.67 mmol) of 2-amino-4-fluorobenzoic acid were treated in the same way as in Example 1 to obtain 2.87 g of the above-identified compound (yield 83.7%). Properties: colorless crystal, Melting point: >200° C., PMR (δppm, DMSO-d6): 6.86 (1H,d), 7.04 (1H,t), 7.76 (2H,d), 7.93 (1H,dd), 8.17 (2H,d), 11.65 (1H,br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([OH:16])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1
Reactant: O=C1c2ccc(Cl)cc2CCc2cccnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1c2ccc(Cl)cc2CCc2cccnc21
Yield: 80.6 %

Procedure:
To a mixture of 25.03 g (103 mmol) of 8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one in 200 mL of MeOH at room temperature and under a nitrogen atmosphere was added portionwise over a period of about 1 hour 4.82 g (124 mmol) of NaBH4. Occasional cooling with an ice bath was necessary at times during the addition in order to avoid excessive reflux. After 1.6 hours the mixture was poured into ice cold water and then extracted with EtOAc (3×). The combined organic portions were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was recrystallized from hot isopropyl ether. The remaining filtrate was purified via flash chromatography (20% EtOAc in hexanes) to yield more product which solidified on standing. Both batches were combined to yield 20.41 g of the title compound as a white solid.
Reaction SMILES: [CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8](Cl)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:17][C:18]([F:25])([F:24])[CH2:19][NH:20][C:21]([NH2:23])=[O:22]>>[CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]([NH:23][C:21]([NH:20][CH2:19][C:18]([F:25])([F:24])[F:17])=[O:22])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)NCC(F)(F)F
Reactant: O=C(Cl)N(C1CCCCC1)C1CCCCC1
Product: O=C(NCC(F)(F)F)NC(=O)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in General Procedure 1 using dicyclohexyl carbamoyl chloride and N-2,2,2-trifluoroethylurea.
Reaction SMILES: FC(F)(F)S([C:6]1[C:7](=[O:27])[N:8]([CH3:26])[C:9]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)(=O)=O.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[CH:11]=[C:6]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:7](=[O:27])[N:8]([CH3:26])[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:13][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(-c2cc(S(=O)(=O)C(F)(F)F)c(=O)n(C)c2-c2ccncc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2cc(-c3ccccc3)c(=O)n(C)c2-c2ccncc2)cc1
Yield: 58.6 %

Procedure:
A mixture of 3-trifluoromethanesulfonyl-5-(4-methoxyphenyl)-6-(4-pyridyl)-1-methyl-1H-pyridin-2-one (0.055 g), benzeneboronic acid (0.25 g) and aqueous sodium carbonate (2M; 2 cm3) in dimethoxyethane (5 cm3) was degassed and purged with nitrogen at room temperature. Tetrakis(triphenylphosphine)palladium (0) (0.1 g) was added and the mixture was refluxed under nitrogen for 2 hours. The mixture was diluted with water (10 cm3) and extracted with ethyl acetate (3×10 cm3). The extracts were dried (sodium sulphate), filtered and concentrated. Preparative thin layer chromatography, eluting with 95:5 dichloromethane-methanol, gave 5-(4-methoxyphenyl)-6-(4-pyridyl)-3-phenyl-1-methyl-1H-pyridin-2-one (0.028 g; 61%) as a pale pink foam. Recrystallised to give a beige powder m.p. 183-185° C. (EtOAc-hexane). δH (360 MHz; CDCl3) 3.39 (3 H, s, NCH3), 3.73 (3 H, s, OCH3), 6.69 (2 H, d, J 9, methoxyphenyl H-2), 6.90 (2 H, d, J 9, methoxyphenyl H-3), 7.13 (2 H, d, J 6, pyridyl H-3), 7.35-7.44 (3 H, m, 3 of Ph), 7.59 (1 H, s, pyridone H-4), 7.77 (2 H, d, J 8, 2 of Ph) and 8.60 (2 H, d, J 6, pyridyl H-2); m/z (ESP+) 369 (MH+; 100%).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH:8]([C:10]1[C:17]([CH3:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:19][CH3:20])[CH:11]=1)=[O:9]>C1COCC1.CS(C)=O>[CH3:20][O:19][C:12]1[CH:11]=[C:10]([CH:8]2[CH2:4][O:9]2)[C:17]([CH3:18])=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: C[S+](C)C
Reactant: COc1cc(C=O)c(C)cc1C#N
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1cc(C2CO2)c(C)cc1C#N
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cool solution of NaH (1.20 g, 30.0 mmol) in THF (300 ml) was added dropwise a solution of trimethylsulfonium iodide (8.74 g, 42.8 mmol) in DMSO (80 mL). The resulting mixture was stirred at 0° C. under N2 for 20 min. The solution of 4-formyl-2-methoxy-5-methylbenzonitrile (5.00 g, 28.5 mmol) in THF (60 mL) was added. The resulting reaction mixture was stirred at 0° C. under N2 for 1 hr, and then it was warmed gradually to room temperature and stirred at that temperature for 12 hr. The starting material was consumed as indicated by TLC (25% ethyl acetate/hexanes). The reaction mixture was cooled to 0° C. and quenched with dropwise addition of water. The mixture was extracted with ethyl acetate (2×200 ml). The combined organic layers were washed with water, brine, then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue was purified via column chromatography (silica gel, 10-30% EtOAc-hexanes) to afford 2-methoxy-5-methyl-4-(oxiran-2-yl)benzonitrile. 1H NMR (CDCl3, 500 MHz) δ 7.35 (s, 1H), 6.88 (s, 1H), 4.01 (s, 1H), 3.92 (s, 3H), 3.25 (s, 1H), 2.65 (d, J=2.6 Hz, 1H), 2.37 (s, 3H); LC/MS: (IE, m/z) [M+1]+=190.0; tR=2.85 min.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[NH:10][C:9](=O)[N:8]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:9]1[N:8]=[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=1
Reactant: O=c1nc(-c2ccc(Cl)s2)cc(C(F)(F)F)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(-c2ccc(Cl)s2)nc(Cl)n1

Procedure:
The title compound was prepared from 4-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-1H-pyrimidin-2-one (10.0 g, 35.6 mmol) and phosphoroxychloride (50 ml) according to the general procedure I. Obtained as a brown oil (10.4 g, 98%). MS (EI) 298.0, 299.9 [(M)+].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41]>C(#N)C.C(OCC)(=O)C>[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41].[NH:12]1[C:13]2[C:9](=[C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]3[CH2:31][CH2:32][CH:27]([C:18]4[CH:19]=[CH:20][C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH:17]=4)[CH2:28][CH2:29]3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:11]1
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Reactant: ClCCCCCOc1cccc2[nH]ccc12
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: c1ccc2cc(C3CCN(CCCCCOc4cccc5[nH]ccc45)CC3)ccc2c1

Procedure:
A solution of 1-chloro-5-(4-indolyloxy)pentane, 4-(2-naphthyl)piperidine and 3 equivalents of potassium carbonate in acetonitrile was heated at reflux for 12 h. The mixture was cooled, diluted with ethyl acetate, and the organic layer was separated and washed with brine. The crude residue was purified by silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient eluent). The resulting free base was dissolved in ethyl acetate and precipitated with one equivalent of oxalic acid in ethyl acetate, to give the title compound in 47% overall yield as a white solid. mp. 178°-180° C. FDMS m/e=412 (M+ of free base).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][C:16]#[N:17])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>O.C(O)C.N.[Rh]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][NH2:17])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC1(CC#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Rh]
Agent: N
Solvent: O
Solvent: CCO
Product: CC1(CCN)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.5 %

Procedure:
To 5% Rh/Al2O3 (0.600 g) suspended in water (2 mL) is added ethanol (5 mL), 4-cyanomethyl-4-methylpiperidine-1-carboxylic acid tert-butyl ester (0.258 g, 1.083 mmol) dissolved in ethanol (10 mL) and 28% NH3 (aq) (0.25 mL). The reaction mixture is subjected to 50 psi hydrogen gas and stirred at room temperature for 18 hours. The reaction mixture is filtered to remove the catalyst, then the filtrate is concentrated and chromatographed on silica gel, eluting with 0-10% (2 M NH3 in MeOH) in dichloromethane to give the title compound (130 mg, 50% yield).
Reaction SMILES: Cl[C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[C:7]([F:13])[CH:8]=2)[N:3]=1.CO[CH:17]([O:20]C)[CH2:18][NH2:19]>>[F:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[F:14])[N:3]1[CH:2]=[CH:11][N:19]=[C:18]1[C:17](=[O:20])[NH:10]2
Reactant: COC(CN)OC
Reactant: Fc1cc2nc(Cl)c(Cl)nc2cc1F
Product: O=c1[nH]c2cc(F)c(F)cc2n2ccnc12

Procedure:
By reacting 2,3-dichloro-6,7-difluoroquinoxaline with aminoacetaldehyde dimethyl acetal, following a procedure that is similar to that described in example 1, there is obtained 7,8-difluoroimidazo[1,2-a]quinoxalin-4(5H)-one (m.p. >300° C.) and, subsequently, 4-chloro-7,8-difluoroimidazo[1,2-]quinoxaline. By reacting this product with cyclopentylamine according to the method described in example 3, there is obtained 4-cyclopentylamino-7,8-dichloroimidazo[1,2-a]quinoxaline. m.p. (DSC)=146.0° C.(onset); IR (KBr): 3263, 2955, 1554 cm-1 ; 1H-NMR (CDCl3): δ7.7 (1H,s), 7.65÷7.15 (3H,m), 6.1 (1H,d), 4.6 (1H,m), 2.3÷1.3 (8H,m); UV (EtOH): λmax =225, 241, 270, 295, 323, 337 nm. Elementary analysis for C15H14F2N4 (m.w. 288.30): calcd. C 62.49, H 4.89, N 19.43%; found C 62.46, H 5.03, N 19.65%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:11]2[CH2:16][C@H:15]([CH3:17])[C@@H:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:13]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:12]2)=[C:4]2[CH2:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1.[C:34]([O:38][C:39]([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55](O)=[O:56])=[O:40])([CH3:37])([CH3:36])[CH3:35].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:29]([O:28][C:27]([NH:26][C@H:13]1[C@H:14]([O:18][Si:19]([C:22]([CH3:23])([CH3:25])[CH3:24])([CH3:20])[CH3:21])[C@@H:15]([CH3:17])[CH2:16][N:11]([C:3]2[C:2]([NH:1][C:55]([C:43]3[N:44]=[C:45]([C:47]4[C:48]([F:54])=[CH:49][CH:50]=[CH:51][C:52]=4[F:53])[S:46][C:42]=3[NH:41][C:39](=[O:40])[O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:56])=[CH:7][N:6]=[C:5]3[O:8][CH2:9][CH2:10][C:4]=23)[CH2:12]1)=[O:33])([CH3:32])([CH3:31])[CH3:30]
Reactant: C[C@H]1CN(c2c(N)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
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: C[C@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.2 %

Procedure:
To a mixture of tert-butyl ((3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (67.8 mg, 0.142 mmol), 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (65.4 mg, 0.184 mmol) and HATU (168.1 mg, 0.4421 mmol) was added DMF (2.0 mL) followed by DIPEA (144.5 mg, 1.118 mmol). The reaction mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-50% EtOAc in hexanes) to afford the sub-title compound as a brown solid (29.2 mg, 25%). LCMS calc. for C39H55F2N6O7SSi (M+H)+: m/z=817.4. found 817.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([F:31])[CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[NH2:32][CH2:33][CH2:34][OH:35].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([F:31])[CH:24]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:32][CH2:33][CH2:34][OH:35])=[O:18])=[N:14][CH:15]=1
Reactant: COc1ccc(S(=O)(=O)C(c2cnc(C(=O)O)cc2C)c2cc(F)ccc2F)cc1F
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(S(=O)(=O)C(c2cnc(C(=O)NCCO)cc2C)c2cc(F)ccc2F)cc1F
Temperature: 25 °C
Reaction time: 19 h
Yield: 80 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(3-fluoro-4-methoxyphenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (113 mg, 0.25 mmol) in methylene chloride (3 ml), 2-aminoethanol (0.017 ml, 0.28 mmol), 1-hydroxybenzotriazole (37 mg, 0.28 mmol), 4-methylmorpholine (0.030 ml, 0.28 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg, 0.28 mmol) were added at room temperature. After stirring for 19 hours at room temperature, the reaction mixture was washed with water and then with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with ethyl acetate was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and diethyl ether, and was collected by filtration, to obtain the title compound (99 mg, 0.20 mmol, 80%) as a white solid.