Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.BrC1C=CC(N[C:18]2[O:19][C:20]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:21]=3[N:22]=2)=CC=1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18]2[O:19][C:20]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:21]=3[N:22]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Cc1cc(C)c2oc(Nc3ccc(Br)cc3)nc2c1
Reactant: Nc1ccc(Br)cc1F
Product: Cc1cc(C)c2oc(Nc3ccc(Br)cc3F)nc2c1

Procedure:
N2-(4-Bromo-2-fluorophenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine was prepared from 4-bromo-2-fluoroaniline (2.000 g, 10.53 mmol) in a manner similar to that used for the preparation of N2-(4-bromophenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine. The compound was formed as a pink solid (1.916 g, 54%). RP-HPLC Rt 17.96 min, 95% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 337 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)[CH2:2][CH:3]=[CH2:4].Br[C:15]1[C:28]2[C:19](=[C:20]3[C:25](=[CH:26][CH:27]=2)[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:23][CH:22]=[N:21]3)[N:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].CO>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[C:28]3[C:19](=[C:20]4[C:25](=[CH:26][CH:27]=3)[C:24]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:23][CH:22]=[N:21]4)[N:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: Brc1ccnc2c1ccc1c(-c3ccccc3)ccnc12
Reactant: C=CCCc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: C=CCCc1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Temperature: 100 °C

Procedure:
4-(3-Butenyl)phenylboronic acid is made by the method of Nakashima and Irie (Nakashima, H.; Irie, M. Macromol. Chem. Phys. 200, 683-692). 4-(3-butenyl)phenylboronic acid (0.44 g) and a solution of Pd(Ph3)4 (58 mg) in 5 mL of degassed toluene is placed in a 50 mL Schlenk tube. The mixture is purged with nitrogen, after which a solution of 4-bromo-7-phenyl-1,10-phenanthroline (0.670 g) and Na2CO3 (428 mg, 4 mmol) in 5 mL of degassed 4:1H2O/CH3OH is added. The mixture is heated under nitrogen at 100° C. with rapid stirring until TLC monitoring shows the reaction to be complete (ca 24 hrs). The reaction mixture is then added to a separatory funnel and washed with ether (3×50 mL). The combined organic fractions are dried over MgSO4 and concentrated by roto-evaporation. The desired product is purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:18][OH:19])([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH3:1][O:2][C:3]1[C:4]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])([CH:18]=[O:19])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC1=CCc2ccccc2C1(CO)CCC(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC1=CCc2ccccc2C1(C=O)CCC(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.9 %

Procedure:
To a solution of Example 179A (0.6 g, 2.3 mmol) in dichloromethane (15 mL) was added Dess-Martin periodanate (1.5 g, 3.5 mmol). The solution was stirred at room temperature for 18 h and then concentrated in vacuo. Column chromatography on silica (10% -20%-30% dichloromethane/hexane) afforded product as a light yellow oil (0.32 g, 53%). 1H NMR (300 MHz, CDCl3) δ ppm 0.63 (m, 1H), 0.76 (dd, J=12.13, 6.62 Hz, 6H), 0.92 (m, 1H), 1.41 (m, 1H), 1.93 (m, 1H), 2.18 (m, 1H), 3.59 (m, 5H), 5.19 (t, J=3.68 Hz, 1H), 7.01 (m, 1H), 7.21 (m, 3H), 9.40 (s, 1H).
Reaction SMILES: [N:1]1[N:2]2[CH:9]=[C:8]([CH2:10][CH2:11][OH:12])[N:7]=[C:3]2[N:4]=[CH:5][CH:6]=1.O[C:14]1[CH:36]=[CH:35][C:17]2[CH2:18][CH:19]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:20](=[O:28])[N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:22][C:16]=2[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[N:1]1[N:2]2[CH:9]=[C:8]([CH2:10][CH2:11][O:12][C:14]3[CH:36]=[CH:35][C:17]4[CH2:18][CH:19]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:20](=[O:28])[N:21]([CH2:23][C:24]([F:26])([F:27])[F:25])[CH2:22][C:16]=4[CH:15]=3)[N:7]=[C:3]2[N:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC1Cc2ccc(O)cc2CN(CC(F)(F)F)C1=O
Reactant: OCCc1cn2nccnc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1Cc2ccc(OCCc3cn4nccnc4n3)cc2CN(CC(F)(F)F)C1=O

Procedure:
To 50 mL of a tetrahydrofuran solution containing 0.81 g (4.94 mmol) of 2-(imidazo[1,2-b][1,2,4]triazin-6-yl)ethanol obtained in the same reaction as in Example 3-(a) were added 1.66 g (4.80 mmol) of ethyl 8-hydroxy-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetate (see WO 98/14192A) and 1.76 g (6.71 mmol) of triphenylphosphine, and the mixture was stirred under ice-cooling. Then, 9 mL of a tetrahydrofuran solution containing 1.26 g (6.23 mmol) of diisopropyl azodicarboxylate was added dropwise to the mixture over 45 minutes, the mixture was gradually elevated to room temperature, and stirred for 12 hours.
Reaction SMILES: [CH2:1]([O:3][C:4]([PH:9](=[O:13])OCC)([O:6][CH2:7][CH3:8])[CH3:5])[CH3:2].[CH3:14][Mg]Cl.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:14][PH:9](=[O:13])[C:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])[CH3:5]
Reactant: C[Mg]Cl
Reactant: CCO[PH](=O)C(C)(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(C)(OCC)[PH](C)=O

Procedure:
By a procedure analogous to that of Example 1, but using ethyl 1,1-diethoxyethylphosphinate (10.5 g) and 33.5 ml of the methylmagnesium chloride solution and adding 14.1 g of potassium carbonate in 30 ml of water to precipitate inorganic salts, methyl (1,1-diethoxyethyl) phosphine oxide is obtained as a colourless oil.
Reaction SMILES: Br[CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[CH:20]1([NH:26][CH3:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[CH:20]1([N:26]([CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CNC1CCCCC1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)N(C)C1CCCCC1
Yield: 28.5 %

Procedure:
Diethyl bromomalonate (17.0 g), triethylamine (9.1 g), and dry toluene (10 ml) were mixed, and with stirring, the mixture was heated under reflux. Then, N-cyclohexyl-N-methylamine (8.1 g) diluted with dry toluene (5 ml) was added dropwise, and the mixture was heated under reflux for 2.5 hours with stirring. The reaction mixture was washed with water three times, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure to give 5.5 g (29%) of diethyl (N-cyclohexyl-N-methylamino)malonate having the following properties.
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]1[CH:12]=[C:11]([CH3:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:7]=1N.[ClH:17]>O.[Cu]Cl>[Cl:17][C:7]1[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]([CH3:13])=[CH:12][C:6]=1[F:5]
Reactant: Cc1cc(F)c(N)cc1[N+](=O)[O-]
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(F)c(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
A solution of sodium nitrite (7.6 g, 110 mmol) in water (20 mL) was added dropwise over 30 min at 0° C. to a stirred suspension of 2-fluoro-4-methyl-5-nitroaniline (17 g, 100 mmol) in concentrated hydrochloric acid (200 mL). The mixture was stirred at 0° C. for 20 min then transferred to a dropping funnel and added dropwise over 30 min to a stirred suspension of copper(I)chloride (16 g) in concentrated hydrochloric acid (150 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 16 h then poured onto ice-water (1.5 L) and extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried (magnesium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; heptane] to give the product (14.2 g, 75%) as a yellow solid. An analytical sample was recrystallised (heptane) to give a white solid: mp 57-58° C.; NMR δH (400 MHz, CDCl3) 8.03 (1H, d, J 7.2 Hz), 7.13 (1H, d, J 9.1 Hz), 2.6 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)=[N:5]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:30]=[C:29]([C:31](O)=[O:32])[NH:28][N:27]=2)[CH:21]=1>>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][CH2:2][NH:1][C:31]([C:29]3[CH:30]=[C:26]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)[NH:27][N:28]=3)=[O:32])[N:5]=2)=[CH:10][C:11]=1[N+:17]([O-:19])=[O:18])#[N:14]
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1[N+](=O)[O-]
Reactant: O=C(O)c1cc(-c2cccnc2)n[nH]1
Product: N#Cc1ccc(-c2ccn(CCNC(=O)c3cc(-c4cccnc4)[nH]n3)n2)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (50 mg) and 3-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid (44 mg) using the method of Example 34(d). Yield 27 mg. 1H-NMR (400 MHz; d6-DMSO): δ 3.74 (m, 2H), 4.42 (t, 2H), 7.07 (d, 1H), 7.17-7.28 (m, 1H), 7.50 (m, 1H), 7.90 (s, 1H), 8.05-8.20 (m, 2H), 8.31-8.42 (m, 1H), 8.52-8.59 (m, 1H), 8.69 (d, 1H), 8.92-9.04 (m, 1H), 13.79 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1.[CH:15]([Mg]Br)=[CH2:16].[NH4+].[Cl-]>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][Cl:1])=[C:6]2[C:7]=1[NH:12][CH:16]=[CH:15]2
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cc(OCCCl)ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: ClCCOc1ccc(Cl)c2[nH]ccc12
Reaction time: 2.25 h
Yield: 158.3 %

Procedure:
To a solution of 1-(2-chloroethoxy)-4-chloro-3-nitrobenzene (10.00 g, 0.04236 mol) in THF (230 mL) stirred in a cold bath at -50 to -40° C. was added a THF solution of vinylmagnesium bromide (132 mL, 1.0 M, 0.132 mol) over 2 minutes. After stirring in the cold bath for 2-2.5 hours, saturated NH4Cl (150 mL) was added to the cold solution and it was removed from the cold bath. Enough 1 M HCl was added to dissolve the precipitated solids. This two phase system was stirred for 0.5 hour at most. The layers were separated and the aqueous phase was extracted once with Et2O. Combination of the Et2O and THF followed by drying over MgSO4 and evaporation gave 15.43 g of a dark oil. This was purified by chromatography on silica gel using a three component elutant which consisted of 80% CH2Cl2 and 20% of a gradient of EtOAc/hexane. This gave the product as a yellow solid: 3.32 g (34%); mp 68-72° C. MS EI m/e 229, 231, 233 (M+); 1H NMR (400 MHz, DMSO-d6) δ 3.99 (t, 2H, J=5.1 Hz), 4.34 (t, 2H, J=5.0 Hz), 6.51 (t, 1H, J=2.7 Hz), 6.53 (d, 1H, J=7.8 Hz), 7.04 (d, 1H, J=8.0 Hz), 7.29 (t, 1H, J=2.7 Hz), 11.43 (s, 1H).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:37]([N:39]1[N:43]=[C:42]([C:44]([CH3:47])([CH3:46])[CH3:45])[S:41][C@H:40]1[C:48]([O:50]CC1C=CC=CC=1)=[O:49])=[O:38])[NH:17][C@H:18]([C:27]([O:29]CC1C=CC=CC=1)=[O:28])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:44]([C:42]1[S:41][C@@H:40]([C:48]([OH:50])=[O:49])[N:39]([C:37](=[O:38])[C@H:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH2:11])[NH:17][C@H:18]([C:27]([OH:29])=[O:28])[CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:43]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)C1=NN(C(=O)[C@H](CCCCNC(=O)OCc2ccccc2)N[C@@H](CCc2ccccc2)C(=O)OCc2ccccc2)[C@H](C(=O)OCc2ccccc2)S1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)C1=NN(C(=O)[C@H](CCCCN)N[C@@H](CCc2ccccc2)C(=O)O)[C@H](C(=O)O)S1

Procedure:
A solution of the product from step d) (1.lg) in ethanol (90ml) was treated with 10% palladium on carbon (0.9g) and the mixture stirred under 1 atmosphere of hydrogen for 1 hour. The catalyst was removed by filtration and the filtrate evaporated. The residue was recrystallised from a mixture of tetrahydrofuran and ethanol to give the title product as a white solid (0.24g)
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][C:6]=2[O:5][C:4]=1/[N:17]=[CH:18]/[N:19](C)C)#[N:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])N>C(#N)C.C(O)(=O)C>[Cl:22][C:23]1[CH:24]=[C:25]([NH:2][C:1]2[C:3]3[C:11]4[CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][C:6]=4[O:5][C:4]=3[N:17]=[CH:18][N:19]=2)[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)N1CCc2c(oc(/N=C/N(C)C)c2C#N)C1
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)N1CCc2c(oc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Reaction time: 20 h
Yield: 22.3 %

Procedure:
Ethyl 3-cyano-2-{[(1E)-(dimethylamino)methylidene]amino}-4,7-dihydrofuro[2,3-c]pyridine-6(5H)-carboxylate from Example 37A (1.20 g, 4.14 mmol) and 3-chloro-4-fluoroaniline (1.20 g, 8.27 mmol) were heated in a mixture of acetonitrile (20 mL) and acetic acid (10 mL) in a microwave oven for 30 min to 160° C. The mixture was then concentrated in vacuo, diluted with water, basified with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The residue was triturated with dichloromethane and left to stand for 20 h. The precipitate was collected by suction filtration. Subsequently, the solid was triturated with methanol. The crystals were collected by suction filtration and washed with diethyl ether to yield 360 mg (22%) of the title compound. A second batch of 159 mg (10%) was obtained from the mother liquor after purification by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:16]([CH2:17][CH2:18][O:19][CH3:20])[CH2:15][CH2:14][O:13][CH3:12]
Reactant: COCCNCCOC
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COCCN(CCOC)c1ccc([N+](=O)[O-])cc1F
Temperature: 80 °C

Procedure:
1.13 g (7.1 mmol) of 3,4-difluoronitrobenzene (Aldrich, Buchs, Switzerland), 1.04 g (7.81 mmol) of bis(2-methoxyethyl)amine (Fluke, Buchs, Switzerland) and 1.96 g (14.2 mmol) of K2CO3 in 7 ml of DMSO are stirred for 1.5 h at rt and then heated at 80° C. for 4 h. The reaction mixture is quenched with H2O and extracted with EtOAc (2×). The organic layers are washed with brine (3×), dried over MgSO4, filtered and evaporated. The residue is purified by flash chromatography on silica gel (hexane-EtOAc 6:1 to 5:1) to give the title compound as a yellow oil. ES-MS: 273 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]O)[CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:38])C(=O)C1>CN(C=O)C>[Br:38][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:1]1[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCCCCC1CCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: BrCCCCCCC1CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
To a solution of 6-cyclobutyl-hexan-1-ol (0.47 g, 3.0 mmol) in DMF (10 mL) was added triphenylphosphine (0.88 g, 3.4 mmol). The solution was cooled to 0° C. and NBS (0.57 g, 3.2 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (0.5 mL). The solution was diluted with ether (60 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford (6-bromo-hexyl)-cyclobutane (0.60 g, 91%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 3.40 (2H, t, J=6.9 Hz), 2.23 (1H, m), 2.02 (2H, m), 1.82 (4H, m), 1.55 (2H, m), 1.12–1.46 (8H, m); 13C NMR (75 MHz, CDCl3) δ 37.19, 36.39, 34.40, 33.11, 29.07, 28.68, 28.51, 27.26, 18.80.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH2:3][N:4]1[C:8]2[CH:9]=[C:10]([N:14]3[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]3=[O:25])[C:11]([F:13])=[CH:12][C:7]=2[N:6]=[C:5]1[C:26]([F:29])([F:28])[F:27].C(=O)([O-])[O-].[K+].[K+].[NH2:37]OS(C1C(C)=CC(C)=CC=1C)(=O)=O>O1CCCC1.O>[NH2:37][N:16]1[C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][C:19](=[O:20])[N:14]([C:10]2[C:11]([F:13])=[CH:12][C:7]3[N:6]=[C:5]([C:26]([F:27])([F:29])[F:28])[N:4]([CH2:3][CH:2]([CH3:30])[CH3:1])[C:8]=3[CH:9]=2)[C:15]1=[O:25]
Reactant: CC(C)Cn1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cn1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(N)c3=O)cc21
Reaction time: 1 h

Procedure:
A solution of 1.3 grams (0.003 mole) of 3-[1-(2-methylpropyl)-2-trifluoromethyl-5-fluorobenzimidazol-6-yl]-6-trifluoromethyluracil (prepared as in Example 2, Steps A-H) in 30 mL of tetrahydrofuran is stirred, and 0.5 gram (0.003 mole) of potassium carbonate, then 0.7 gram (0.003 mole) of 1-aminooxysulfonyl-2,4,6-trimethylbenzene are added. Upon completion of the addition, the reaction mixture is stirred for one hour. The reaction mixture is then diluted with water and extracted with three portions of ethyl acetate. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue, which is purified by column chromatography, yielding 1-amino-3-[1-(2-methylpropyl)-2-trifluoromethyl-5-fluorobenzimidazol-6-yl]-6-trifluoromethyluracil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[C:23](#[N:31])[CH:24]=[CH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].N12CCCN=C1CCCCC2.C(#N)C>>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:12]1[C:8]2[N:9]=[CH:10][N:11]=[C:6]([C:4]3[CH:5]=[N:1][N:2]([CH:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:24][C:23]#[N:31])[CH:3]=3)[C:7]=2[CH:14]=[CH:13]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CCCCCC=CC#N
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Yield: 89.89 %

Procedure:
A mixture of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (prepared substantially as described in Example 65 of U.S. Pat. App. Pub. No. 2007/0135461 or International App. No. PCT/US2006/047369 (published as WO 2007/070514); 12 g, 0.038 mol), oct-2-enenitrile (6.0 g, 0.049 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 4.6 mL, 0.030 mol) in acetonitrile (120 mL, 2.3 mol) was stirred at room temperature overnight. After being concentrated in vacuo, the resultant residue was purified on silica gel (eluting with 0 to 40% EtOAc in hexanes) to give the desired product (15 g, 89.89%). The enantiomers (first peak retention time 11.02 min, second peak retention time 14.10 min) were separated on a ChiralCel OD-H column (30×250 mm, 5 μM), eluting with mobile phase of 15% ethanol and 85% hexane at 25 mL/min. MS calculated for C23H35N6OSi(M+H)+: m/z=439.264. Found: 439.4. 1H NMR (300 MHz, CDCl3) δ 8.91 (1H, s), 8.38 (1H, s), 8.37 (1H, s), 7.46 (1H, d, J=3.8 Hz), 6.86 (1H, d, J=3.8 Hz), 5.73 (2H, s), 4.59 (1H, m), 3.60 (2H, t, J=8.3 Hz), 3.06 (2H, td, J=16.8 and 7.5 Hz), 2.21 (1H, m), 2.01 (1H, m), 1.40-1.21 (6H, m), Hz), 0.91 (3H, t, J=6.3 Hz), 0.00 (9H, s) ppm.
Reaction SMILES: O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:12]([O:14][CH:15]([O:22][CH2:23][CH3:24])[CH2:16][C:17](OCC)=[O:18])[CH3:13]>O>[CH2:12]([O:14][CH:15]([O:22][CH2:23][CH3:24])[CH2:16][CH2:17][OH:18])[CH3:13]
Reactant: CCOC(=O)CC(OCC)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(CCO)OCC
Temperature: 10 °C
Reaction time: 1 h
Yield: 109.4 %

Procedure:
In the following, tetrahydrofuran (THF) to be used was dehydrated on molecular sieves of 4 angstrom overnight. Inside of a 5 L four-neck flask was substituted with nitrogen gas and 2.2 kg of THF was placed therein, followed by cooling to 10° C. or lower. Then, 50 g of lithium aluminum hydride was placed therein and 250 g of ethyl 3,3-diethoxypropionate was added dropwise so that inner temperature did not exceed 10° C. After completion of the dropwise addition, temperature was elevated to 20° C. and reaction was carried out for 1 hour. After the reaction, 420 g of distilled water was added and the whole was stirred for 2 hours, then filtration was performed through No. 2 filtration paper, and subsequently a cake was washed with 1.1 kg of THF. The filtrate was concentrated at 40° C. to obtain 213 g of crude 3,3-diethoxy-1-propanol (hereinafter 33DEP).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[N:28][NH:29][CH:30]=3)=[C:22]([O:31][CH3:32])[N:21]=2)=[CH:13]\[C@@H:14]2[NH:18][C:17](=[O:19])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1.[H][H]>CO.[Pd]>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:30]=[N:29][NH:28][CH:27]=3)=[C:22]([O:31][CH3:32])[N:21]=2)[CH2:13][C@@H:14]2[NH:18][C:17](=[O:19])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(Cl)cc2)ccc1-c1cn[nH]c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COc1nc(C(C[C@H]2CCC(=O)N2)c2ccc(Cl)cc2)ccc1-c1cn[nH]c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.8 %

Procedure:
10% palladium-activated carbon (60 mg) and acetic acid (2 mL) were added to a solution of (5R)-5-{(E)-2-(4-chlorophenyl)-2-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]ethenyl}pyrrolidin-2-one (122 mg) in methanol (3 mL) in a hydrogen gas stream, and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered through celite, and then the solvent was evaporated under reduced pressure. Saturated aqueous sodium bicarbonate was added to the residue, followed by extraction with chloroform. The solvent was evaporated from the organic layer under reduced pressure to give a crude product of (5R)-5-{2-(4-chlorophenyl)-2-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]ethyl}pyrrolidin-2-one as a yellow oil (77 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11](C=O)[O:10][C:9]=2[C:8]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:7][CH:6]=1)=[O:4].[C:22](O)(=O)[CH2:23][C:24]([OH:26])=[O:25].N1CCCCC1.Cl>C1(C)C=CC=CC=1>[CH:17]1([O:16][C:8]2[C:9]3[O:10][C:11](/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25])=[CH:12][C:13]=3[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1ccc(OC2CCCC2)c2oc(C=O)cc12
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OC2CCCC2)c2oc(/C=C\C(=O)O)cc12
Temperature: 25 °C
Yield: 66.3 %

Procedure:
To a well stirred solution of Methyl-2-formyl-7-cyclopentyloxybenzo[b]furan-4-carboxylate (21.0 g, 0.0868 moles) in toluene (250.0 mL) was added malonic acid (13.5 g, 0.1302 moles) and Piperidine (5.0 ml). The reaction mixture was then refluxed for 3-4 hours. Reaction mixture was cooled to room temperature, acidified with 10% aqueous HCl solution and extracted with ethyl acetate (2×250 mL). The combined organic layers were washed with water (2×100 mL) and dried over anhydrous sodium sulfate. Removal of solvent under vacuo gave product (19 g) as light yellow solid.