Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[CH:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1.[N+]([O-])([O-])=O.[NH2:27][N+:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])[CH:13]=[CH:14][CH:15]=3)=[N:27][N:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][C:33]=23)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc[n+](N)c1
Reactant: O=C(Nc1cccc(C=Cc2ccnc(Cl)n2)c1)C(F)(F)F
Agent: O=[N+]([O-])[O-]
Product: Cc1ccc2c(-c3ccnc(Cl)n3)c(-c3cccc(NC(=O)C(F)(F)F)c3)nn2c1
Yield: 21.3 %

Procedure:
N-[3-(2-Chloro-pyrimidin-4-ylethenyl)-phenyl]-2,2,2-trifluoro-acetamide (5.00 g, 18.45 mmol) and 1-amino-3-methylpyridinium nitrate (6.19 g, 36.90 mmol) were combined in a procedure analogous to Example 67, Step A to afford 1.80 g of crude material, which was purified via HPLC separation to give N-{3-[3-(2-chloro-4-pyrimidinyl)-6-methylpyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (1.70 g, 21%). 1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 8.73 (s, 1H), 8.43 (d, J=5.6 Hz, 1H), 8.28 (d, J=9.2 Hz, 1H), 7.92 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.56-7.49 (m, 2H), 7.45-7.40 (m, 1H), 7.03 (d, J=5.6 Hz, 1H), 2.37 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([N:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:31])[CH:27]=3)[N:22]=[CH:21]2)[C:9]([NH:11][C:12]2[S:13][C:14]([C:17]([OH:19])=O)=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][CH2:57][N:58](CC)[CH2:59][CH3:60]>CN(C=O)C>[CH:1]1([CH2:7][CH:8]([N:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:31])[CH:27]=3)[N:22]=[CH:21]2)[C:9]([NH:11][C:12]2[S:13][C:14]([C:17]([N:58]([CH2:59][CH3:60])[CH2:57][CH3:56])=[O:19])=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cnc(NC(=O)C(CC2CCCCC2)n2cnc3ccc(F)cc3c2=O)s1
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1cnc(NC(=O)C(CC2CCCCC2)n2cnc3ccc(F)cc3c2=O)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of Compound 143 (0.1 g, 0.225 mmol) and HBTU (256 mg, 0.675 mmol) was dissolved in anhydrous DMF (1 mL) and Et3N (0.125 mL, 0.9 mmol) and stirred for 30 min. To this solution was added Et2N (0.028 mL, 0.270 mmol) and the mixture was stirred at RT overnight. The reaction was poured onto ice to crash out the crude product. The product was purified via preparative HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88-1.25 (m, 12H) 1.48-1.81 (m, 5H) 2.00-2.13 (m, 1H) 2.21-2.36 (m, 1H) 3.46 (s, 4H) 5.80 (dd, J=11.87, 4.80 Hz, 1H) 7.73-7.92 (m, 4H) 8.52 (s, 1H). [M+H] calc'd for C25H30FN5O3S, 500; found, 500.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].Cl[C:9]1[C:10]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:15][C:11]=2[N:12]=[CH:13][N:14]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(OC)(C)(C)C.O>[CH3:1][O:2][CH:3]([CH2:6][O:7][C:9]1[C:10]2[C:17]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)=[C:16]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:15][C:11]=2[N:12]=[CH:13][N:14]=1)[CH2:4][OH:5]
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: COC(CO)CO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(CO)OC)c23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Put 1.014 g (9.65 mmol) 2-methoxypropane-1,3-diol in 20 ml THF. Add 542 mg (4.825 mmol) potassium tert.-butylate and stir for 15 min at RT. Then cool to 0° C. and add a solution of 650 mg (1.93 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine in 10 ml THF dropwise in the space of 30 min. Then leave to return to RT and stir overnight at RT. Next, dilute with tert.-butylmethyl ether and water. Acidify with 10% citric acid solution and separate the phases. Re-extract the aqueous phase once with tert.-butylmethyl ether. Combine the organic phases and wash once with satd. sodium chloride solution. Then dry over magnesium sulphate and concentrate by evaporation. Purify the residue by chromatography on silica gel (solvent: cyclohexane/ethyl acetate 7:3); 587 mg (74.8% of theor.) of the target compound is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH2:11][CH3:12])[C:5]([C:6]([OH:8])=O)=[C:4]([CH2:13][CH3:14])[CH:3]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl:48][C:49]1[CH:56]=[CH:55][C:52]([CH2:53][NH2:54])=[CH:51][CH:50]=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:13][CH3:14])[C:5]([C:6]([NH:54][CH2:53][C:52]2[CH:55]=[CH:56][C:49]([Cl:48])=[CH:50][CH:51]=2)=[O:8])=[C:9]([CH2:11][CH3:12])[CH:10]=1
Reactant: CCc1cc(Br)cc(CC)c1C(=O)O
Reactant: NCc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(Br)cc(CC)c1C(=O)NCc1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 75 %

Procedure:
To a solution of 4-bromo-2,6-diethyl-benzoic acid (0.30 g, 1.20 mmol) in dichloromethane (3.6 ml) are added diisopropylethylamine (0.58 ml, 3.56 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.54 g, 1.42 mmol) at 0° C. and the mixture is stirred for 20 min followed by the addition of 4-chloro-benzyl amine (0.17 ml, 1.42 mmol). The resulting mixture is stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC) the reaction mixture is diluted with dichloromethane (20 ml) and washed with water (30 ml). The organic layer is dried over sodium sulfate and concentrated in vacuo. The resulting crude product is purified column chromatography (silica gel, 25% ethyl acetate/hexane) to obtain 4-bromo-N-[(4-chlorophenyl)-methyl]-2,6-diethyl-benzamide (0.34 g, 0.90 mmol, 75%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Cl[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Cc1ccc(CCl)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CN2CC[C@@H](NC(=O)OC(C)(C)C)C2)cc1
Temperature: 70 °C
Yield: 75.2 %

Procedure:
To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (4.0 g) and 1-(chloromethyl)-4-methylbenzene (3.17 g) in DMF(40 mL) was added N-ethyl-N-isopropyl-2-propanamine (5.55 g) at ambient temperature and the resulting mixture was heated at 70° C. for four hours. The mixture was allowed to cool to ambient temperature and extracted with ethyl acetate (100 mL). The organic phase was washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by a flash chromatography eluting with gradient solvent system (ethyl acetate-hexane from 1:4 v/v to 1:1 v/v) to give tert-butyl [(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]carbamate (4.69 g) as a pale yellow syrup.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[C:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:18])=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[CH:12]=1)#[N:6].N1C=CC=CC=1.O>C(OCC)C>[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:18][S:1](=[O:2])[O:15][CH2:14][C:13]([CH3:16])([CH3:17])[C:11]=2[CH:12]=1)#[N:6]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(CO)c1cc(C#N)ccc1O
Solvent: CCOCC
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)COS(=O)Oc2ccc(C#N)cc21
Reaction time: 3 h
Yield: 32.2 %

Procedure:
Thionyl chloride (4.2 g) in diethyl ether (10 ml) was added dropwise with stirring at 0°-5° C. to a solution of 2-(5-cyano-2-hydroxyphenyl)-2-methyl-1-propanol (5 g) prepared as in Example 26, and pyridine (5.5 g) in diethyl ether (80 ml). The mixture was stirred for 3 hours at 0°-20° C. Water was then added and the mixture was filtered. The ether solution was then washed with dilute hydrochloric acid, when with aqueous sodium bicarbonate and water (twice), then dried over magnesium sulphate and run down. The residue was recrystallised from ethanol, giving the title product (2.0 g) as white crystals, mp 87°-88° C.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH:12]([C:20](=[O:22])[CH3:21])C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][C:20](=[O:22])[CH3:21]
Reactant: CC(=O)C(C(=O)OC(C)(C)C)c1c([N+](=O)[O-])ccc(O)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(O)c1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To tert-butyl 2-(2-fluoro-3-hydroxy-6-nitrophenyl)-3-oxobutanoate in dichloromethane from above was added further dichloromethane (123 1) followed by trifluoroacetic acid (158 kg) whilst maintaining the temperature at 25° C. The reaction was stirred for 20 hours. The mixture was distilled, removing 283 kg of distillate. Toluene (176 1) was added and the mixture distilled, removing 208 kg of distillate. Further toluene (176 1) was added and the mixture distilled, removing 133 kg of distillate. To the residue was added 7.4% w/w aqueous sodium hydroxide (−705 kg) until the mixture was pH 10.5. The aqueous layer was separated and washed with toluene (250 1). The aqueous layer was diluted with water (250 1), heated to 40° C. and acetic acid (191.4 kg) added, reducing the pH from 10.1 to 3.8. The pH was then adjusted to 1 with 20% w/w sulphuric acid (˜315 kg). The mixture was cooled to 0° C. and seeded with 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one. Further water (600 kg) was added and the solid isolated by filtration. The filter cake was washed with water (300 1). The product was dried under vacuum (50 mbar) at 40° C. Yield: 56.0 kg, 74% based on 1,2,3-trifluoro-4-nitrobenzene.
Reaction SMILES: [CH3:1][C:2]1([CH2:11][OH:12])[CH2:6][CH2:5][C:4]2([CH2:10][CH2:9][CH2:8][O:7]2)[O:3]1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[CH3:1][C:2]1([CH2:11][O:12][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6][CH2:5][C:4]2([CH2:10][CH2:9][CH2:8][O:7]2)[O:3]1
Reactant: CC1(CO)CCC2(CCCO2)O1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(COCc2ccccc2)CCC2(CCCO2)O1
Yield: 54.1 %

Procedure:
A solution of 1.70 g of 2-methyl-1,6-dioxaspiro[4.4]nonane-2-methanol in 20 ml of dimethylformamide was treated sequentially with 0.60 g of 60% sodium hydride-mineral oil dispersion at 15°-25° C. for 1 hour and then with 1.71 g of benzyl bromide at 0°-25° C. for 1 hour. The resulting mixture was poured into 150 ml of water and extracted with diethyl ether. The ether extract was washed with water, dried and distilled to yield 1.40 g of the desired product as a colorless liquid, b.p. 105°-110° C. (0.3 torr.).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.[C:14]([NH:21][CH2:22][CH2:23][CH2:24]Br)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:17]([O:16][C:14](=[O:15])[NH:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCOc1ccc(C=O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of 4-hydroxy-naphthalene-1-carbaldehyde (15.2 g, 58.1 mmol) in DMF (50 mL) at r.t. was added N-Boc 3-bromo-propylamine (15.2 g, 63.9 mmol), followed by potassium carbonate (12 g, 87.2 mmol). The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and extracted by CH2Cl2. The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was recrystallized from EtOAc/hexane to afford [3-(4-formyl-naphthalen-1-yloxy)-propyl]-carbamic acid tert-butyl ester (13.8 g, 72%) as a light yellow solid.
Reaction SMILES: C(N(CCCC)CCCC)CCC.[CH:14]([OH:17])([CH3:16])[CH3:15].[O:18]=[C:19]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27][C:26]([C:35](O)=[O:36])=[C:25]2[N:20]1[CH2:21][CH2:22][C:23]1[CH:40]=[CH:39][S:38][C:24]=12.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)Cl>[O:18]=[C:19]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27][C:26]([C:35]([O:17][CH:14]([CH3:16])[CH3:15])=[O:36])=[C:25]2[N:20]1[CH2:21][CH2:22][C:23]1[CH:40]=[CH:39][S:38][C:24]=12
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2
Reactant: CC(C)O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)OC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2

Procedure:
7.1 ml of tri-n-butylamine and 6.1 ml of isopropanol were added to a suspension of 2.0 g of 4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2.3-a]quinolizine-10-carboxylic acid and 3.8 g of N-methyl-2-chloropyridinium iodide in 12.5 ml of methylene chloride, the reaction mixture was stirred under reflux for 24 hours, evaporated in vacuo and the residue was chromatographed on silica gel with toluene/ethyl acetate (9:1). After crystallization from methanol, there was obtained pure isopropyl 4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylate of m.p. 165.5°-166°.
Reaction SMILES: [CH:1]([N:4]([C:12](=[O:17])[CH2:13][C:14]([CH3:16])=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:18]N(C)C=O.[H-].[Na+].CI>O>[CH:1]([N:4]([C:12](=[O:17])[CH:13]([CH3:18])[C:14]([CH3:16])=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(=O)CC(=O)N(c1ccc(Cl)cc1)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC(=O)C(C)C(=O)N(c1ccc(Cl)cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A one liter reaction flask equipped with a power stirrer, condener, drying tube, thermometer and nitrogen inlet tube was charged with 48.5 g (0.19 mole) of N-isopropyl-4'-chloroacetoacetanilide and 145 ml of dry dimethylformamide. With efficient stirring in a nitrogen atmosphere, portionwise addition of 7.2 g of 57% sodium hydride in mineral oil (0.17 mole) was completed in one hour (excessive foaming). Methyl iodide (24.1 g, 0.17 mole) was added dropwise and the reaction mixture was stirred for two hours at ambient temperature. The mixture was poured into one liter of cold water and stirred. The organic material was extracted into toluene and the latter was water washed. Most of the toluene was removed on the rotary evaporator. Hexane was added which caused the mass to crystallize. There was obtained 36.4 g (80%) of white material, M.P. 77°-79°. N.M.R. (CDCl3) ∂0.9-1.4 (CH3, 9 protons), 2.0 (0=C--CH3), 2.9-3.2 (CH), 4.7-5.2 (CH, isopropyl), 6.9-7.5. (aromatic).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][NH:9][CH:8]([C:16]([OH:18])=[O:17])[CH2:7]2.[CH2:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>CO>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][NH:9][CH:8]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:7]2
Reactant: COc1cc2c(cc1OC)CC(C(=O)O)NC2
Reactant: OCc1ccccc1
Agent: Cl
Solvent: CO
Product: COc1cc2c(cc1OC)CC(C(=O)OCc1ccccc1)NC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid, hydrochloride (S-form) and 600 ml of benzyl alcohol was saturated with hydrogen chloride gas. The temperature rose to 45° C. The mixture was stirred at room temperature for three days. A relatively small amount of solid was filtered off and the filtrate was treated with ca 2-liters of ether to precipitate crude product; wt 37.5 g; yield, 83%. Purification was effected by treatment with excess saturated sodium bicarbonate, extraction of base into ethyl acetate and precipitation of hydrochloride salt with HCl gas. Recrystallization from methanol-ether gave pure product; mp 255°-260° C.; [α]D 23=-81.3° (1.0% MeOH); tlc (20% MeOH-CHCl3 /SiO2) one spot Rf 0.8.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:50]1[CH2:55][CH2:54][CH:53]([O:56][C:57]2[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=2)[C:60]#[N:61])[CH2:52][CH2:51]1>CN(C=O)C.O>[C:60]([C:59]1[CH:58]=[C:57]([CH:64]=[CH:63][CH:62]=1)[O:56][CH:53]1[CH2:54][CH2:55][N:50]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]2[N:18]=[N:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:22])[CH2:51][CH2:52]1)#[N:61]
Reactant: N#Cc1cccc(OC2CCNCC2)c1
Reactant: O=C(O)CNC(=O)c1cn(-c2ccccc2)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(OC2CCN(C(=O)CNC(=O)c3cn(-c4ccccc4)nn3)CC2)c1
Reaction time: 0.03 h
Yield: 32.6 %

Procedure:
DIPEA (167.9 mg, 1.3 mmol) was added to a stirred solution of [(1-phenyl-1H-[1,2,3]triazole-4-carbonyl)-amino]-acetic acid (80 mg, 0.32 mmol) in DMF (3 mL) followed by HOBt (48.2 mg, 0.35 mmol) and EDCI (124.5 mg, 0.65 mmol). After 2 minutes of stirring, 3-(piperidin-4-yloxy)-benzonitrile hydrochloride (prepared by the method used for the synthesis of Intermediate 15) (77.5 mg, 0.32 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was added and precipitate was collected. The solid was purified by column chromatography (using 70% ethyl acetate in hexane as eluent) to afford 45 mg (32.6% Yield) of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(3-cyano-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 431.18, 85.06%. 1H NMR (300 MHz, DMSO-d6): δ 9.35 (s, 1H), 8.5 (t, 1H), 8.0 (d, 2H), 7.7-7.6 (m, 2H), 7.58-7.45 (m, 3H), 7.45-7.32 (m, 2H), 4.75 (m, 1H), 4.2 (d, 2H), 4.0-3.9 (m, 1H), 3.8-3.7 (m, 1H), 2.1-1.9 (m, 2H), 1.75-1.5 (m, 2H).
Reaction SMILES: C#N.C(=O)C1C=CC=CC=1.[C:11]([CH:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:12]>ClCCl.[Ti]>[C:11]([C@H:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:12]
Reactant: N#CC(O)c1ccccc1
Agent: [Ti]
Agent: C#N
Solvent: O=Cc1ccccc1
Solvent: ClCCl
Product: N#C[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of L(+)-diethyl tartarate (412 mg) in absolute dichloromethane (20 ml), tetaraisopropyl titanate (568 mg) was dropwise added and stirred at room temperature for 30 minutes. After evaporating volatile components off in the same manner as in Example 1, to the residue, dichloromethane (20 ml) was added and stirred at room temperature to obtain a homogeneous solution. After cooling the resulting solution to 0° C., hydrogen cyanide (0.4 ml) and then benzaldehyde (212 mg) were added and stirred at room temperature for 15 hours. Thereafter, the reaction mixture was treated in the same manner as in Example 1 and analyzed by HPLC to reveal that α-cyanobenzyl alcohol was produced in the yield of 55% which contained the R(+) isomer with the enantiomer excess percentage of 77%.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][NH:16][C:15](=O)[C:14]=3[CH:21]=2)=[CH:6][CH:5]=1.CO.[ClH:26]>C1COCC1.B>[F:23][C:2]([F:1])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:21]=2)=[CH:6][CH:5]=1.[ClH:26]
Reactant: O=C1NCCOc2ccc(-c3ccc(OC(F)(F)F)cc3)cc21
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(-c2ccc3c(c2)CNCCO3)cc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a solution of 7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (660 mgs, 2.0 mmol) in THF (6 mL), 1.0M Borane in THF (6.0 mL, 6.0 mmol) was added and the mixture was heated at 70° C. After 16 h, the mixture was cooled to rt and Methanol (22 mL) and 6.0M HCl (22 mL) was added and stirred at rt for 2 h. The reaction mixture was then concentrated and the solids formed were filtered and washed with ether and dried to give 7-(4-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine as HCl salt. The above compound (100 mgs, 0.29 mmol), pyrimidine-2-carboxylic acid (47 mgs, 0.38 mmol), HATU (143 mgs, 0.38 mmol), in DMF (1 mL) was added NMM (0.1 mL, 0.86 mmol) and stirred at 60° C. for 30 min. The reaction mixture was then diluted with EtOAc and washed with NaHCO3, brine and dried (MgS(O)4). The mixture was the filtered, concentrated and chromatographed (SiO2, 50% EtOAc/DCM) to provide the title compound.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][C:7]([F:10])([F:9])[CH2:6][CH2:5][N:4]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])#[N:2]>[Ni].CO>[NH2:2][CH2:1][CH:3]1[CH2:8][C:7]([F:10])([F:9])[CH2:6][CH2:5][N:4]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(F)CC1C#N
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(F)(F)CC1CN

Procedure:
Raney nickel (0.36 mL, 5.40 mmol) was washed with MeOH (2×) and charged into a parr shaker. A solution of tert-butyl 2-cyano-4,4-difluoro-piperidine-1-carboxylate, 13h, (1.33 g, 5.40 mmol) in methanol (50 mL). The reaction mixture was subject to hydrogenation conditions overnight on the parr shaker (46PSI). The mixture was filtered through celite and washed thoroughly with CH2Cl2. All volatiles were removed at reduced pressure and the crude material was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:16]([O-])([O-])=O.[Cs+].[Cs+].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1CBr.CCOCC>CC(C)=O>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[CH:9][C:2]=1[O:1][CH2:16][C:24]1[CH:25]=[CH:26][O:22][CH:23]=1)#[N:5]
Reactant: BrCc1ccco1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Nc2nccs2)cc1O
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: N#Cc1ccc(Nc2nccs2)cc1OCc1ccoc1
Yield: 11 %

Procedure:
Following the general procedure for O-alkylation, Method B, a mixture of 2-hydroxy-4-(thiazol-2-ylamino)benzonitrile (70 mg, 0.32 mmol) and Cs2CO3 (0.32 mmol) in acetone (4.4 mL) was treated with a freshly prepeared solution of 2-furylbromomethane in ether (71 mg, 0.32 mmol) at RT. Reaction control by TLC showed full conversion after 2 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 65/35) in 11% yield (10 mg).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][CH:17]([CH:25]([OH:52])[CH:26]([NH:34][C:35](=[O:51])[C@H:36]([CH:48]([CH3:50])[CH3:49])[NH:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N=C=N.CO>C(Cl)(Cl)Cl>[C:1]([NH:8][C@H:9]([C:13]([NH:16][CH:17]([CH:25]([OH:52])[CH:26]([NH:34][C:35](=[O:51])[C@H:36]([CH:48]([CH3:50])[CH3:49])[NH:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15])[CH:10]([CH3:11])[CH3:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Agent: N=C=N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C

Procedure:
Boc-valine was coupled to the resultant compound of Example 69 using the carbodiimide coupling procedure of Example 55 to provide, after silica gel chromatography using 3% methanol in chloroform, the desired compound (82%, Rf 0.7, 10% methanol in chloroform) as a white solid, m.p. 184°-184° C. Mass spectrum: (M+H)+ =703.