Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccccc2)c1
Yield: 78 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (293 mg, yield: 78.0%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23]>CN(C)C=O>[F:23][C:22]([F:25])([F:24])[CH2:21][CH2:20][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(C(F)(F)F)cc1
Yield: 42 %

Procedure:
Using 0.50 g of (4-(trifluoromethyl)benzyl)malononitrile, 6 ml of N,N-dimethylformamide, 98 mg of sodium hydride (60% in oil), and 0.43 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.30 g of 2-(3,3,3-trifluoropropyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (74)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([S:32]([OH:35])(=[O:34])=O)=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38].S(Cl)(Cl)=O.CN(C=O)C.[CH3:48][O:49][C:50](=[O:54])[C@@H:51]([CH3:53])[NH2:52]>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([S:32]([NH:52][C@H:51]([CH3:53])[C:50]([O:49][CH3:48])=[O:54])(=[O:35])=[O:34])=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38]
Reactant: COC(=O)[C@@H](C)N
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](C)NS(=O)(=O)c1cc(F)c(CSc2ncc(C(C)(C)c3ccc(Cl)c(OC)c3)n2-c2ccc(F)cc2)c(F)c1
Temperature: 65 °C
Yield: 70.4 %

Procedure:
To a solution of 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorbenzenesulfonic acid (3.0 g, 5.1 mmol) in DCM (15 mL) was added thionyl chloride (7.5 mL) and DMF (0.1 mL). The mixture was heated at 65° C. for 1 h then concentrated in vacuo and azeotroped with toluene (10 mL) and DCM (10 mL). The pale yellow foam was dissolved in DCM (15 mL) and was added dropwise to a solution of D-alanine methyl ester (2.9 g, 20.6 mmol) in 2M Na2CO3 (30 mL) with vigorous stirring. Upon complete addition the layers were separated and the organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with 0-70% ethyl acetate/hexane to afford a white foam (2.4 g, 77%). MS (EI) m/z 601.3 (M+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[CH2:8][NH:9][C@@H:10]1[C@@H:15]([OH:16])[C@H:14]([CH2:17][C:18]2[CH:23]=[C:22]([O:24][CH2:25][C:26](F)(F)F)[C:21]([N+:30]([O-])=O)=[C:20]([F:33])[CH:19]=2)[CH2:13][S:12](=[O:35])(=[O:34])[CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[ClH:41].[CH3:42][OH:43]>CCOCC>[ClH:41].[ClH:41].[NH2:30][C:21]1[C:22]([O:24][CH2:25][CH2:26][O:43][CH3:42])=[CH:23][C:18]([CH2:17][C@H:14]2[C@H:15]([OH:16])[C@@H:10]([NH:9][CH2:8][C:7]3[CH:36]=[CH:37][CH:38]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=3)[CH2:11][S:12](=[O:35])(=[O:34])[CH2:13]2)=[CH:19][C:20]=1[F:33]
Reactant: CC(C)(C)c1cccc(CN[C@H]2CS(=O)(=O)C[C@@H](Cc3cc(F)c([N+](=O)[O-])c(OCC(F)(F)F)c3)[C@@H]2O)c1
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Product: COCCOc1cc(C[C@@H]2CS(=O)(=O)C[C@H](NCc3cccc(C(C)(C)C)c3)[C@H]2O)cc(F)c1N
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a solution of (3R,4S,5S)-3-(3-tert-butyl-benzylamino)-5-[3-fluoro-4-nitro-5-(2,2,2-trifluoro-ethoxy)-benzyl]-1,1-dioxo-hexahydro-1lambda*6*-thiopyran-4-ol (0.082 g, 0.166 mol) in MeOH (5 mL) was added NiCl2-6H2O (0.038 g, 0.155 mmol) and at 0° C. NaBH4 (0.024 g, 0.62 mmol) in two portions. After stirring for 1 h at 0-5° C. the reaction was quenched by addition of 1N aq. HCl. The reaction mixture was stirred for 0.5 h at 25° C. and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Chromatographic purification (Combi-Flash, 4 g, hexane-THF 90:10 to 10:90 containing 0.5% NEt3) provided a pure yellow oil which was converted into the hydrochloride salt with 1N HCl in Et2O to yield the title compound as a white amorphous solid: TLC (hexane-THF 2:3) Rf=0.22; HPLC RtA=1.56 min; ESIMS [M+NH4]+=509; 1H NMR (600 MHz, DMSO-d6): δ 9.89 (s, 1H), 9.08 (s, 1H), 7.67 (s, 1H), 7.43 (m, 1H), 7.38 (m, 2H), 6.62 (m, 2H), 6.18 (s, 1H), 4.24 (m, 2H), 4.14 (m, 2H), 3.82 (m, 1H), 3.3-3.7 (m, 5H), 3.29 (s, 3H), 3.24 (m, 2H), 3.03 (dd, 1H), 2.77 (m, 1H), 2.40 (dd, 1H), 2.04 (m, 1H), 1.35 (d, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([Cl:10])=[C:8]([C:11](Cl)=[O:12])[S:7][C:6]=2[CH:14]=1.[CH3:15][OH:16].Cl[Si](C)(C)C.II>C(OCC)(=O)C.CCCCCC>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([Cl:10])=[C:8]([C:11]([O:16][CH3:15])=[O:12])[S:7][C:6]=2[CH:14]=1
Reactant: Cc1ccc2c(Cl)c(C(=O)Cl)sc2c1
Reactant: CO
Agent: C[Si](C)(C)Cl
Agent: II
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1sc2cc(C)ccc2c1Cl
Reaction time: 24 h

Procedure:
Crude 6-methyl-3-chlorobenzo[b]thiophene-2-carbonyl chloride (5 g, 20.46 mmoles) was transferred to a 250 ml round bottomed flask. Anhydrous methanol (Aldrich, 80 ml) was added and the acid chloride dissolved by stirring. To this stirred solution was added chlorotrimethylsilane (3.0 equivalents, 61.38 mmole, 6.68 g, 7.80 ml). The reaction mixture was stirred at room temperature and the progress of the reaction monitored by TLC (Silica, 1:1 hexane:ethyl acetate, and 100% ethyl acetate, iodine and UV visualization). The reaction was shown to be complete after 24 hours. The resulting slurry was concentrated in vacuo to give 4.80 g of a yellow solid, which was shown by 1H NMR (DMSO-D6, 400 MHz) to be the desired material. The crude methyl ester was shown to be pure and used directly.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11](CN)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>O1CCCC1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 1-Boc-4-aminomethylpiperidine (2140 mg, 10 mmol) in tetrahydrofuran (25 ml), FmocNCS (3091 mg, 11 mmol) was added and the mixture was stirred at room temperature overnight. Upon completion of the reaction, the reaction mixture was concentrated, and then purified by silica gel column chromatography (hexane/ethyl acetate=85/15→4/1) to obtain [({[fluoren-9-ylmethoxy]carbonylamino}thioxomethyl)amino]methyl]piperidinecarboxylic acid tert-butyl ester. The compound was identified by LC-MS.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:21][C:22]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2c1F
Reactant: CC1(C)OB(c2cc(-c3ccccc3C#N)ccc2F)OC1(C)C
Product: CC(C)(O)c1ccn2c(-c3cc(-c4ccccc4C#N)ccc3F)cnc2c1F
Yield: 56 %

Procedure:
2-(3-Bromo-8-fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 4′-fluoro-3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-2-carbonitrile (prepared as described in WO 02/074773) as described in Example 1 to give 4′-fluoro-3′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-2-carbonitrile as an off-white solid (217 mg, 56%): δH (360 MHz, CDCl3) 1.74 (6H, s), 2.15 (1H, s), 7.22 (1H, t, J 7), 7.40 (1H, t, J 9), 7.48-7.73 (5H, m), 7.79-7.81 (2H, m), 8.06 (1H, dd, J 7 and 2); m/z (ES+) 390 [MH+].
Reaction SMILES: [CH:1]([NH:3][CH:4]([C:8]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:11][CH2:10][CH2:9]1)[CH2:5][CH2:6][CH3:7])=O.[CH3:20]COCC.Cl.C=O>CC(O)C.C(O)=O.O>[ClH:18].[CH3:1][N:3]([CH:4]([C:8]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:11][CH2:10][CH2:9]1)[CH2:5][CH2:6][CH3:7])[CH3:20]
Reactant: CCCC(NC=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: CCOCC
Agent: C=O
Agent: Cl
Solvent: O=CO
Solvent: O
Solvent: CC(C)O
Product: CCCC(N(C)C)C1(c2ccc(Cl)c(Cl)c2)CCC1

Procedure:
The product of Example 7 (8.3 g), diethyleneglycoldimethyl ether (50 ml), water (20 ml) and concentrated hydrochloric acid (20 ml) were mixed and heated under reflux for sixteen hours. The mixture was poured into water aqueous NaOH was added and the product extracted into ether. Evaporation gave a dark oil. A sample of this oil (7.9 g), water (0.7 ml) and formic acid (6.5 ml) were mixed and formaldehyde (6.5 ml) added. The mixture was heated under reflux for three hours and then concentrated hydrochloric acid (10 ml) and propan-2-ol (10 ml) were added. Evaporation to dryness gave N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine hydrochloride (m.p. 195°-196°) as a white solid (Formula I R1 =propyl; R2 =H; R3, R4 =Me; R5 =4-Cl and R6 =3-Cl).
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([C:36]([C:38]2[S:42][C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[C:39]=2[Cl:47])=[O:37])[CH2:16][C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CCO.C(Cl)Cl>[C:1]([O:5][C:6](=[O:48])[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([C:36]([C:38]2[S:42][C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[C:39]=2[Cl:47])=[O:37])[CH2:16][C:17]2[CH:18]=[C:19]([C:24]3[CH:25]=[CH:26][C:27]([CH:30]([OH:35])[C:31]([F:33])([F:32])[F:34])=[CH:28][CH:29]=3)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(N(Cc2cc(-c3ccc(C(=O)C(F)(F)F)cc3)ccc2F)C(=O)c2sc3ccccc3c2Cl)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)C1CCC(N(Cc2cc(-c3ccc(C(O)C(F)(F)F)cc3)ccc2F)C(=O)c2sc3ccccc3c2Cl)CC1
Temperature: 25 °C

Procedure:
Trifluoroacetophenone (265) (90 mg, 0.13 mmol) was dissolved in EtOH (0.9 mL) with a little DCM. Sodium borohydride (8 mg, 0.21 mmol) was added portionwise and the reaction stirred at RT until complete. H2O (5 mL) was added and the product extracted with EtOAc (2×5 mL). Drying (MgSO4), filtration, reduction in vacuo and chromatography with EtOAc/heptanes gave the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])C=CC=CC=1.[C:26]1(=[O:33])[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[O:33]=[C:26]1[CH2:27][CH2:28][C:29](=[C:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH2:30][CH2:31]1
Reactant: O=C1CCC(=O)CC1
Reactant: COC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)=C1CCC(=O)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 2-(triphenylphosphoranylidene)propanoate (2.5 g, 7.18 mmol) and cyclohexane-1,4-dione (1.609 g, 14.35 mmol) in toluene (25 mL) was stirred at 100° C. overnight and then concentrated in vacuo. The residue was triturated with a mixture of hexanes (100 mL) and ethyl acetate (100 mL), and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on Analogix IntelliFlash280 eluting with 0 to 50% ethyl acetate/hexanes to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 1.85 (p, J=1.5 Hz, 3H), 2.27-2.35 (m, 2H), 2.41 (dd, J=8.0, 5.8 Hz, 2H), 2.55-2.65 (m, 2H), 2.81-2.90 (m, 2H), 3.66 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N+:11]([O-])=[C:10]([CH3:15])[CH:9]=2)=[CH:4][CH:3]=1.C[Si]([C:20]#[N:21])(C)C.CN(C)C(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:15])[N:11]=[C:12]([C:20]#[N:21])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(-c2ccc(F)cc2)cc[n+]1[O-]
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(-c2ccc(F)cc2)cc(C#N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 162 %

Procedure:
To a solution of 1.30 g (6.4 mmol) of 4-(4-Fluoro-phenyl)-2-methyl-pyridine 1-oxide in 20 ml of methylene chloride was added dropwise 1.00 ml (8.0 mmol, 1.25 equiv.) of Trimethylsilyl cyanide. Then 0.73 ml (0.86 g, 8.0 mmol, 1.25 equiv.) of Dimethylcarbamoyl chloride was added dropwise over a period of 5 min. After stirring overnight at room temperature, 8 ml of saturated sodium carbonate solution were added. The aqueous phase was extracted twice with 15 ml of methylene chloride. The combined organic phases were washed with 20 ml of brine, dried over magnesium sulfate, and concentrated in vaccuo to yield 2.2 g of a beige solid which was purified by flash chromatography (ethyl acetate/hexane 1:4) to yield the title compound (0.75 g, 55%) as a crystalline white solid, MS (ISP): m/e=213.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=2)[N:5]2[CH:21]=[CH:22][N:23]=[C:4]2[CH:3]=1.[CH:24]([N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1)([CH3:26])[CH3:25].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>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].O1CCOCC1>[CH:24]([N:27]1[CH:31]=[C:30]([C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[N:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=3)[N:5]3[CH:21]=[CH:22][N:23]=[C:4]3[CH:3]=2)[CH:29]=[N:28]1)([CH3:26])[CH3:25]
Reactant: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Si](C)(C)CCOCn1cc(-c2nc(Cl)cc3nccn23)cn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2cc3nccn3c(-c3cnn(COCC[Si](C)(C)C)c3)n2)cn1
Temperature: 65 °C
Yield: 78 %

Procedure:
To a flask charged with 7-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation G; 0.200 g, 0.572 mmol), 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.202 g, 0.857 mmol) (Table 2, compound a), and potassium phosphate (0.857 mL, 1.71 mmol) was added 5 mL of Dioxane and argon was bubbled through for 10 minutes before dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.0545 g, 0.114 mmol) and tris(dibenzylideneacetone)dipalladium (0.0523 g, 0.0572 mmol) were added quickly and argon was bubbled through the reaction for 10 minutes before it was sealed and heated to 65° C. overnight. The reaction was diluted with ethyl acetate (100 mL) and washed with aqueous saturated sodium bicarbonate (40 mL) and brine (40 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography, eluting with a mixture of ethyl acetate and 0.5% ammonium hydroxide to afford 7-(1-isopropyl-1H-pyrazol-4-yl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.191 g, 0.446 mmol, 78.1% yield). MS (apci) m/z=424.2 (M+H).
Reaction SMILES: [SH2:1].[Br-].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([C:8](=[N+]2CCCCC2)[S:9][CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.C(=O)=O>C(O)C>[C:11]([CH2:10][S:9][C:8](=[S:1])[C:7]1[CH:19]=[CH:20][C:4]([Cl:3])=[CH:5][CH:6]=1)#[N:12]
Reactant: S
Reactant: N#CCSC(c1ccc(Cl)cc1)=[N+]1CCCCC1
Agent: O=C=O
Agent: [Br-]
Solvent: CCO
Product: N#CCSC(=S)c1ccc(Cl)cc1
Temperature: -20 °C

Procedure:
Hydrogen sulfide gas is added to a stirred suspension of 1-[p-chloro-α-(cyanomethylthio)benzylidene]piperidinium bromide (13.7 g; 0.037 mol) in ethanol (50 ml), using a dry ice condenser to contain the gas. The reaction mixture slowly becomes a clear, red solution and the temperature rises to 25° C. The reaction mixture is chilled to -20° C., and an excess of hydrogen sulfide is maintained in the reaction mixture for 3 hours, as evidenced by the condensation of same throughout this period in the dry ice, chilled condenser. The reaction mixture is then allowed to warm up to room temperature, and the excess hydrogen sulfide allowed to evaporate overnight. The reaction mixture is then concentrated in vacuo to yield 8.9 g of a red oil. The red oil is chromatographed on silica gel (300 g) and eluted with a 1:1 mixture of methylene chloride:hexane. Collection of the main fraction affords 4.25 g (50%) of title product, a red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2/[CH:12]=[C:13](\[F:16])/[CH:14]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:17]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH2:20][CH3:21])=[O:18]>ClCCl>[CH2:20]([O:19][C:17](=[O:18])/[CH:22]=[CH:14]/[C:13](/[F:16])=[CH:12]\[C@@H:10]1[CH2:11][C@H:9]1[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:21]
Reactant: O=C/C(F)=C/[C@@H]1C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/C(F)=C\[C@@H]1C[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 91.6 %

Procedure:
The above aldehyde (0.5 g) was dissolved in dichloromethane (5 ml) under nitrogen and treated with carboethoxymethylenetriphenylphosphorane (0.67 g) at 25°. After 18 hours at 25° the solution was concentrated in vacuo and the residue washed with hexane. Combined hexane washings were concentrated in vacuo to give (±)-(2E,4E)-Ethyl-4-fluoro-5-[trans-2-(3,4-dichlorophenyl) cyclopropyl]penta-2,4-dienoate (0.58 g). NMR 1H: 7.30(1H,d), 7.00(3H,m), 6.05(1H,d), 5.90(1H,m), 4.20(2H,q), 2.00(2H,m), 1.30(3H,t), 1.30(2H,m).
Reaction SMILES: [C:1]([CH:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]1(O)[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].O=S(Cl)Cl>N1C=CC=CC=1>[C:1]([C:3]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[C:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C(C#N)c2ccccc2)CC1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(=C(C#N)c2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
To tert-butyl 4-[cyano(phenyl)methyl]-4-hydroxypiperidine-1-carboxylate (1.8 g, 5.69 mmol) in pyridine (4 ml) was added SOCl2 (2.076 ml, 28.4 mmol) and the reaction was stirred for 10 min. The reaction mixture was concentrated in vacuo. The resulting crystalline solid was adsorbed onto silica gel and purified by silica gel chromatography in an Isco Companion. The desired fractions were combined and concentrated in vacuo. 1.18 g, 70% over two steps.
Reaction SMILES: [Cl:1][SiH:2]([CH3:4])[CH3:3].[C:5]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[CH2:6][CH2:7][CH:8]=[CH2:9]>>[Cl:1][Si:2]([CH3:4])([CH3:3])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: C=CCCC(=O)OCc1ccccc1
Reactant: C[SiH](C)Cl
Product: C[Si](C)(Cl)CCCCC(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a mixture of chlorodimethylsilane (0.730 g; 6.57 mmol) and benzyl pent-4-enoate (1.25 g; 6.57 mmol) under argon was added one drop of Karstedt's catalyst solution (in xylenes; ˜2% Pt). The reaction vessel was sealed and the mixture was heated to 60° C. for 13.5 hours. The crude liquid was used without purification.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]([C:25]([O:27]CC)=[O:26])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[CH:12][CH:11]=2)[C:7]2[CH:30]=[CH:31][CH:32]=[C:33]([CH3:34])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[OH-].[Na+]>C(O)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH:17]([C:25]([OH:27])=[O:26])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[CH:14][CH:15]=2)[C:7]2[CH:30]=[CH:31][CH:32]=[C:33]([CH3:34])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cccc2n1Cc1ccc(OC(C(=O)OCC)c2ccccc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc2c(C)cccc2n1Cc1ccc(OC(C(=O)O)c2ccccc2Cl)cc1

Procedure:
Prepared analogously to Example 1b from 2-n-propyl-4-methyl-1-[4-[(α-ethoxycarbonyl)-2-chlorobenzyloxy]-benzyl]benzimidazole and 2N sodium hydroxide solution in ethanol.
Reaction SMILES: [F:1][C:2]([O:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)=[C:3]([F:5])[F:4].[Li]C(C)(C)C.CN([CH:22]=[O:23])C>C(OCC)C>[F:1][C:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:22]=[O:23])=[CH:9][CH:8]=1)=[C:3]([F:5])[F:4]
Reactant: FC(F)=C(F)Oc1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: O=Cc1ccc(OC(F)=C(F)F)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Compound 32 intermediates: To a solution of 4-(trifluorovinyloxy)-bromobenzene (9.25 g, 36.6 mmol) in dry diethyl ether (60 mL) at −78° C. was added t-BuLi (23.7 mL, 1.7 M in pentane) dropwise. One hour later, DMF (4.3 mL, 1.5 eq) was added dropwise. The reaction mixture was stirred at −78° C. for 1 h. Then the reaction mixture was allowed to warm up to room temperature for about 45 min, and quenched by adding water (10 mL). The ethereal layer was collected and the aqueous layer was extracted with diethyl ether. The combined organic layer was washed with water twice (50 mL×2), and dried over sodium sulfate. After filtration and evaporation of the solvent, the product was dried in vacuum overnight to give 4-(trifluorovinyloxy)benzaldehyde as yellow oil, which can be used in next step without further purification. 1H NMR (CDCl3): δ 10.18 (s, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.8 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=1[N+:18]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].CCOC(C)=O>C1COCC1.O>[NH2:18][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:10]=1[S:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])[C:14]#[N:15]
Reactant: N#Cc1ccc(Sc2cc(Cl)ccc2Cl)c([N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(Sc2cc(Cl)ccc2Cl)c(N)c1
Temperature: 45 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
A solution of compound 27 (11.8 g, 36.36 mmol) in THF (200 mL) was combined with a solution of sodium hydrosulfite (37.98 g, 218.1 6 mmol) in water (50 mL). The combined solution was stirred vigorously overnight at 45° C. The reaction was monitored by TLC (25% EtOAc in hexanes), and was complete after 16 hrs as indicated by absence of the starting material. The reaction was removed from heat and THF was evaporated. Aqueous solution was filtered to yield a white solid. The solid was washed with water and dried in a vacuum oven overnight to yield compound 28 (9.077 g, 97% HPLC purity, 84.6% yield). 1H NMR (500 MHz, DMSO-d6): δ 7.55 (d, J=8 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 7.28 (dd, J1=2 Hz, J2=7 Hz, 1H), 7.19 (d, J=2 Hz, 1H), 6.99 (dd, J1=2 Hz, J2=8 Hz, 1H), 6.50 (d, J=2 Hz, 1H), 6.04 (s, 2H).