Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][C:16](=[O:18])[NH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:21][O:22][CH2:23][CH2:24]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:20][C:2]([F:1])([F:19])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][C:16](=[O:18])[N:15]([CH2:24][CH2:23][O:22][CH3:21])[N:14]=2)=[CH:9][CH:8]=1
Reactant: COCCCl
Reactant: O=c1[nH]nc(-c2ccc(OCCCC(F)(F)F)cc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1nc(-c2ccc(OCCCC(F)(F)F)cc2)oc1=O
Temperature: 100 °C
Yield: 83.2 %

Procedure:
1.8 g of 5-[4-(4,4,4-trifluorobutoxy)phenyl]-1,3,4-oxadiazol-2(3H)-one, 0.77 g of 2-chloroethyl methyl ether and a solution of 2.15 g of potassium carbonate in 20 ml of dimethylformamide are introduced into a 25 ml three-necked flask. The mixture is heated to 100° C. for 1 h 45 min and is then cooled and poured into 100 ml of water. The precipitate formed is drained, washed with 3 times 50 ml of water and then dissolved in ethyl acetate. The solution is dried over sodium sulphate and filtered, and the solvent is evaporated off. 1.8 g of product are obtained, which product is recrystallized in 10 ml of 96 % ethanol. 1.5 g of product are finally obtained.
Reaction SMILES: [CH3:1][CH2:2][O:3][CH2:4][PH:5]([CH2:7][CH2:8][CH:9](C(OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:6].[N:20](OCC)=[O:21].[O-]CC.[Na+]>C(O)C>[CH2:2]([O:3][CH2:4][PH:5]([CH2:7][CH2:8][C:9](=[N:20][OH:21])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:6])[CH3:1]
Reactant: CCOC[PH](=O)CCC(C(=O)OCC)C(=O)OCC
Reactant: CCON=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC[PH](=O)CCC(=NO)C(=O)OCC
Temperature: -10 °C
Reaction time: 16 h

Procedure:
To a solution of the product of step (a) (32.2 g) in ethanol (90 ml) cooled to -10° C. was added ethyl nitrite (18 ml) followed by a solution of sodium ethoxide (from sodium (2.65 g) in ethanol (90 ml)), added dropwise over 90 min. The reaction mixture was then stirred at -10° C. for 16 hours evaporated in vacuo and the residue was dissolved in ethanol (150 ml) and acidified to pH 4.0 by the addition of conc. hydrochloric acid. The resulting solution was evaporated in vacuo and the residue treated with a mixture of ether and ethanol (10:1; 150 ml). Sodium chloride was filtered off and the filtrate evaporated in vacuo to give the oxime as a red oil (23.4 g). The n.m.r. spectrum supported the required structure.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][CH2:20][OH:21])=[CH:14][CH:13]=2)=[CH:6][C:5]=1[OH:22].[Li+].[OH-]>C1COCC1.O>[OH:22][C:5]1[CH:6]=[C:7]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]#[C:19][CH2:20][OH:21])=[CH:16][CH:17]=2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:23])=[O:2]
Reactant: COC(=O)c1ccc(NCc2ccc(C#CCO)cc2)cc1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(NCc2ccc(C#CCO)cc2)cc1O
Temperature: 90 °C
Yield: 17.3 %

Procedure:
2-Hydroxy-4-[4-(3-hydroxy-prop-1-ynyl)-benzylamino]-benzoic acid methyl ester (22 mg; 0.07 mmol) was dissolved in THF/H2O (1 mL/0.25 mL) and LiOH was added (17 mg; 0.7 mmol). The reaction mixture was heated to 90° C. for 1 hour. THF was removed by evaporation and EtOAc (3 mL) and H2O (0.5 mL) was added. The organic phase was isolated, dried (Na2SO4), filtered, evaporated to dryness and purified by flash column chromatography (SiO2-PE80-100° C./EtOAc/CH3COOH=1:1:1%) to yield 3.6 mg (17%) of pure product.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)[C:5](=[O:19])[NH:4][NH:3]1.[ClH:20].O1CCOCC1>C(Cl)Cl>[ClH:20].[NH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:2](=[O:1])[NH:3][NH:4][C:5]1=[O:19]
Reactant: CC(C)(C)OC(=O)NCCCCn1c(=O)[nH][nH]c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCCCn1c(=O)[nH][nH]c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To tert-butyl 4-(3,5-dioxo-1,2,4-triazolidin-4-yl)butylcarbamate (I-8b: 590 mg, 2.167 mmol) in CH2Cl2 (10.800 mL) was added HCl in dioxane (5.42 mL, 21.67 mmol) dropwise. The mixture was stirred at room temperature for 4 h, then concentrated and dried on pump, giving 4-(4-aminobutyl)-1,2,4-triazolidine-3,5-dione hydrochloride (I-14a: 461 mg, quantitative) as a beige solid. 1H NMR (400 MHz, dmso-d6) δ ppm 1.41-1.71 (m, 4 H) 2.68-2.87 (m, 2 H) 3.37 (t, J=6.44 Hz, 2 H) 7.86 (br. s., 2 H) 10.13 (s, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13](O)=[O:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CO>C1COCC1>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][CH2:13][OH:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CCC(=O)O)cc(OC)c1
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CCCO)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(3,5-dimethoxyphenyl)propanoic acid (2.00 g, 9.51 mmol) in THF (2.0 mL) was added dropwise to a stirred solution of borane-tetrahydrofuran complex (20.93 mL, 20.93 mmol) so as to maintain reaction temperature below 35° C. The mixture was allowed to stir overnight at room temperature. Methanol was added dropwise to the stirred mixture until visible reaction had ceased. An additional 20 mL of methanol was added and the reaction was stirred for 4 hours. The crude mixture was concentrated, filtered and purified by silica gel chromatography (1:1 heptane:EtOAc as eluant). Fractions containing product were combined and concentrated to give 3-(3,5-dimethoxy-phenyl)-propan-1-ol as an oil.
Reaction SMILES: [Br:1]Br.[C:3]1([NH:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O>>[Br:1][C:26]1[CH:27]=[CH:28][C:20]([NH:19][C:3]2[C:16]3[C:15](=[O:17])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8](=[O:18])[C:7]=3[CH:6]=[CH:5][CH:4]=2)=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23]
Reactant: O=C(O)c1ccccc1Nc1cccc2c1C(=O)c1ccccc1C2=O
Reactant: BrBr
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(Br)ccc1Nc1cccc2c1C(=O)c1ccccc1C2=O

Procedure:
which comprises first adding 1-1.5 molar equivalents of bromine to a reaction medium consisting essentially of 2-(1-anthraquinonylamino)-benzoic acid of formula II ##STR14## and 96 to 100% sulfuric acid at a temperature of 0°-25° C. to form a 5-bromo-2-(1-anthraquinonylamino)benzoic acid of the formula I ##STR15## in at least 92% absolute yield and then removing excess bromine and product hydrogen bromide and then raising the temperature to 50°-100° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:2]2[O:3][C:4]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccccc1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1oc(Sc2ccc(O)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A mixture of methyl 3-(2-chloro-4-phenyl-5-oxazolyl)propionate (500 mg), 4-hydroxythiophenol (475 mg), potassium carbonate (520 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 3-[2-(4-hydroxyphenylthio)-4-phenyl-5-oxazolyl]propionate as colorless crystals (637 mg, yield 95%). The crystals were recrystallized from toluene-hexane. melting point: 157–158° C.
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.CN(C)C=O>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([C:2]#[C:1][C:3]2([OH:11])[CH:8]3[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]3)[CH2:4]2)=[CH:18][CH:17]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: Brc1ccc(-c2ccccn2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: OC1(C#Cc2ccc(-c3ccccn3)cc2)CN2CCC1CC2
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
A mixture of 3-ethynyl-3-hydroxyquinuclidine (516 mg), 2-(4-bromophenyl)pyridine (400 mg), bis(triphenylphosphine)palladium (II) chloride (100 mg), copper(I) iodide (50 mg) triethylamine (15 ml) and dimethylformamide (10 ml) was stirred at 90° C. under an atmosphere of argon for 2.5 hours. The mixture was allowed to cool to room temperature, alumina (5 g) added and the solvents removed by evaporation. This pre-absorbed material was chromatographed on alumina (30 g) using a mixture of 10% ethanol in ethyl acetate as eluent. There was thus obtained a residue which was crystallised from ethanol/hexane to give 3-[2-(4-[2-pyridyl]phenyl)ethynyl]-3-hydroxyquinuclidine as a solid, m.p. 205°-206° C.; microanalysis, found: C, 77.7; H, 6.4; N, 9.0%; C20H2ON2O.0.25H2O requires: C, 77.8; H, 6.5; N, 9.08%; NMR (DMSO-d6): 1.3(1H, m), 1.6(1H, m), 1.8-2.0(3H, m), 2.7(4H, m), 2.85(1H, d), 3.1(1H, d), 5.6(1H, s), 7.4(1H, m), 7.5(2H, d), 7.85-8.05(2H, m), 8.1(1H, d) and 8.7(1H, d); m/Z 305 (M+H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[NH:6][CH2:7][C:8](=[O:14])[NH:9]2.Br[CH2:16][C:17]#[N:18]>C1COCC1.[Cl-].[Na+].O>[F:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[NH:6][CH2:7][C:8](=[O:14])[N:9]2[CH2:16][C:17]#[N:18]
Reactant: N#CCBr
Reactant: O=C1CNc2c(F)cccc2N1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CCN1C(=O)CNc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%, 84 mg, 2.1 mmol) was added to a solution of 5-fluoro-3,4-dihydro-1H-quinoxalin-2-one from Example B (316 mg, 1.9 mmol) in THF (2.0 ml) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 30 mins. Bromoacetonitrile (146 μl, 2.1 mmol) was added and the mixture was stirred for 18 h. Brine was added and the mixture evaporated in vacuo. The residue was portioned between EtOAc and water, separated and the organic phase was dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant 100% pet ether then EtOAc:pet. ether 20:80); yield 183 mg, 47%.
Reaction SMILES: C1(C[O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]([CH3:18])[C:13]4[CH2:19][CH:20]([CH2:22][OH:23])[CH2:21][C:12]=4[C:11]=3[CH:10]=2)C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:23][CH2:22][CH:20]1[CH2:19][C:13]2[N:14]([CH3:18])[C:15]3[CH:16]=[CH:17][C:9]([OH:8])=[CH:10][C:11]=3[C:12]=2[CH2:21]1
Reactant: Cn1c2c(c3cc(OCc4ccccc4)ccc31)CC(CO)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cn1c2c(c3cc(O)ccc31)CC(CO)C2
Yield: 68.2 %

Procedure:
To a suspension of 10% Pd/C (1.2 g) in 50 ml of ethanol was added a solution of 1,2,3,4-tetrahydro-7-phenylmethoxy-4-methylcyclopent[b]indole-2-methanol (8.4 g, 0.027 mole) in 200 ml of ethanol in a Parr hydrogenation bottle. After shaking at 50° C., under 50 psi hydrogen for two hours, the mixture was cooled, filtered, and then concentrated to a dark oil. The oil was eluted on a silica gel column with ethyl acetate/dichloromethane (1:2) via HPLC. The desired fractions were combined and then concentrated to a light yellow solid. The material was triturated with ether and dried to give 4.0 g (66%) of the product as an off-white solid, m.p. 153°-4° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[F:12].O.[NH2:15][NH2:16]>C(O)C>[F:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:3]([NH:15][NH2:16])=[O:2]
Reactant: COC(=O)c1ccc(OC)cc1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)NN)c(F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.6 %

Procedure:
To a solution of 5.04 g (27.2 mmol) of 2-fluoro-4-methoxybenzoic acid methyl ester in ethanol (50 mL) are added 36.9 mL (408.6 mmol) of hydrazine hydrate. The reaction is stirred at room temperature for 15 h. The mixture is concentrated under reduced pressure and the solid is washed with DCM/heptane (2:1) to give 4.26 g (23.0 mmol) of 2-fluoro-4-methoxybenzoic acid hydrazide. Yield: 85%, ES-MS: m/z [M+H] 185.
Reaction SMILES: [H-].[Na+].[CH:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([OH:19])[C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)=[O:4].Cl.[Cl:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Cl)[CH:33]=1>CS(C)=O.O>[Cl:30][CH2:31][C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=1)[CH2:38][O:19][C:8]1[C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[CH:11]=[C:12]2[C:7]=1[CH:6]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[N:5]([CH:3]=[O:4])[CH2:14][CH2:13]2
Reactant: ClCc1cccc(CCl)c1
Reactant: COc1cccc(CC2c3c(cc(OC)c(OC)c3O)CCN2C=O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cccc(CC2c3c(cc(OC)c(OC)c3OCc3cccc(CCl)c3)CCN2C=O)c1
Reaction time: 0.17 h

Procedure:
To a suspension of sodium hydride (80 mg, 1.96 mmole, 60%) in dimethyl sulfoxide (1 ml) was added a solution of intermediate 2 obtained in Referential Example 2 (350 mg, 0.98 mmole) at room temperature under nitrogen, and the reaction mixture was stirred for 10 minutes. The resulting mixture was added dropwise to a solution of α,α'-dichloro-m-xylene (172 mg, 0.98 mmole) in dimethyl sulfoxide (1 ml) at room temperature, and stirred for 2 hours. The reaction mixture was chilled in ice, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel/ethyl acetate) to give the desired compound (387 mg) as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:16][C:17]([OH:19])=O)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=1)#[N:2].[NH2:20][C:21]1[N:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[C:33]([N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:17](=[O:19])[CH2:16][C:5]3[CH:6]=[CH:7][C:8]([C:9]4[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=4)=[C:3]([C:1]#[N:2])[CH:4]=3)=[N:26][CH:25]=2)[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: N#Cc1cc(CC(=O)O)ccc1-c1ccnc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(F)c4)c(C#N)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-cyano-4-(2-fluoropyridin-4-yl)phenyl)acetic acid 206-6 (50 mg, 0.20 mmol) was dissolved in DMF (2 mL). 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone (52 mg, 0.23 mmol) and DIEA (170 uL, 0.98 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (111 mg, 0.29 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(3-cyano-4-(2-fluoropyridin-4-yl)phenyl)acetamide 211. MS m/z 459.2 (M+1)); 1H NMR 400 MHz (DMSO-d6) δ 10.64 (s, 1H), 8.41 (d, 1H), 8.05 (d, 1H), 7.98 (d, 1H), 7.91 (d, 1H), 7.81 (dd, 1H), 7.71 (d, 1H), 7.62 (dt, 1H), 7.49 (s, 1H), 7.42 (dd, 1H), 3.85 (s, 2H), 3.59-3.54 (m, 4H), 3.15 (t, 2H), 3.08 (t, 2H), 2.04 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([C:20]#[N:21])=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:11]=2[CH2:20][NH2:21])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5′-Isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile (996.2 mg, 3.12 mmol) was dissolved in Et2O (33 mL) and cooled to 0° C. LAH (12.49 mL of a 1 M solution in Et2O, 12.49 mmol) was added dropwise by syringe. After stirring at 0° C. for 10 minutes, the reaction was warmed to room temperature and stirred at room temperature for 6 hours. The reaction was then quenched by slow dropwise addition of 1.5 mL of H2O (vigorous evolution of gas), followed by 1.5 mL of 30% NaOH, followed by 3.0 mL of H2O. The resulting gelatinous precipitate was washed with 5×20 mL of CH2Cl2; the organic washes were dried over Na2SO4, filtered and concentrated. Purification of the residue by flash chromatography with 2% MeOH/CH2Cl2 containing 0.1% Et3N afforded 1-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanamine. Rf=0.30 (10% MeOH/CH2Cl2). LCMS=324.3 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.77 (s, 1H), 7.55 (d, J=6.8 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.25 (dd, J=8.3, 2.1 Hz, 1H), 7.00 (d, J=2.1 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 3.66-3.74 (m, 5H), 2.91 (m, 1H), 1.26 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:22])[C:13]([N:15]([CH3:21])[N:16]=CC(C)C)=[O:14])[CH3:2].NO>CO>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:22])[C:13]([N:15]([CH3:21])[NH2:16])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=CC(C)C
Agent: NO
Solvent: CO
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 76.7 %

Procedure:
To a 25 mL volume three-necked flask, 1.0 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(2-methyl-1-propylidene)hydrazine ((40-b)-(15)-4), 3.8 ml of methanol and 330 mg of 50 wt % hydroxylamine aqueous solution were added, and the mixture was stirred at 50° C. for 2.5 hours and then 60° C. for 14.5 hours. The reaction mixture was concentrated under reduced pressure and water and t-butyl methyl ether were added to the residue. The precipitated crystals were collected by filtration, washed with hexane and dried to give 0.63 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39).
Reaction SMILES: [N:1]1([C:7]2([C:11]#[N:12])[CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[N:1]1([C:7]2([CH:11]([NH2:12])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#CC1(N2CCOCC2)CCC1
Reactant: [Li]c1ccccc1
Product: NC(c1ccccc1)C1(N2CCOCC2)CCC1

Procedure:
The title compound, light yellow liquid, MS: m/e=247.3 [(M+H)+], was prepared in accordance with the general method of intermediate B from 1-morpholin-4-yl-cyclobutanecarbonitrile (intermediate T) and phenyllithium.
Reaction SMILES: [CH:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:18][O:19][CH2:20][CH2:21][O:22][CH2:23]Cl>C(Cl)Cl>[CH:1]([C:4]1[N:5]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: COCCOCCl
Reactant: CC(C)c1ncc[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCn1ccnc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
A mixture of 2-isopropylimidazole (3.0 g, 27.2 mmol) and DIEA (5.28 g, 40.9 mmol) in DCM (75 mL) was treated drop-wise with methoxyethoxymethyl chloride [MEM-Cl] (4.24 g, 34.0 mmol) and stirred at RT for 16 h. The mixture was washed with water, then brine, dried over Na2SO4 and concentrated to dryness to afford 2-isopropyl-1-((2-methoxyethoxy)methyl)-1H-imidazole (3.91 g, 72%). 1H NMR (400 MHz, DMSO-d6): δ 7.11 (d, J=1.3 Hz, 1H), 6.74 (d, J=1.3 Hz, 1H), 5.30 (s, 2H), 3.47-3.46 (m, 2H), 3.38-3.37 (m, 2H), 3.19 (s, 3H), 3.08-3.07 (m, 1H), 1.18 (d, J=6.8 Hz, 6H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([O:19][C:20]2[CH:42]=[CH:41][C:23]3[C:24]4[N:28]([CH2:29][CH2:30][O:31][C:22]=3[CH:21]=2)[CH:27]=[C:26]([C:32]2[N:33]([CH:38]([CH3:40])[CH3:39])[N:34]=[C:35]([CH3:37])[N:36]=2)[N:25]=4)[CH3:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH3:43][C:44]([CH3:46])=O>CO.[Pd]>[CH:38]([N:33]1[C:32]([C:26]2[N:25]=[C:24]3[C:23]4[CH:41]=[CH:42][C:20]([O:19][CH:17]([CH:14]5[CH2:15][CH2:16][N:11]([CH:44]([CH3:46])[CH3:43])[CH2:12][CH2:13]5)[CH3:18])=[CH:21][C:22]=4[O:31][CH2:30][CH2:29][N:28]3[CH:27]=2)=[N:36][C:35]([CH3:37])=[N:34]1)([CH3:39])[CH3:40]
Reactant: CC(C)=O
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)C4CCN(C(=O)OCc5ccccc5)CC4)cc2OCC3)n(C(C)C)n1
Agent: [Pd]
Solvent: CO
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)C4CCN(C(C)C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 42 %

Procedure:
To a solution of 4-{1-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]ethyl}piperidine-1-carboxylic acid benzyl ester from Example 11 (60 mg, 0.10 mmol) in acetone (2 mL) and MeOH (0.5 mL) was added 10% Pd/C (50 mg). The reaction mixture was stirred at RT under a hydrogen atmosphere for 48 h. The suspension was then filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% 2M NH3/MeOH in DCM) affording 216 (20 mg, 42%). LCMS: RT 3.03 min [M+H]+ 379.2. 1H NMR (CDCl3, 400 MHz): δ 8.39 (1H, d, J=8.96 Hz), 7.56 (1H, s), 6.70 (1H, dd, J=8.98, 2.55 Hz), 6.52 (1H, d, J=2.51 Hz), 5.99-5.84 (1H, m), 4.51-4.34 (4H, m), 4.19 (1H, m), 3.00-2.78 (2H, m), 2.77-2.63 (1H, m), 2.41 (3H, s), 2.18-2.05 (3H, m), 1.95-1.85 (1H, m), 1.77-1.67 (1H, m), 1.56 (6H, d, J=8.76 Hz), 1.52-1.32 (2H, m), 1.28 (3H, d, J=8.24 Hz), 1.05 (6H, d, J=6.54 Hz)
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]=3[CH:8]=2)=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=[CH:3]1.[F:26]C1C=CC(C2N=CN(C)C=2C2SC3N=CN=C(SC)C=3C=2)=CC=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[C:6]=2[C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]=3[CH:8]=2)=[CH:21][CH:22]=1
Reactant: CSc1ncnc2sc(-c3c(-c4ccc(F)cc4)ncn3C)cc12
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Product: Cn1cnc(-c2ccc(F)cc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 17 but using 6-[4-(4-fluorophenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylthio)thieno[2,3-d]pyrimidine (Intermediate 49) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (example 7). Yellow solid (80 mg, 73%);