Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]2[CH:19]=[C:18]([C:20]([C:27]3[CH:28]=[N:29][C:30]([S:33][CH3:34])=[CH:31][CH:32]=3)=[CH:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:17]([S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:14]2=[N:15][CH:16]=1)=[O:10]>O.CO>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]2[CH:19]=[C:18]([C:20]([C:27]3[CH:28]=[N:29][C:30]([S:33]([CH3:34])=[O:2])=[CH:31][CH:32]=3)=[CH:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:17]([S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:14]2=[N:15][CH:16]=1)=[O:10]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(SC)nc1)n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)=O)nc1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 97.8 %

Procedure:
To a mixture of sodium metaperiodate (360 mg, 1.69 mmol) in water (10 ml) was added a solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methylsulfanyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (300 mg, 0.56 mmol) in methanol (40 ml). The reaction mixture was stirred at 25° C. for 60 h. The suspension was filtered. The filtrate was concentrated and extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with water (2×20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfinyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (301 mg, 97%) as a solid which was used in the next step without further purification: LC/MS m/e calcd for C28H27N3O5S2 [M+H]+ 550.67, observed 549.9.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19])=[O:9].[C:20](=O)([O:23]C)[O:21][CH3:22].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OC)(C)(C)C>[CH3:19][O:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[C:8](=[O:9])[CH2:7][C:20]([O:21][CH3:22])=[O:23]
Reactant: COC(=O)OC
Reactant: COc1ccc(C(C)=O)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: COC(C)(C)C
Product: COC(=O)CC(=O)c1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a three-necked round-bottomed flask equipped with a mechanical stirrer under N2 was added potassium tert-butoxide (1M in THF, 108.77 mL, 108.77 mmol), followed by a solution of 2,4-dimethoxyacetophenone (10.00 g, 54.38 mmol) and dimethyl carbonate (13.93 mL, 163.15 mmol) in methyl tert-butyl ether (50 mL) dropwise via an addition funnel over 1.5 hours. During addition, reaction turned from a initial cloudy yellow mixture to a thick red-orange slurry. Reaction mixture was stirred at room temperature overnight. Aqueous citric acid solution (0.5 N, 110.95 mL, 54.39 mmol) was added via addition funnel to quench the reaction. Exotherm was observed during quenching and solids dissolved to give an orange mixture. The layers were separated and the aqueous layer was extracted with methyl tert-butyl ether (2×25 mL). The combined organic extracts were concentrated to low volume. Heptane (50 mL) was added and brown solids precipitated. The resulting slurry was stirred under N2 overnight at room temperature. Solids were filtered and dried under N2 to give the title compound (11.05 g, 85% yield) as a beige colored powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([N:16]2[C@@H:17]3[C@@H:22]([C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[CH2:19][CH2:18]3)[CH2:13][CH2:14][CH2:15]2)=[O:7])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: COc1ccc(C(=O)O)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)cc1N
Yield: 63 %

Procedure:
The title compound is prepared from 3-amino-4-methoxy-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 63% of theory; LC (method 4): tR=1.79 min; Mass spectrum (ESI+): m/z=337 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: [BH4-]
Agent: [Na+]
Product: OCc1cccc(Cl)c1Cl
Reaction time: 1.5 h

Procedure:
To a solution of 2,3-dichlorobenzaldehyde (Aldrich, 50 gms) in alcohol (800 mL) at room temperature was added NaBH4 (8.54 gms) and the resulting mixture stirred for 1.5 hours. The reaction was quenched with water and the solvent evaporated in vacuo before partitioning the residue between CHCl3 and saturated NaHCO3 solution. The organic phase was washed with brine, dried over MgSO4, filtered and the solvent evaporated in vacuo to leave a
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=1.F[B-](F)(F)F.[CH3:27][O+](C)C.[OH-].[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:27])[CH:6]=[C:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=1
Reactant: C[O+](C)C
Reactant: CCOc1cccc(-c2cc(=O)[nH]c3ccc(Br)cc23)c1
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: CCOc1cccc(-c2cc(OC)nc3ccc(Br)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
To a suspension of 6-bromo-4-(3-ethoxy-phenyl)-1H-quinolin-2-one (7.4 g, 21.5 mmol) in 60 ml dichloroethane was added trimethyloxonium tetrafluoroborate (BF4OMe3, 3.66 g, 24.7 mmol). The resulting mixture was stirred at ambient temperature overnight. After cooling to 0° C., was added 60 ml of 10% aqueous NaOH dropwise. The reaction mixture was stirred for another six hours at ambient temperature. It was then partitioned between dichloromethane and water. The organic layer was washed brine, dried over MgSO4, filtered and concentrated under vacuum to give an off-white solid. The solid was chromatographed on flash silica gel eluting with dichoromethane to yield the titled compound of 23A as a white solid (4.48 g, 58% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][C:29]([F:32])([F:31])[F:30]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:28][C:29]([F:32])([F:31])[F:30])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: FC(F)(F)CI
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cc(OCC(F)(F)F)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 150 °C
Yield: 27.4 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (25 mg, 0.095 mmol), potassium carbonate (53 mg, 0.38 mmol) and 2-iodo-1,1,1-trifluoroethane (28 μL, 0.28 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 150° C. for 5 minutes hour. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography of the residue using hexanes/ethyl acetate/dichlrormethane (3.5:0.5:4) afforded 9 mg (27%) of 3-(2-pyridyl)-5-(3-cyano-5-(2,2,2-trifluoroethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.87 (d, 1H), 8.27 (s, 1H), 8.24 (d, 1H), 8.08 (s, 1H), 7.92 (t, 1H), 7.50 (m, 2H), 4.53 (q, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH:6]=O)[CH3:5].[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2C=CN[CH:16]=2)[CH:14]=1.CI>O>[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:6][N:4]([CH3:5])[CH:3]=2)[CH:14]=1
Reactant: Brc1cncc(-c2cc[nH]c2)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1ccc(-c2cncc(Br)c2)c1

Procedure:
Sodium hydride (60% in oil) (6 mg) was added to a DMF (1 ml) solution containing 3-bromo-5-(1H-pyrrol-3-yl)pyridine (28 mg), followed by stirring. Methyl iodide (9 μl) was added, followed by stirring at room temperature for 3 hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=30:1 to 3:1), and a white solid of 3-bromo-5-(1-methyl-1H-pyrrol-3-yl)pyridine (18 mg) was thus obtained.
Reaction SMILES: C([NH:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[O:14])=[CH:9][CH:8]=1)([CH3:6])[CH3:5])=O.O.Cl>C(O)(=O)C>[NH2:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])=[O:14])=[CH:9][CH:8]=1)([CH3:5])[CH3:6]
Reactant: CC(C)(NC=O)c1ccc(C(=O)C(=O)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(N)c1ccc(C(=O)C(=O)c2ccccc2)cc1

Procedure:
4(2-formamidoprop-2-yl)-benzil, prepared as described in Step 6 (6.17 g) was dissolved in 100 ml of glacial acetic acid, 84 ml of water and 6 ml of concentrated HCl. The mixture was stirred at reflux for 3 hours and then the solvent removed under vacuum at 60 C. The residue was converted to the free based form, extracted with organic solvent, washed with water, dried and concentrated to provide the title compound as an oil.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:13])[C@H:8]([CH:10]([CH3:12])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][NH:9][C@@H:8]([CH:10]([CH3:11])[CH3:12])[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:13])[CH3:27]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CN[C@H](C(=O)OC(C)(C)C)C(C)C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of (L)-valine tert-butyl ester hydrochloride (4.94 g, 23.6 mmol) in N,N-dimethylformamide (55 mL) was added triethylamine (3.28 mL, 1 equivalent), and the mixture was stirred for 1 h. The reaction was filtered to remove solid salts, and the filtrate was treated with triethylamine (9.85 mL, 3 equivalents) and ethyl bromoacetate (7.84 mL, 3 equivalents), and the reaction was stirred for 3 h at 25° C. The reaction was partitioned between ethyl acetate and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated to give 4.48 g (78%) of the product which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13].C(=O)([O-])[O-].[K+].[K+].Cl[C:21]1[C:26]([F:27])=[CH:25][C:24]([C:28]#[N:29])=[C:23]([Cl:30])[N:22]=1>CS(C)=O.O>[F:27][C:26]1[C:21]([N:4]2[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:9])([F:11])[F:10])[N:2]([CH3:1])[C:3]2=[O:13])=[N:22][C:23]([Cl:30])=[C:24]([C:28]#[N:29])[CH:25]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)[nH]c1=O
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2nc(Cl)c(C#N)cc2F)c1=O
Temperature: 130 °C

Procedure:
A mixture of 0.776 g 1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidin-dione, 0.760 g potassium carbonate and 0.768 g 2,6-dichloro-3-fluoro-5-cyanopyridin in 40 ml dimethylsulfoxide is stirred under nitrogen at 130° C. until conversion is complete. Then the reaction mixture is cooled down and diluted with ice and water. The pH of the mixture is adjusted to neutral and the mixture is extracted several times with ethyl acetate. The organic layers are washed with water, dried, evaporated and the residue is purified by silicagel chromatography (hexane/ethyl acetate 7/3) to yield the title compound as a solid of m.p. 146-148° C.
Reaction SMILES: CON(C)[C:4](=[O:16])[CH2:5][C@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1>CCOCC>[O:16]=[CH:4][CH2:5][C@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7]
Reactant: CON(C)C(=O)C[C@@H](C)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H](CC=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 83.2 %

Procedure:
To a solution of (R)-tert-butyl 4-(methoxy(methyl)amino)-4-oxobutan-2-ylcarbamate (2.48 g, 10.1 mmol) in Et2O (25 mL) cooled to −5° C. was added dropwise a 2.0 M solution of LAH in THF (6.28 mL, 12.6 mmol). After the addition, the resulting slightly milky solution was stirred at 0° C. for 1.5 hr. The reaction mixture was quenched with 1 M aqueous KHSO4 (20 mL) and diluted with water (30 mL). The resulting solution with white milky precipitate was extracted with Et2O (3×). The combined Et2O extracts were washed with 0.5 M aqueous KHSO4 (2×20 mL), saturated aqueous NaHCO3, water, and saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The residue was dried under vacuum to give (R)-tert-butyl 4-oxobutan-2-ylcarbamate (1.57 g, 8.40 mmol, 84% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 9.76 (s, 1H), 4.64 (s, 1H), 4.20-4.08 (m, 1H), 2.69-2.52 (m, 2H), 1.43 (s, 9H), 1.24 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][N:39]([CH3:45])[CH:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>>[CH3:38][N:39]([CH3:45])[CH:40]1[CH2:44][CH2:43][N:42]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:41]1
Reactant: CN(C)C1CCNC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CN(C)C1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)C1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and dimethyl-pyrrolidin-3-yl-amine according to conditions described in general procedure C. Mp: 106-108° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.07-2.17 (m, 10H), 2.45-3.15 (m, 3 H), 3.27 (t, J=4.4 Hz, 4 H), 3.77 (t, J=5.1 Hz, 4H), 6.15 (m, 1 H), 7.05 (d, J=12.1 Hz, 1 H), 7.27 (d, J=9.5 Hz, 1 H), 7.42-7.62 (m, 5 H), 7.85-7.87 (m, 1 H), 8.00 (d, J=7.7 Hz, 1 H), 8.23 (d, J=5.5 Hz, 1 H), 10.47 (s, 1 H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8](=[O:12])[CH2:9][NH:10][CH3:11])=[O:6].[N:13]([O-])=[O:14].[Na+].CO>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:13]=[O:14])[C:5]([NH:7][C:8](=[O:12])[CH2:9][NH:10][CH3:11])=[O:6]
Reactant: CNCC(=O)NC(=O)NCCCl
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CO
Product: CNCC(=O)NC(=O)N(CCCl)N=O
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
N-[N'-(2-Chloroethyl)carbamoyl]sarcosine amide (100 mg, 0.516 mmol.) was dissolved in a 99% formic acid (0.7 ml) under ice-cooling, to which sodium nitrite (53.4 mg, 1.5 moles per mole of the starting compound) was slowly added and the mixture was held under stirring for further 30 minutes to complete the reaction. Then, Amberlite IR-120 (H+ form), a strongly acidic cation exchange resin made and sold by Rohm & Haas Company, (1 ml) and methanol (1 ml) were added to the resulting reaction solution and the mixture was stirred for 10 minutes. After the resin was removed by filtration, the reaction solution was concentrated in vacuo to leave an oily residue. The residue was purified by column chromatography on silica gel (Wako-gel C-300) with a developer system of toluene-ethanol (3:1 by volume), where the eluate was collected in fractions and the fractions containing the main product were collected together and concentrated in vacuo to afford N-[N'-(2-chloroethyl)-N'-nitrosocarbamoyl]sarcosine amide (62 mg) as a white crystalline residue.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH2:8][N:7]([C:14](=[O:16])[CH3:15])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1>>[C:14]([N:7]1[CH2:8][CH2:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:19]3[N:24]=[C:23]([NH:25][C:26]4[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=4[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=3)=[CH:17][C:6]1=2)(=[O:16])[CH3:15]
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)N1CCCC(C)(C)c2ccc(N)cc21
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)N(C(C)=O)CCCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 1-(8-Amino-5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide to yield a yellow solid (43%). LCMS: m/z=511.47 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.89 (bs, 1H), 8.08 (s, 1H), 7.60 (d, 1H, J=1.8 Hz), 7.39 (m, 2H), 7.25 (m, 3H), 6.91 (d, 1H, J=8.3 Hz), 6.85 (bs, 1H), 4.62 (m, 1H), 2.97 (d, 3H, J=4.8 Hz), 2.41 (m, 1H), 2.15 (m, 1H), 1.72 (s, 3H), 1.65 (m, 2H), 1.47 (m, 1H), 1.34 (s, 3H), 1.13 (s, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].S(C1C=CC(C)=CC=1)(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O.S(=O)(=O)(O)O>O>[CH2:1]([N:3]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCNc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCN(CC(F)(F)F)c1ccccc1

Procedure:
484 parts of N-ethylaniline, 106 parts of sodium carbonate and 254 parts of 2,2,2-trifluoro-ethyl tosylate are heated for 48 hours at 190°-200° C. The cooled reaction mixture is diluted with 1000 parts by volume of distilled water and acidified with sulphuric acid until it is distinctly acid to Congo red paper. The N-ethyl-N-(2,2,2-trifluoro-ethyl)-aniline which is formed is then steam distilled. The lower organic layer of the distillate is separated and subjected to distillation under reduced pressure. 182 parts of N-ethyl-N-(2,2,2-trifluoro-ethyl)-aniline are thus obtained, distilling at 53°-54° C. under 1 mm of mercury, of which the elementary analysis is as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C:11]1[N:12]=[N:13][CH:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:24]([F:35])([F:34])[F:23])[CH:3]=2)[N:10]=1
Reactant: Fc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)c(F)c1
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: Fc1ccc(-c2nncc(-c3ccc(F)c(-c4ccccc4C(F)(F)F)c3)n2)c(F)c1

Procedure:
5-(3-Bromo-4-fluorophenyl)-3-(2,4-difluorophenyl)-[1,2,4]triazine was coupled to 2-trifluoromethylphenylboronic acid by the method of Example 12 to give 3-(2,4-difluorophenyl)-5-(2-fluoro-2′-trifluoromethylbiphenyl-5-yl)-[1,2,4]triazine as a pale yellow solid: δH (400 MHz, CDCl3) 6.98-7.09 (2H, m), 7.35-7.42 (2H, m), 7.65 (2H, dd, J 7.4, 17.6 Hz), 7.84 (1H, d, J 7.8 Hz), 8.21 (1H, dd, J 2.2, 6.8 Hz), 8.28-8.36 (2H, m), 9.61 (1H, s); m/z (ES+) 432.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C@@H:13]1[CH2:15][O:14]1.[F:16][C:17]([F:23])([F:22])[C:18]([OH:21])([CH3:20])[CH3:19].B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[CH:13]([O:21][C:18]([CH3:20])([CH3:19])[C:17]([F:23])([F:22])[F:16])[CH2:15][OH:14]
Reactant: Cc1cc2ccccc2c(Cl)c1[C@@H]1CO1
Reactant: CC(C)(O)C(F)(F)F
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc2ccccc2c(Cl)c1C(CO)OC(C)(C)C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (R)-2-(1-chloro-3-methylnaphthalen-2-yl)oxirane (340 mg, 1.56 mmol) and 2-trifluoromethyl-2-propanol (4.3 mL, 38.97 mmol) in CH2Cl2 (4.3 mL), boron trifluoride diethyl etherate (1.9 mL, 15.60 mmol) was added at 0° C. The reaction mixture was stirred for 16 h at 0° C. and allowed to warm to room temperature overnight. The mixture was quenched with saturated aqueous NaHCO3, and then diluted with CH2Cl2. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give 2-(1-chloro-3-methylnaphthalen-2-yl)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)ethanol. 1H-NMR: 400 MHz, (CDCl3) δ 8.27 (d, J=8.4 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.57-7.49 (m, 3H), 5.90 (dd, J=9.6, 4.4 Hz, 1H), 3.98 (t, J=11.2 Hz, 1H), 3.66 (dd, J=12.0, 4.0 Hz, 1H), 2.69 (s, 3H), 2.18 (br s, 1H), 1.45 (s, 3H), 1.19 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C@@H:7]([C:36](=[O:55])[N:37]([CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[CH:45][CH:44]=2)[CH2:38][CH2:39][CH3:40])[C@@H:8]([NH:29][C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[C@H:9]([O:11][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:46]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:45]=[CH:44][C:43]([CH2:42][CH2:41][N:37]([CH2:38][CH2:39][CH3:40])[C:36]([C@@H:7]2[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][C@@H:9]([OH:11])[C@H:8]2[NH:29][C:30](=[O:35])[C:31]([F:32])([F:33])[F:34])=[O:55])=[CH:48][CH:47]=1
Reactant: CCCN(CCc1ccc(-c2ccccc2)cc1)C(=O)[C@@H]1OC(C(=O)OC)=C[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H]1NC(=O)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCN(CCc1ccc(-c2ccccc2)cc1)C(=O)[C@@H]1OC(C(=O)O)=C[C@@H](O)[C@H]1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
To a solution of (4R,5R,6R)-6-[(2-biphenyl-4-yl-ethyl)propylcarbamoyl]-4-(tertbutyldiphenylsilanyloxy)-5-(2,2,2-trifluoroacetylamino)-5,6-dihydro-4-H-pyran-2-carboxylic acid methyl ester (1.03 g) in tetrahydrofuran (5.5 ml) was added a solution of tetra-n-butyl ammonium fluoride in tetrahydrofuran (1.45 ml of a 1M solution). The orange solution was stirred at room temperature for 4 hours before the solvent was removed in vacuo to give an orange gum. This was dissolved in ethyl acetate (50 ml) and washed with water (2×40ml). The organic phase was dried over anhydrous magnesium sulphate and the solvent was removed in vacuo and the residue was chromatographed over silica (Merck 7734, 65 g) and dichlormethane/methanol (95:5 v/v) as the eluant. The required fractions were combined and the solvent removed in vacuo to give the title compound as a white foam (0.64 g). 1H NMR (250 MHz, CDCl3 rotamers) 7.63-7.24 (9H, m), 6.96+6.92 (1H, 2×d, J=8 Hz), 6.13+6.06 (1H, 2×d, J=4 Hz), 5.16+4.86 (1H, 2×d, J=7, 5 Hz), 4.72+4.58 (1H, 2×m), 4.3 (1H, m), 3.82+3.79 (3H, 2×s), 3.78-3.23 (4H, m), 3.02+2.87 (2H, 2×t, J=8 Hz), 2.90+2.78 (2H, 2×broad s), 1.82-1.50(2H, m), 0.96+0.92 (3H, 2×t, J=8 Hz).