Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=4)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32]1([S:38]([N:41]=[C:42]=[O:43])(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:32]1([S:38]([NH:41][C:42]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][CH:19]3[CH2:20][CH2:21][CH2:22][CH:23]=[C:18]3[C:9]3[O:10][C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=3)[CH:26]=2)=[O:43])(=[O:39])=[O:40])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Nc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Solvent: ClCCl
Product: O=C(Nc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of (±)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenylamine (110 mg, 0.27 mmol) in methylene chloride (3 ml) was added benzenesulfonylisocyanate (0.037 ml, 0.27 mmol) at 5° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated, and the residue was purified by silica gel column chromatography (methylene chloride-MeOH, 30:1 elution) to give (±)-1-benzenesulfonyl-3-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenyl}urea (159.0 mg, 100%).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[CH:24]=[CH:25][C:26](=[O:28])[CH3:27]>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[CH:24]1[CH2:3][C:2](=[O:1])[CH2:27][C:26](=[O:28])[CH2:25]1
Reactant: CC[O-]
Reactant: CC(=O)C=Cc1cc(Cl)ccc1Cl
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: O=C1CC(=O)CC(c2cc(Cl)ccc2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (6.2 g) were added at room temperature ethanol (150 ml) and diethyl malonate (14.6 g), and then added little by little 4-(2,5-dichlorophenyl)-3-buten-2-one (19.0 g). The mixture was stirred at room temperature for 30 minutes, refluxed for 2 hours and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated, and to the residue was added 2M sodium hydroxide (50 ml). The mixture was refluxed for 2 hours and cooled, and to the mixture was added 2.5M sulfuric acid (50 ml) for 15 minutes. The mixture was refluxed for 1.5 hours and cooled, and precipitated crystals were filtered and washed with water and toluene to give 5-(2,5-dichlorophenyl)cyclohexane-1,3-dione (9.9 g) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)Cl.[CH3:15][O:16]C(Cl)Cl>O.[Ti](Cl)(Cl)(Cl)Cl>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]=1[CH:15]=[O:16]
Reactant: COC(Cl)Cl
Reactant: COc1ccc([N+](=O)[O-])cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])cc1C=O
Temperature: 25 °C
Reaction time: 42 h

Procedure:
p-Nitroanisole (25 g., 0.163 mole) was dissolved in 400 ml. of methylene chloride and cooled to 10° C. Titanium tetrachloride (61.8 g., 36 ml., 0.326 mole) was added, followed by 1,1-dichloromethyl methyl ether added over 2 minutes. The mixture was warmed to room temperature and stirred for 42 hours. The reaction mixture was diluted with 1 liter of ice and water and extracted with three 500 ml. portions of methylene chloride. The organic extracts were combined, washed with two portions of water and one of brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil (20 g.). The oil was chromatographed on 600 g. silica gel, using 2:1 methylene chloride: hexane as eluant, collecting 15 ml. fractions, and monitoring by tlc. Clean product fractions 79-185 were combined and evaporated to yield 2-methoxy-5-nitrobenzaldehyde (3.8 g.; m.p. 87-89, literature m.p. 89°-90°).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].O[CH:9]1CC[CH:15]2[CH:10]1[CH2:11][CH:12]=[C:13]([O:18][CH3:19])[CH2:14]2>N1C=CC=CC=1>[C:5]([O:4][CH:1]1[CH2:9][CH2:10][CH:15]2[CH:2]1[CH2:11][CH:12]=[C:13]([O:18][CH3:19])[CH2:14]2)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: COC1=CCC2C(O)CCC2C1
Solvent: c1ccncc1
Product: COC1=CCC2C(CCC2OC(C)=O)C1
Reaction time: 60 h
Yield: 91.7 %

Procedure:
Acetic anhydride (62.3 g) was added to a solution of 7-hydroxy-3-methoxybicyclo[4,3,0]non-3-ene (51.4 g; prepared as described in Reference Example 2) in pyridine (166 ml), and the mixture was left to stand at the ambient temperature for 60 hours. Concentration under reduced pressure gave 7-acetoxy-3-methoxybicyclo[4,3,0]non-3-ene (58.9 g).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][S:5]1(=[O:10])=[O:9].[Br:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[N:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[Br:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14]([O:18][CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][CH2:6][S:5]2(=[O:10])=[O:9])[CH:13]=1
Reactant: O=S1(=O)CCCN1CCCl
Reactant: Oc1cncc(Br)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S1(=O)CCCN1CCOc1cncc(Br)c1
Temperature: 60 °C
Yield: 20.3 %

Procedure:
To a solution of 2-(2-chloro-ethyl)-isothiazolidine-1,1-dioxide (0.046 g, 0.253 mmol) and 5-bromopyridin-3-ol (0.04 g, 0.230 mmol) in DMF (1 mL) was added K2CO3 (0.064 g, 0.46 mmol), followed by KI (0.008 g, 0.046 mmol) and the reaction mixture was heated to 60° C. and stirred over night. The mixture was diluted with EtOAc, poured into a sat. NaHCO3 solution (5 mL) and the aqueous layer was extracted with EtOAc (2×10 mL). Combined organics were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.015 g, 20%) as a yellow oil which was used with no further purification. MS: 321.3 and 323.2 (M+H+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH3:35]>CN(C)C=O>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([CH2:34][CH3:35])[C:12]([S:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(COCc2ccccc2)[nH]c1Sc1cc(F)cc(F)c1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(COCc2ccccc2)nc(C(C)C)c1Sc1cc(F)cc(F)c1
Yield: 4.3 %

Procedure:
In dimethylformamide (10 ml) was dissolved 432 mg (1.2 mmol) of 2-benzyloxymethyl-5-(3,5-difluorophenylthio)-4-isopropyl-1H-imidazole (16f), followed by addition of 192 mg (1.4 mmol) of potassium carbonate and 153 mg (1.4 mmol) of bromoethane at room temperature with stirring, the mixture was stirred at the same temperature for 3 days. The reaction mixture was extracted with ether, and the ether layer was washed with water, dried over magnesium sulfate, and filtered. The ether layer was concentrated under reduced pressure, and the residual oil was purified by silica gel column chromatography (methanol:methylene chloride=3:97). From the first fraction, 20 mg (yield 4.3%) of positional isomer (17z') of the target compound was obtained. From the subsequent fraction, 300 mg of 2-benzyloxymethyl-5-(3,5-difluorophenylthio)-1-ethyl-4-isopropyl-1H-imidazole (17z), which was useful compound for the next reaction, was obtained (yield 65%). Oil.
Reaction SMILES: NC(N)=O.[CH2:5]([NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([NH2:18])[C:12]=1[OH:19])(=[O:10])=[O:9])[CH3:6].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]=[C:28]=[O:29]>>[Cl:17][C:16]1[CH:15]=[CH:14][C:13]([NH:18][C:28]([NH:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[Cl:20])=[O:29])=[C:12]([OH:19])[C:11]=1[S:8]([NH:7][CH2:5][CH3:6])(=[O:9])=[O:10]
Reactant: CCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: O=C=Nc1ccccc1Cl
Agent: NC(N)=O
Product: CCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Cl)c1O
Yield: 33.1 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-ethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (266 mg, 1.06 mmol) and 2-chlorophenylisocyanate (163 mg, 1.06 mmol) were coupled to form the desired urea (142 mg, 33%). LC-MS (m/z) 04.0 (M+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>CCOCC>[CH2:7]([O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH2:17][NH2:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NC(=O)c1ccccc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NCc1ccccc1OCc1ccccc1
Reaction time: 21 h

Procedure:
In a Soxhlet apparatus 18.4 g of lithium aluminium hydride in 1800 ml of dry ether are boiled under a nitrogen atmosphere at a bath temperature of 70°, 5.3 g of 2-benzyloxybenzamide being introduced into the Soxhlet thimble. After 21 hours the reaction mixture is immersed in an ice bath, and 18.4 ml of water, 18.4 ml of 15% sodium hydroxide solution and 55 ml of water are added dropwise in succession, whilst stirring. The temperature may be allowed to rise to a maximum of +10°. Stirring of the mixture is then continued at 20° and the resulting precipitate is suction-filtered and washed with ether. The filtrate is concentrated by evaporation in vacuo and the oil remaining is stirred with 500 ml of 10% hydrochloric acid and 400 ml of ether for 2 hours, whilst cooling with ice. The precipitated 2-benzyloxybenzylamine hydrochloride is suction-filtered, washed with water and ether and dried in vacuo. Melting point 190°-191°.
Reaction SMILES: I[C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12]>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN1CCCC1=O>[CH3:10][Si:11]([C:14]#[C:15][C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1)([CH3:13])[CH3:12]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ccc(I)c(N)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: C[Si](C)(C)C#Cc1ccc(N)nc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a mixture of 3-iodo-pyridin-2,6-diamine (20.0 g, 85.2 mmol) described in Manufacturing Example 13-1-1, trimethylsilyl acetylene (24.2 mL, 170 mmol), copper (I) iodide (3.25 g, 17.0 mmol) N,N-diisopropylethylamine (19.1 g, 148 mmol) and N-methylpyrrolidinone (286 mL) was added tetrakis(triphenylphosphine)palladium (0) (9.81 g, 8.52 mmol) under argon atmosphere, which was stirred for 30 minutes at room temperature. The reaction solution was partitioned into water and ethyl acetate. The ethyl acetate layer was washed with water 4 times and dried over sodium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel chromatography (heptane:ethyl acetate=4:1 then 1:1). The solids obtained by concentrating the eluate under a reduced pressure were washed with heptane containing a small amount of ethyl acetate to obtain the title compound (10.5 g, 60.0%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][C:10](=O)[O:11]C1C=CC=CC=1)=[O:8].Cl.[NH:20]1[CH2:25][CH2:24][C:23](=[CH:26][C:27]2[CH:28]=[C:29]([CH:41]=[CH:42][CH:43]=2)[O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=2)[CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C>C(#N)C>[F:39][C:37]([F:40])([F:38])[C:34]1[CH:35]=[CH:36][C:31]([O:30][C:29]2[CH:28]=[C:27]([CH:43]=[CH:42][CH:41]=2)[CH:26]=[C:23]2[CH2:24][CH2:25][N:20]([C:10]([NH:9][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[O:8])=[O:11])[CH2:21][CH2:22]2)=[N:32][CH:33]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(NC(=O)c1ccccn1)Oc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(NC(=O)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1)c1ccccn1
Temperature: 50 °C
Yield: 66.7 %

Procedure:
Phenyl picolinoylcarbamate (145 mg, 0.599 mmol, from Step 1), 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (175 mg, 0.472 mmol) (from Example 1, Step 5), and diisopropylethyl amine (0.16 mL, 0.92 mmol) were combined in acetonitrile (5 mL) and warmed to 50° C. After 3 hours the mixture was cooled to room temperature and concentrated to form a residue. The residue was purified by silica gel chromatography (20-75% EtOAc in CH2Cl2) to provide the title compound (0.152 g). MS APCI M+ 483.1, 376.1, 335.1; M− 481.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.45-2.72 (m, 4H) 3.64 (m, 4H) 6.47 (s, 1H) 6.96-7.06 (m, 2H) 7.08-7.20 (m, 2H) 7.40 (td, J=7.65, 0.91 Hz, 1H) 7.63 (ddd, J=7.63, 4.76, 1.23 Hz, 1H) 8.02 (td, J=7.75, 1.69 Hz, 1H) 8.08 (ddd, J=8.71, 2.55, 0.61 Hz, 1H) 8.18 (dt, J=7.86, 1.08 Hz, 1H) 8.42 (td, J=1.72, 0.80 Hz, 1H) 8.67 (ddd, J=4.76, 1.69, 0.95 Hz, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]([CH3:13])[C:11](=[O:14])[CH:10]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[N:8]=2)[CH2:3]1.Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29].CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.O1CCOCC1>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]([CH3:13])[C:11](=[O:14])[CH:10]=[C:9]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)[N:8]=2)[CH2:3]1
Reactant: Cn1c(N2CC[C@@H](N)C2)nc(-c2ccncc2)cc1=O
Reactant: COc1ccccc1Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1ccccc1N[C@@H]1CCN(c2nc(-c3ccncc3)cc(=O)n2C)C1
Yield: 29.7 %

Procedure:
A solution of 2-((R)-3-aminopyrrolidin-1-yl)-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (0.20 g, 0.74 mmol), 2-bromoanisole (0.13 g, 0.74 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (0.061 g, 0.059 mmol), sodium tertbutoxide (0.10 g, 1.03 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.11 g, 0.18 mmol) in toluene (12 ml) and dioxane (2 ml) was stirred for 19 hours at 90° C. The solvent was evaporated off under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate/methanol=5/1) to afford 2-[(R)-3-(2-methoxyphenylamino)pyrrolidin-1-yl]-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (0.083 g, 29%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH:8]=O.[CH3:10][C:11]([S@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12]>C1COCC1>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1/[CH:8]=[N:16]/[S@@:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15]
Reactant: CC(C)(C)[S@](N)=O
Reactant: Cn1ncc(C=O)c1Cl
Solvent: C1CCOC1
Product: Cn1ncc(/C=N/[S@](=O)C(C)(C)C)c1Cl
Temperature: 25 °C
Yield: 87.3 %

Procedure:
5-chloro-1-methyl-1H-pyrazole-4-carbaldehyde (1130 mg, 7.82 mmol) was suspended in THF (20 ml), Ti(OEt)4 (4.29 ml, 16.4 mmol) was added followed by (R)-(+)-2-methyl-2-propanesulfinamide and the reaction heated to reflux for 18 hours. The reaction was then cooled to room temperature, poured onto EtOAc:Brine (20 ml: 20 ml) filtered through celite and washed through with EtOAc (2×20 ml). The organic layer was then separated, washed with brine (20 ml), dried over Na2SO4, filtered and concentrated to give the title compound as a brown viscous oil (1690 mg, 87.3% yield). 1H NMR (400 MHz, CDCl3) 1.22-1.23 (9H s) 3.88 (3H s) 7.92 (1H s) 8.43 (1H br. s) MS (ESI/APCI) m/z 248 (M+H)+
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6]>C(O)C.[Pd]>[CH3:17][C:2]([CH3:1])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)/C=C/C(C)(C)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC(C)(C)Cc1ccccc1

Procedure:
A solution of ethyl (E)-4,4-dimethyl-5-phenyl-2-pentenoate (55.97 g, 240.9 mmol) in ethanol (150 ml) was hydrogenated using 10% palladium/carbon (containing water by 50%) (5 g) as a catalyst at room temperature overnight under normal pressure. The recovered catalyst of the reaction solution was filtered off and the catalyst was washed with ethanol. The recovered solvent of the filtrate was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1-9/1) to give the objective substance.
Reaction SMILES: [Cl-:1].[NH4+:2].CO[C:5]1[CH:6]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]([CH2:10][CH2:11][CH3:12])[CH2:8][N:9]=1>C(O)C>[Cl-:1].[CH2:13]([CH:6]1[CH:7]([CH2:10][CH2:11][CH3:12])[CH2:8][NH:9][C:5]1=[NH2+:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCC1CN=C(OC)C1Cc1ccccc1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CCO
Product: CCCC1CNC(=[NH2+])C1Cc1ccccc1
Yield: 60 %

Procedure:
Ammonium chloride (155 mg, 2.9 mmol) was added to a solution of 4-benzyl-3-propyl-3,4-dihydro-2H-5-pyrrolyl methyl ether (0.67 g, 2.9 mmol) in ethanol (15 ml) and the mixture was heated to reflux for 4 hours. The reaction mixture was filtered and the filtrate was distilled off under reduced pressure. The residue was crystallized from ethyl acetate to yield the title compound (440 mg) as a white crude product. 1H-NMR (DMSO-d6) δ(ppm) 0.62 (3H, t, J=7.2 Hz), 0.87-1.20 (4H, m), 2.01-2.15 (1H, m), 2.72-2.85 (1H, m), 2.88-2.98 (1H, m), 3.05-3.25 (1H, m), 3.50-3.62 (1H, m), 7.19-7.40 (5H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=3[CH3:26])[C:20]([OH:22])=O)=[CH:16][C:11]2=[N:10][N:9]=1.S(Cl)(Cl)=O.[CH3:31][N:32]1[C:36]([NH2:37])=[CH:35][CH:34]=[N:33]1.C(N(CC)CC)C>C([O-])([O-])=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=3[CH3:26])[C:20]([NH:37][C:36]3[N:32]([CH3:31])[N:33]=[CH:34][CH:35]=3)=[O:22])=[CH:16][C:11]2=[N:10][N:9]=1
Reactant: Cn1nccc1N
Reactant: Cc1ccc(C(=O)O)cc1-c1ccn2c(-c3ccccc3Cl)nnc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Nc2ccnn2C)cc1-c1ccn2c(-c3ccccc3Cl)nnc2c1
Temperature: 95 °C

Procedure:
A mixture of 3-(3-(2-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-4-methylbenzoic acid (2.44 g, 6.7 mmol) and thionyl chloride (30 ml, 411 mmol, Aldrich) was heated to 95° C. for 2 h. The volatiles were removed in vacuo. The solids were re-dissolved in CH2Cl2 (30 ml). A 10 ml aliquot of this solution (860 mg, 2.2 mmol) was treated with 1-methyl-1H-pyrazol-5-amine (656 mg, 6.7 mmol, Maybridge), followed by triethylamine (939 μl, 6.7 mmol, Aldrich). The mixture was diluted with 10% Na2CO3 and extracted with CH2Cl2 (3×). The combined organics were dried over Na2SO4, filtered and concentrated over silica gel. The residue was purified using column chromatography (Acetone/Hexanes=0-50%). The mixture was dissolved in MeOH and loaded onto an Agilent AccuBOND II SCX solid phase extraction column. After washing with MeOH, the title compound was eluted with 2M NH3 in MeOH. The residue was recrystallized from MeOH yielding the title compound as a white solid. HRMS (TOF) Calcd for C24H20ClN6O+: 443.1382, found: 443.1389.
Reaction SMILES: [C:1]([N:4]1[C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:17]=[C:18](Cl)[C:19]([F:21])=[CH:20][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1.C(N1C2C=CC=CC=2C=CC2N=C(C3C=NC(OC)=CC=3)C(F)=CC=2C1)(=O)C>>[C:1]([N:4]1[C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:17]=[C:18]([C:28]3[CH:27]=[N:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=3)[C:19]([F:21])=[CH:20][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccc(Cl)cc21
Agent: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2cc(Cl)ccc2C=C3)cn1

Procedure:
The title compound was prepared from 6D and 2A by a route analogous to that used for the preparation of 2B. HPLC Rt=3.412 min; LCMS Found: (M+H)+=410.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH2:13][CH2:14][NH:15][CH2:16][C:11]3=[N:10][C:9]=2[C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[Cl:51][C:52]1[C:60]([C:61]([F:64])([F:63])[F:62])=[CH:59][CH:58]=[CH:57][C:53]=1[C:54](Cl)=[O:55]>ClCCl>[Cl:51][C:52]1[C:60]([C:61]([F:63])([F:64])[F:62])=[CH:59][CH:58]=[CH:57][C:53]=1[C:54]([N:15]1[CH2:14][CH2:13][N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:9]([C:17]([F:18])([F:19])[F:20])[N:10]=[C:11]2[CH2:16]1)=[O:55]
Reactant: Fc1ccc(-c2c(C(F)(F)F)nc3n2CCNC3)cc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nc(C(F)(F)F)c2-c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-(4-Fluorophenyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (I14) (285 mg, 1 mmol) and diethylaminomethyl polystyrene (1000 mg, 3.20 mmol) were slurried in dichloromethane (DCM) (10 mL) and treated with 2-chloro-3-(trifluoromethyl)benzoyl chloride (267 mg, 1.100 mmol). The slurry was stirred at RT for 24 h, whereupon the resin was filtered and washed with dichloromethane (20 mL). The filtrate was concentrated in vacuo to afford crude product. The product was purified by flash chromatography (Isolera, 10 g, 0-100% ethyl acetate/iso-hexane) to afford product in 428 mg.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][C:4]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:5]=1[C:6]#[N:7].[Br:22][C:23]1[N:27]=[C:26](Cl)[S:25][N:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C.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]>[Br:22][C:23]1[N:27]=[C:26]([C:9]2[CH:10]=[CH:11][C:4]([CH2:3][CH:2]([CH3:1])[CH3:21])=[C:5]([CH:8]=2)[C:6]#[N:7])[S:25][N:24]=1
Reactant: CC(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C#N
Reactant: Clc1nc(Br)ns1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)Cc1ccc(-c2nc(Br)ns2)cc1C#N
Temperature: 80 °C
Yield: 88.5 %

Procedure:
To a solution of 2-(2-methylpropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (D59) (500 mg), 3-bromo-5-chloro-1,2,4-thiadiazole (699 mg) and tripotassium phosphate (1116 mg) in N,N-dimethylformamide (DMF) (6 mL) and water (1.500 mL) stirred under nitrogen was added PdCl2(dppf) (154 mg). The reaction mixture was sealed and heated under microwave at 80° C. for 1 h. After cooling the reaction, the mixture was diluted with ethyl acetate, the organic phase was washed with water, dried and concentrated, the residue was purified by column chromatography to afford 5-(3-bromo-1,2,4-thiadiazol-5-yl)-2-(2-methylpropyl)benzonitrile (D60) (500 mg). δH (CDCl3, 400 MHz): 0.99 (6H, d), 2.04 (1H, m), 2.80 (2H, d), 7.46 (1H, d), 8.05 (1H, dd), 8.22 (1H, d). MS (ES): C13H12BrN3S requires 321. found 322.0 (M+H+).