Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][C:16](=N)N)[CH:9]=1)[CH3:6].ClC[CH2:21][CH2:22][C:23]#[N:24].[OH-].[Na+]>O.C(O)C>[CH3:6][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][CH2:16][CH2:21][CH2:22][C:23]#[N:24])[CH:9]=1)[CH3:4]
Reactant: N#CCCCCl
Reactant: CN(C)Cc1ccnc(CSC(=N)N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)Cc1ccnc(CSCCCC#N)c1
Reaction time: 5 h
Yield: 80.7 %

Procedure:
To a solution of S-(4-dimethylaminomethyl-2-pyridylmethyl)isothiourea trihydrochloride (11.88 g) and 4-chlorobutyronitrile (5.21 g) in water (50 ml) and ethanol (35 ml) at 0° C. (ice-salt bath) under nitrogen, was added dropwise over 20 minutes a solution of sodium hydroxide (6.4 g) in water (65 ml), keeping the temperature below 5° C. After having been stirred for 5 hours and allowed to stand for 20 hours, the solution was extracted with 3:1 chloroform:ethanol (3×100 ml) and the combined extracts washed with water and dried (MgSO4). Solvent was evaporated at reduced pressure and the residue vacuum-distilled to give 4-(4-dimethylaminomethyl-2-pyridylmethylthio)butyronitrile (7.16 g) as a pale yellow liquid, b.p.0.01 mm 170° C.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C:6](OCC)=[O:7])C.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+]>C(O)C.O1CCCC1.O>[C:24]([O:23][C:21](=[O:22])[NH:20][C:5]([CH2:4][OH:3])([CH2:6][OH:7])[CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)C(CCOC1CCCCO1)(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC(CO)(CO)CCOC1CCCCO1
Reaction time: 2 h
Yield: 54.6 %

Procedure:
Compound 21-1 (50.0 g) was dissolved in a mixture of ethanol (530 ml), tetrahydrofuran (130 ml) and water (260 ml). Calcium chloride (27.5 g) was added to this solution at 0° C., sodium borohydride (18.8 g) was subsequently added in portions, and the mixture was stirred at the same temperature for 2 hr, and further at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, added to saturated aqueous ammonium chloride solution (31), and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel chromatography to give the object product (21.6 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][C@@H:18]3[CH2:27][CH3:28])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:29]([O:32][CH2:33][C:34]1[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][C:37]([F:49])=[CH:36][C:35]=1[N:50]1[C:62](=[O:63])[C:61]2[S:60][C:59]3[CH2:58][CH2:57][CH2:56][CH2:55][C:54]=3[C:53]=2[CH:52]=[N:51]1)(=[O:31])[CH3:30].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:29]([O:32][CH2:33][C:34]1[C:35]([N:50]2[C:62](=[O:63])[C:61]3[S:60][C:59]4[CH2:58][CH2:57][CH2:56][CH2:55][C:54]=4[C:53]=3[CH:52]=[N:51]2)=[CH:36][C:37]([F:49])=[CH:38][C:39]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][C@@H:18]3[CH2:27][CH3:28])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:31])[CH3:30]
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3COC(C)=O)cn(C)c2=O)nc1
Temperature: 25 °C
Yield: 40.5 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with (S)-5-bromo-3-(5-(2-ethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one 114e (179 mg, 0.40 mmol), (4-fluoro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 117e (200 mg, 0.40 mmol), Pd(dppf)Cl2 (29 mg, 0.04 mmol), K3PO4 (170 mg, 0.8 mmol), sodium acetate (66 mg, 0.8 mmol), acetonitrile (5 mL), and water (1.0 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 120a as a yellow solid (120 mg, 41%). MS: [M+H]+ 740.3
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].N([O-])=O.[Na+].[C:18](Cl)(=[O:21])[CH:19]=[CH2:20].C(O)C>C(=O)([O-])[O-].[K+].[K+]>[C:18]([NH:5][C@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[CH:3]=[O:2])(=[O:21])[CH:19]=[CH2:20]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: C=CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: CCO
Product: C=CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Glucosamine hydrochloride (0.1 mol; 21.56 g) and sodium nitrite (0.2 g) as inhibitor were dissolved under nitrogen atmosphere in 100 ml of a 0.3 M potassium carbonate solution, and the mixture was cooled to 0° C. Under vigorous stirring, acryloyl chloride (0.2 mol; 18.1 g) was added while the temperature was kept below 5° C. Stirring was continued for 3 h at 0°-5° C. and further 2 h while the mixture was allowed to come to room temperature. Finally, it was left at room temperature for 14 h. The solution was poured into 1 l of dry ethanol and strongly mixed. The resulting suspension was filtered by suction, and the cake was washed three times with 250 ml of 95% ethanol. To the combined filtrates and washings 1 l of ether was added and the solution was kept at 0° C. for 24 h. The desired product crystallized as white cubes, while the yellowish needles that might appear were a by-product. It could be separated by stirring up the whole mixture and decanting the liquid with the floating needles while the product remained on the ground of the reaction flask. By addition of 1 l of ether to the mother liquid a second crop could be isolated. The product was recrystallized two times from water/ethanol/ether. Yield 8.1-10.5 g (35-45%), m.p.:124°-125° C.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[F:7][C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10]>C(Cl)Cl.N1C=CC=CC=1.CCOC(C)=O>[F:7][C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4]
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ccccc1F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccccc1F
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of ethanesulfonyl chloride (0.368 ml, 3.89 mmol) in DCM (1 ml) and pyridine (1 ml) was added 2-fluoroaniline (0.360 ml, 3.89 mmol) at rt and the reaction was stirred at 50° C. for 5 hours. The reaction was then stirred at rt overnight. The reaction was diluted with EtOAc and washed with H2O and sat. NaCl solution. The organic layer was dried over Na2SO4 and concentrated. Purification of the residue by flash chromatography on silica gel (eluent: 0% to 35% EtOAc/hexane) provided the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([OH:13])[CH3:12])[C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(O)c1cc(Cl)cc2c1OCO2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)cc2c1OCO2
Reaction time: 16 h
Yield: 58.9 %

Procedure:
1-(5-Chlorobenzo[d][1,3]dioxol-7-yl)ethanol (155 mg, 0.77 mmol) was dissolved in 6 mL of dichloromethane. PCC (416 mg, 1.93 mmol) was added portionwise and the mixture was stirred for 16 h (reaction is likely to be completed earlier). The mixture was filtered through a plug of celite. The solvent was removed by rotary evaporation to collect the desired product (90 mg, 59% yield). 1H NMR (400 MHz, CDCl3): δ 7.36 (d, 1H), 6.96 (d, 1H), 6.14 (s, 2H), 2.59 (s, 3H).
Reaction SMILES: S([O-])([O-])(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].C([O:13][CH:14]=[C:15]([C:21]([O-])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.[OH-].[Na+]>O>[CH2:19]([O:18][C:16]([C:15]1[C:14]([OH:13])=[N:10][C:8]([O:7][CH3:6])=[N:9][CH:21]=1)=[O:17])[CH3:20]
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Reactant: COC(=N)N
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1cnc(OC)nc1O
Yield: 80 %

Procedure:
The applicant company has found that the operation can more advantageously be carried out in water: an aqueous solution of 1 mol of the neutral sulphate of O-methylisourea (concentration of between 5 and 10%) has the corresponding amount (2 mols) of ethyl ethoxymethylenemalonate added thereto, and the mixture is stirred vigorously so as to keep the second reagent emulsified. An aqueous solution of an alkali metal hydroxide is then added thereto at a rate such that the temperature of the mixture remains between 20° and 30° C. The mixture is stirred for another two hours at room temperature, after the addition of the alkaline reagent. If sodium hydroxide solution is used as the reagent, the sodium salt of the ester (XVI) precipitates in the medium which is brought to pH 5 by the addition of an inorganic or organic acid when the reaction has finished. The solution obtained, which is filtered if necessary in order to remove a small amount of insoluble matter, is extracted with an appropriate solvent chosen, preferably, from the polyhalogenated aliphatic hydrocarbons, more especially chloroform. After washing and drying the organic solution, evaporation in vacuo leaves 5-ethoxycarbonyl-4-hydroxy-2-methoxy-pyrimidine (XVI), which is practically pure, with a yield of about 80%. The product can then be purified by recrystallisation from a suitable solvent, especially isopropanol.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[C:24]([N:27]([CH2:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])[C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)(=[O:26])[CH3:25]>>[C:24]([N:27]([C:28]1[CH:33]=[CH:32][C:31]([NH:34]/[C:17](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[CH2:18][CH3:19])=[CH:30][CH:29]=1)[CH2:35][CH2:36][CH2:37][N:38]([CH3:39])[CH3:40])(=[O:26])[CH3:25]
Reactant: CC(=O)N(CCCN(C)C)c1ccc(N)cc1
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Product: CC/C(Nc1ccc(N(CCCN(C)C)C(C)=O)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and N-acetyl-N-(3-dimethylamino-propyl)-p-phenylenediamine
Reaction SMILES: C[O:2][C:3](=O)/[CH:4]=[CH:5]/[C:6]1[N:7]([CH:22]([CH3:24])[CH3:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH:22]([CH3:23])[CH3:24])[C:6]=2/[CH:5]=[CH:4]/[CH2:3][OH:2])=[CH:16][CH:17]=1
Reactant: COC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)n1c(/C=C/CO)c(-c2ccc(F)cc2)c2ccccc21
Yield: 102.2 %

Procedure:
As in Example 227, (E)-3-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-2-propenoic acid methyl ester (4.43 g) in dry dichloromethane (60 mL) was treated with diisobutylaluminum hydride in toluene (1.5M; 30 mL) at -65° C. for 1 hour, then was worked up as previously described to give 4.15 g of (E)-3-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-2-propen-1-ol as a yellow oil. A portion (0.2 g) was purified by chromatography over silica gel (diethyl ether-hexane; 1:19) to furnish 0.175 g of the analytically pure alcohol as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[C@:10]([OH:14])([CH2:11]2)[C@@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[CH2:1]([N:8]1[CH2:13][CH:12]2[C@:10]([O:14][CH2:32][C:33]3[CH:34]=[C:35]([C:43]([F:45])([F:46])[F:44])[CH:36]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:38]=3)([CH2:11]2)[C@@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@]12CC1CN(Cc1ccccc1)[C@H]2c1ccccc1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(CO[C@]23CC2CN(Cc2ccccc2)[C@H]3c2ccccc2)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
To Intermediate 28, mixture of diastereomers ((1R,2S)-3-benzyl-2-phenyl-3-aza-bicyclo[3.1.0]hexan-1-ol (0.40 g, 1.5 mmol) and tetrabutylammonium iodide (0.26 g, 0.70 mmol) in a flask was added THF (15 mL) and the mixture cooled to −78° C. Potassium bis(trimethylsilyl)amide (0.5M/toluene, 4.5 mL, 2.2 mmol) was added dropwise and the reaction was stirred for 10 minutes. 1-Bromomethyl-3,5-bis-trifluoromethyl-benzene (0.39 mL, 2.1 mmol) was added dropwise and the reaction stirred for an additional 10 minutes, then allowed to warm to room temperature. The solvent was removed at reduced pressure and the residue partitioned between H2O and EtOAc, the organics washed with brine and dried over calcium sulfate, filtered and concentrated. The crude product was purified on a Biotage flash 40 system eluted with a gradient of 1% ETOAc/Hexanes to 2% ETOAc/Hexanes to give the title compound as an oil. (0.55 g, 74% yield).
Reaction SMILES: Br[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[CH:34]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1B(O)O)([CH3:36])[CH3:35]>>[CH:34]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1)([CH3:36])[CH3:35]
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Reactant: CC(C)Oc1ccccc1B(O)O
Agent: OB(O)c1ccccc1
Product: COc1cc2c(cc1-c1ccccc1OC(C)C)C(c1cccc(C#N)c1)=NCC(=O)N2C
Yield: 86 %

Procedure:
Prepared from 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 using the same method described for Example 1 and instead of using benzene boronic acid, we used 2-isopropoxyphenyl boronic acid. The title compound (147 mg) was obtained as a white solid, (yield=86%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C:25]2[N:26]=[C:27]([CH:35]3[CH2:38][CH2:37][CH2:36]3)[N:28]3[C:33]=2C(=O)NC=N3)[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C:25]2[N:26]=[C:27]([CH:35]3[CH2:36][CH2:37][CH2:38]3)[N:28]3[C:33]=2[C:5]([NH2:1])=[N:4][CH:3]=[N:2]3)[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=c1[nH]cnn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4)c3)c12
Reactant: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1ncnn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,2,4-triazole (167 mg, 2.417 mmol) in anhydrous pyridine (1.5 mL) was added phosphorous oxychloride (POCl3) (75 μL, 0.806 mmol) and stirred at rt for 15 min. To this mixture was added dropwise a solution of 5-(3-benzyloxy-phenyl)-7-cyclobutyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (100 mg, 0.269 mmol) in anhydrous pyridine (2.5 mL) over a 3.5 min period and stirred at rt for an additional 3 h. The reaction was cooled to 0° C. and quenched with 2M NH3 in i-PrOH (10 mL ) and stirred for an additional 30 min at rt. The mixture was filtered through a fritted funnel and the filtrate was concentrated in vacuo, partitioned between CHCl3 and H2O and separated. The aqueous layer was re-extracted with CHCl3 (3×) and the combined CHCl3 fractions were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo and the crude material was chromatographed on silica gel [eluting with 2% MEOH in CHCl3] resulting in a dark brown oil which was crystallized from EtOAc/hexanes to obtain the title compound as a light tan solid. 1H NMR (CDCl3, 400 MHz) δ 1.95-2.08 (m, 1H), 2.09-2.22 (m, 1H), 2.39-2.50 (m, 2H), 2.59-2.72 (m, 2H), 4.14 (quint, J=8.4 Hz, 1H), 5.16 (s, 2H), 5.57 (brs, 2H), 7.02-7.09 (m, 1H), 7.22-7.28 (m, 3H), 7.31-7.50 (m, 5H), 7.85 (s, 1H); MS (ES+): m/z 372.1 (100) [MH+]; HPLC: tR=3.05 min (MicromassZQ, nonpolar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](=[O:16])[CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=2)=[CH:13][CH:12]=1
Reactant: Fc1cccc(CBr)c1
Reactant: O=C(Cl)c1ccc(Br)cc1
Product: O=C(Cc1cccc(F)c1)c1ccc(Br)cc1

Procedure:
The title compound was prepared according to the procedure of step 1 in the Example 169 using 3-fluorobenzyl bromide and 4-bromobenzoyl chloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[CH:9][N:10](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:11]=1.Cl>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[CH:9][NH:10][CH:11]=1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc(-c3ccccn3)c2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: c1ccc(-c2c[nH]cn2)nc1
Yield: 46.4 %

Procedure:
A solution of the crude 4-(2-pyridyl)-1-trityl-1H-imidazole (0.69g) in tetrahydrofuran (14 mL) was treated with 2 N hydrochloric acid (7.2 mL) and heated at reflux for 45 minutes. After cooling the reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (20 mL). The organic solution was successively washed with aqueous 1N sodium hydroxide (10 mL), water (20 mL) and brine (20 mL). The organic solution was then dried over anhydrous sodium sulfate, filtered, and concentrated in-vacuo to afford 0.12 g of crude 4-(2-pyridyl)imidazole, as a sticky white solid.
Reaction SMILES: C(C1C=CC([CH:15]2[CH:20]([NH2:21])[CH2:19][CH:18]=[CH:17][CH2:16]2)=CC=1)=CC1C=CC=CC=1.Cl[C:23]([O:25][C:26]1C=CC=C[CH:27]=1)=[O:24]>C(Cl)Cl.N1C=CC=CC=1>[C:20]1([NH:21][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NC1CC=CCC1c1ccc(C=Cc2ccccc2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccccc1
Temperature: 25 °C
Yield: 170.3 %

Procedure:
To a stirred solution of 6-(4'-styrylphenyl)cyclohex-3-enylamine (0.44 g, 1.66 mmol) in methylene chloride (21 mL) and pyridine (10 mL) at 0° C. is added phenyl chloroformate (0.25 g, 1.6 mmol). The reaction is warmed to room temperature and partitioned between methylene chloride and water. The organic extracts are washed with brine, dried (MgSO4) and evaporated. The residue is triturated with diethyl ether and purified by flash chromatography (2% diethyl ether/toluene) to give the intermediate phenyl urethane (0.45 g, 70%); Rf=0.26. MS (FAB+ion) m/z 396 (M+H).
Reaction SMILES: [N:1]1([CH:6]([C:8]#[CH:9])[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16]>O1CCCC1>[C:18]1([C:15]([OH:17])([C:9]#[C:8][CH:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:7])[CH3:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)c1ccccc1
Reactant: C#CC(C)N1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C#CC(C)(O)c1ccccc1)N1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(pyrrolidin-1-yl)-but-3-yne (0.1.23 g) in dry tetrahydrofuran (20 ml) was treated at -78° C. with a solution of n-butyl lithium in hexanes (2.5 M, 4.4 ml) and the mixture was allowed to stir at -78° C. for 30 minutes and them permitted to warm to room temperature over the course of one hour. Upon recooling to -78° C. this mixture was treated with a solution of acetophenone (1.2 g) in tetrahydrofuran (5 ml). The reaction was permitted to warm to room temperature over the course of two hours, and was then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the pooled organic phase was washed with water, brine, and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give a crude product, which was purified by column chromatography over silica gel (5-10% methanol in dichloromethane was used as the eluant) to afford the product as an oil that solidified on standing. MS(+ES), m/z: 244 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23](Cl)[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[C:29]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C1COCC1.CCOCC.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[C:29]=1[C:23]1[CH:22]=[CH:21][C:10]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1
Reactant: COc1cccc(OC)c1B(O)O
Reactant: O=C(OCc1ccccc1)c1ccc(Cl)cc1OCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(OC)c1-c1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
A mixture of of 2-benzyloxy-4-chlorobenzoic acid, benzyl ester (1.0)g, 2.83 mmol), 2,6-dimethoxybenzene boronic acid (0.62 g, 3.4 mmol), Pd2dba3 (0.26 g, 0.28 mmol), Cs2CO3 (1.38 g, 4.2 mmol), and t-Bu3P (0.12 g, 0.57 mmol) was dissolved in 8.0 mL of THF and warmed to reflux for 24 h. The reaction mixture was cooled, diluted with Et2O and H2O and the layers were separated. The organic layer was successively washed with 1N HCl (2×100 ml), saturated NaHCO3 solution (2×50 ml), brine (1×50 ml), dried over anhydrous MgSO4 and concentrated. The residue was purified by flash column chromatography on silica gel eluted with a gradient of 25-50% Et2O in hexanes to give 4-(2′,6′-dimethoxyphenyl)-2-benzyloxy-benzoic acid, benzyl ester as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:15]([NH:17][NH2:18])=[O:16].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][NH:17][C:15](=[O:16])[C:14]2[CH:19]=[CH:20][C:21]([CH3:22])=[C:12]([OH:11])[CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1ccc(C(=O)NN)cc1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NNC(=O)c2ccc(Cl)cc2)cc1O
Temperature: 85 °C

Procedure:
A mixture of 4-chlorobenzoyl chloride (0.92 mL, 7.22 mmol) (Aldrich), 3-hydroxy-4-methyl-benzoic acid hydrazide (1.0 g, 6.02 mmol) (from Example 6 supra) and triethylamine (1.36 mL) in tetrahydrofuran (20 mL) was heated at 85° C. for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The precipitate washed with ethyl acetate and dichloromethane and dried to give 3-hydroxy-4-methyl-benzoic acid N′-(4-chloro-benzoyl)-hydrazide. (Yield 1.28 g, 70%).