Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=1)#[CH:2].[CH2:16]([O:18][C:19]1[CH:24]=[C:23](I)[CH:22]=[CH:21][N:20]=1)[CH3:17]>C(#N)C.[Cu]I>[CH2:16]([O:18][C:19]1[CH:24]=[C:23]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=2)[CH:22]=[CH:21][N:20]=1)[CH3:17]
Reactant: C#Cc1ccc(CC(C)NC(C)=O)cc1
Reactant: CCOc1cc(I)ccn1
Agent: [Cu]I
Solvent: CC#N
Product: CCOc1cc(C#Cc2ccc(CC(C)NC(C)=O)cc2)ccn1
Temperature: 25 °C

Procedure:
To 100 mg (0.50 mmol) N-[2-(4-ethynyl-phenyl)-1-methyl-ethyl]-acetamide (I58.2) and 124 mg (0.50 mmol) 2-ethoxy-4-iodo-pyridine (I6.1) in 5.00 mL ACN are added 20.3 mg (0.03 mmol) 1,1′-bis[diphenylphosphino]ferrocenepalladium dichloride dichloromethane complex (1:1), 4.83 mg (0.03 mmol) CuI and 0.16 mL (1.16 mmol) TEA. The mixture is stirred at r.t. over night, then poured onto water and extracted with DCM. The organic layer is dried with MgSO4 and the solvent is removed in vacuo. The residue is purified by column chromatographie (silica gel; PE/EtOAc 1/1→EtOAc 100%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[NH:10][C:11]1[N:15]2[CH:16]=[CH:17][CH:18]=[N:19][C:14]2=[N:13][C:12]=1[C:20]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:21]=1[C:22]([NH:24][NH2:25])=[O:23].Cl[C:35](OC(Cl)(Cl)Cl)=[O:36]>O1CCOCC1>[Cl:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[C:4]=1[NH:10][C:11]1[N:15]2[CH:16]=[CH:17][CH:18]=[N:19][C:14]2=[N:13][C:12]=1[C:20]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:21]=1[C:22]1[O:23][C:35](=[O:36])[NH:25][N:24]=1
Reactant: COc1cc(OC)c(-c2nc3ncccn3c2Nc2c(Cl)cccc2Cl)c(C(=O)NN)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(OC)c(-c2nc3ncccn3c2Nc2c(Cl)cccc2Cl)c(-c2n[nH]c(=O)o2)c1

Procedure:
115 mg of 2-[3-(2,6-dichlorophenylamino)imidazo[1,2-a]pyrimidin-2-yl]-3,5-dimethoxybenzohydrazide hydrochloride and 26 μl of trichloromethyl chloroformate (diphosgene) are heated under reflux for 2 hours in 5 ml of dioxane. The reaction mixture is evaporated, and water and DCM are added. The aqueous phase is rendered neutral, extracted a number of times with DCM, and the combined organic phases are dried and evaporated. Purification by column chromatography (ethyl acetate/methanol) and washing of the resultant solid by stirring with heptane gives 35 mg (33%) of “A6”; MS-FAB (M+H+)=499.4; Rf (polar method): 1.61 min.
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[C:5](=[O:13])[O:4][CH2:3]1>C(Cl)Cl>[Br:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:13])[O:4][CH:3]=[CH:2]2
Reactant: O=C1OCC(Br)c2cc(Br)ccc21
Solvent: ClCCl
Product: O=c1occc2cc(Br)ccc12

Procedure:
4,6-dibromo-3,4-dihydro-1H-isochromen-1-one (1.76 g, 5.75 mmol) was dissolved in DCM (15 mL) then added TEA (20 mL, 143 mmol) and stirred at room temperature for 72 hrs. The mixture was concentrated then took up the residue with DCM and washed with 1N HCl. Repeated the wash with brine then dried over Na2SO4 and evaporated to dryness. The residue was purified by MPLC with 0-100% ETOAc/hexane to yield 6-bromo-1H-isochromen-1-one. LC-MS (IE, m/z): 227 [M+2]+; 1H-NMR (500 MHz, CDCl3) δ ppm 8.18 (d, J=8.5 Hz, 1H), 7.67 (dd, J=1.8, 6.4 Hz, 1H), 7.64 (d, J=1.9 Hz, 1H), 7.33 (d, J=5.7 Hz, 1H), 6.47 (d, J=5.8 Hz, 1H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=Cc1ccc(Br)s1
Product: COc1ccc(-c2ccc(C=O)s2)cc1
Yield: 82 %

Procedure:
The title compound was prepared from 5-bromo-thiophene-2-carbaldehyde (2.0 g, 10.5 mmol) and (4-methoxyphenyl) boronic acid (1.6 g, 11 mmol) using the procedure of Example 159, step 1 with 82% yield (1.9 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.C(OC(=O)C)(=O)C.[N+:20]([O-])([OH:22])=[O:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][C:4]=1[N+:20]([O-:22])=[O:21]
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(CC(C)=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of 4-methoxyphenylacetone 9 (6.56 g, 4 mmol) in acetic anhydride (16 mmol) was added 90% HNO3 dropwise at −5° C. After adding HNO3, the ice-bath was removed and allowed to warm up to room temperature. The reaction was quenched by adding ice water. The resulting solution was extracted with ethyl acetate three times. The organic phase was dried over Na2SO4. Removal of the solvent under reduced pressure afforded crude product. Purification of the crude product by using silica gel column gave 10 (4.9 g, 59%). 1HNMR(CDCl3): 7.70 (d, J=2.1 Hz, 1H), 7.37 (dd, J=2.2 Hz, 8.5 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H), 3.95 (s, 3H), 3.74 (s, 2H), 2.21 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:26](O)=[O:27])=[C:13]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])[N:14]=1)=[O:8].[CH:31]([NH2:34])([CH3:33])[CH3:32]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:26]([NH:34][CH:31]([CH3:33])[CH3:32])=[O:27])=[C:13]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])[N:14]=1)=[O:8]
Reactant: O=C(Nc1nc(-c2c(F)c(F)c(F)c(F)c2F)c(C(=O)O)s1)c1cc(Br)ccc1O
Reactant: CC(C)N
Product: CC(C)NC(=O)c1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1c(F)c(F)c(F)c(F)c1F
Yield: 23.9 %

Procedure:
Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)-thiazol-5-carboxylic acid and isopropylamine as the raw materials, the same operation as the example 212(2) gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:31]([O:33]C1C=CC=CC=1N=C=O)[CH3:32].Cl>>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[O:33][CH2:31][CH3:32])[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCOc1ccccc1N=C=O
Reactant: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccccc1
Agent: Cl
Product: CCOc1ccccc1N1CCN(CCN2CCC(c3noc4cc(F)ccc34)CC2)C1=O

Procedure:
This product is obtained in the same manner as the compound of Example 5, but with replacement of the phenyl isocyanate by 2-ethoxyphenyl isocyanate in Step 1 of the synthesis. The hydrochloride of the title compound melts at 214°-218° C.
Reaction SMILES: C(N(CC)[C:4](=[O:15])[CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:14])C.FC(F)(F)C(O)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:13][O:12][C:11]1[C:6]2[CH2:5][C:4](=[O:15])[O:14][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CCN(CC)C(=O)Cc1c(O)cccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1cccc2c1CC(=O)O2
Temperature: 125 °C
Reaction time: 1.18 h
Yield: 82.2 %

Procedure:
A solution of 0.47 g (2.0 mmol) of N,N-diethyl-(2-hydroxy-6-methoxyphenyl)acetamide in 5.0 mL of toluene was added with 0.92 mL (1.36 g, 12 mmol) of trifluoroacetic acid and heated and stirred on a 125° C. oil bath of for 71 minutes. The mixture was cooled under room temperature, and after that added with 24 mL of 0.5 N aqueous sodium hydroxide, while being stirred, and then transferred into a separatory funnel and settled. The aqueous layer was separated and discarded and after the organic layer was washed with 5 mL of water twice, the solvent was evaporated to obtain 0.27 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[S:10]2(=[O:21])=[O:20])=[CH:5][C:4]=1[CH3:22].[F:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([F:34])[C:25]=1[CH2:26]Br.C([O-])([O-])=O.[K+].[K+].COC1C(C)=CC(N2C(=O)N(CC3C(F)=CC(F)=CC=3F)C3C=CC=CC=3S2(=O)=O)=CC=1C>CN(C=O)C>[F:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([F:34])[C:25]=1[CH2:26][N:13]1[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10](=[O:21])(=[O:20])[N:9]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[C:4]([CH3:22])[CH:5]=2)[C:14]1=[O:15]
Reactant: COc1ncc(N2C(=O)Nc3ccccc3S2(=O)=O)cc1C
Reactant: COc1cc(F)c(CBr)c(F)c1
Agent: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(F)c(CN2C(=O)N(c3cnc(OC)c(C)c3)S(=O)(=O)c3ccccc32)c(F)c1
Yield: 26 %

Procedure:
The title compound (60 mg, 0.13 mmol) was prepared from 2-(6-methoxy-5-methylpyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide (IntA28) (161 mg, 0.50 mmol), 2,6-difluoro-4-methoxybenzyl bromide (179 mg, 0.76 mmol) and K2CO3 (104 mg, 0.75 mmol) in DMF (3 mL) using the methods of (115).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH3:16].CO>[Ni]>[F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[S:11][C:10]([CH2:12][NH2:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: N
Reactant: O=Cc1ccc(Cc2ccc(F)cc2)s1
Agent: [Ni]
Solvent: CO
Product: NCc1ccc(Cc2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 15.1 %

Procedure:
7N ammonia/methanol (30 mL) and Raney nickel (500 mg) were added to 5-(4-fluorobenzyl)thiophene-2-carbaldehyde described in Preparation Example 37 (460 mg, 2.09 mmol), and the mixture was stirred for 14 hours under hydrogen atmosphere at room temperature. The catalyst was removed by filtering through Celite pad, then, purification by silica gel column chromatography (ethyl acetate, then ethyl acetate:methanol=4:1) was carried out, and the title compound (70 mg, 0.316 mol, 15.1%) was obtained as an oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2S(C2C=CC(C)=CC=2)(=O)=O)=[C:4]([C:21]2[N:22]=[C:23]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[C:24]3[S:29][C:28]([CH2:30]OS(C4C=CC(C)=CC=4)(=O)=O)=[CH:27][C:25]=3[N:26]=2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:54][C@H:55]1[CH2:60][NH:59][CH2:58][C@@H:57]([CH3:61])[NH:56]1.[OH-].[Na+].[Cl-].[NH4+]>CN(C=O)C.C(Cl)Cl.O>[CH3:54][C@H:55]1[NH:56][C@@H:57]([CH3:61])[CH2:58][N:59]([CH2:30][C:28]2[S:29][C:24]3[C:23]([N:42]4[CH2:43][CH2:44][O:45][CH2:46][CH2:47]4)=[N:22][C:21]([C:4]4[CH:3]=[C:2]([F:1])[CH:10]=[C:9]5[C:5]=4[CH:6]=[CH:7][NH:8]5)=[N:26][C:25]=3[CH:27]=2)[CH2:60]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Cc1ccc(S(=O)(=O)OCc2cc3nc(-c4cc(F)cc5c4ccn5S(=O)(=O)c4ccc(C)cc4)nc(N4CCOCC4)c3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2cc3nc(-c4cc(F)cc5[nH]ccc45)nc(N4CCOCC4)c3s2)C[C@H](C)N1

Procedure:
To a solution of toluene-4-sulfonic acid 2-[6-fluoro-1-(toluene-4-sulfonyl)-1H-indol-4-yl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl ester (100 mg, 0.144 mmol) in DMF (1 mL) were added potassium carbonate (100 mg, 0.724 mmol) and (cis)-2,6-dimethyl-piperazine (33 mg, 0.289 mmol). The reaction mixture was stirred at RT for 2 h before water and DCM were added. The phases were separated using a hydrophobic frit and the organic phase was concentrated in vacuo. The resultant residue was dissolved in dioxane (1 mL) and IMS (1 mL), and an aqueous solution of NaOH (12 M, 1 mL, 12 mmol) was added. The mixture was stirred at RT for 3 h before a sat. aqueous solution of ammonium chloride and DCM were added.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:10][C:11]1[CH:12]=[C:13]2[C:18]3=[C:19]([CH2:21][CH2:22][N:17]3[CH2:16][C@@H:15]3[CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25][C@H:14]23)[CH:20]=1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH3:9])=[CH:3][C:2]=1[NH:10][C:11]1[CH:12]=[C:13]2[C:18]3=[C:19]([CH2:21][CH2:22][N:17]3[CH2:16][C@@H:15]3[CH2:23][NH:24][CH2:25][C@H:14]23)[CH:20]=1
Reactant: Cc1ccc(Cl)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCc4cc(N)cc(c43)[C@H]2C1
Product: Cc1ccc(Cl)c(Nc2cc3c4c(c2)[C@H]2CNC[C@H]2CN4CC3)c1

Procedure:
Using 3-bromo-4-chlorotoluene and following the procedures described in EXAMPLE 17, Parts B and C, (±)-cis tert-butyl 2-amino-4,5,7a,8,10,10a-hexahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinoline-9(7H)-carboxylate was converted into (±)-cis-N-(2-chloro-5-methylphenyl)-4,5,7,7a,8,9,10,10a-octahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinolin-2-amine, bis-trifluoroacetic acid salt, after HPLC purification (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA). This material was free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to the title compound of EXAMPLE 117 as the free base. 1H NMR (CDCl3) δ: 7.18 (d, 1H, J=8.0 Hz), 6.91 (s, 1H), 6.71 (app s, 2H), 6.52 (dd, 1H, J=8.0, 1.4 Hz), 5.83 (s, 1H), 3.79 (dd, 1H, J=11.4, 8.1 Hz), 3.63 (dd, 1H, J=11.5, 7.1 Hz), 3.54 (q, 1H, J=7.5 Hz), 3.37-3.22 (m, 3H), 3.15 (dd, 1H, J=11.3, 8.4 Hz), 3.08-2.92 (m, 4H), 2.85 (dd, 1H, J=10.4, 7.5 Hz). LRMS (ES)+: 340.3 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]#[N:13])[C:8]([C:14]#[N:15])=[CH:7][CH:6]=2.[Br:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([C:24]2[O:25][C:26]([CH2:29]Cl)=[N:27][N:28]=2)[CH:23]=1>>[Br:17][C:18]1[CH:23]=[C:22]([C:24]2[O:25][C:26]([CH2:29][N:4]3[C:5]4[C:10](=[C:9]([C:12]#[N:13])[C:8]([C:14]#[N:15])=[CH:7][CH:6]=4)[CH:11]=[C:3]3[CH:2]([F:1])[F:16])=[N:27][N:28]=2)[CH:21]=[N:20][CH:19]=1
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1C#N
Reactant: ClCc1nnc(-c2cncc(Br)c2)o1
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2nnc(-c3cncc(Br)c3)o2)c1C#N

Procedure:
Synthesized as described in Example 23 from 2-(difluoromethyl)-1H-indole-4,5-dicarbonitrile and 3-bromo-5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyridine: MS (ES) m/z 455 and 457 (M+1 Br isotopes).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CCN(CC)CC>C(Cl)Cl>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1nc(Cl)nc(N2CCOCC2)n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
To a solution of cyanuric chloride (2.5 g, 13.5 mmol) in CH2Cl2 (150 mL) was added dropwise morpholine (1.14 g, 13.5 mmol) at −78° C., followed by addition of Et3N (3.0 mL, 21.5 mmol). The resulting reaction mixture was stirred at −78° C. for 20 min, and then diluted with CH2Cl2. The organic phase was washed with water and brine, and dried over MgSO4. The solvent was removed in vacuum to give the title compound as white crystalline solid (3.027 g, 95% yield). MS (ESI) m/z 235.1.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.C([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:33])=[CH:26][CH:25]=1)C1C=CC=CC=1>CCCCCC.C1COCC1>[CH:34]1([C:32]2([CH2:31][CH2:30][C:27]3[CH:26]=[CH:25][C:24]([OH:23])=[CH:29][CH:28]=3)[O:33][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(CCc1ccc(OCc2ccccc2)cc1)C1CCCCC1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=C(O)CC(CCc2ccc(O)cc2)(C2CCCCC2)O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The title compound was prepared as described in General Method 6 using 11.6 g (99.9 mmol) of methyl acetoacetate, 4.19 g (105 mmol) of NaH (60% dispersion in oil), 64.0 mL (102 mmol) of 1.6M n-butyl lithium in hexane, 16.1 g (49.9 mmol) of 3-(4-benzyloxy-phenyl)-1-cyclohexyl-propan-1-one (prepared in Example G) and 550 mL of THF. After addition of the ketone, the reaction was stirred for 120 minutes at 0° C., then 1 hour at room temperature. The reaction was quenched with acetic acid (12 mL) and worked up in the usual manner. The crude product was carried on without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:18][NH:19][CH3:20]>C(#N)C>[CH3:18][N:19]([CH3:20])[CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 84 %

Procedure:
To a mixture of 4-nitrobenzyl bromide (4 g, 18.5 mmol) and potassium carbonate (7.65 g, 55.5 mmol) in acetonitrile (50 ml) at 0-5° C. was added 40% aqueous dimethyl amine solution (1.5 eq). After 1 hr at room temperature, the solvent was evaporated; the crude material was dissolved in water and extracted with ethyl acetate. The organic layer was dried and concentrated to give dimethyl-(4-nitro-benzyl)-amine (2.8 g, 84%)
Reaction SMILES: [CH:1]([Si:3]([Cl:6])([Cl:5])[Cl:4])=[CH2:2].[Cl:7][SiH2:8][Cl:9]>[CH-]=O.[CH-]=O.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Co].[Co+2]>[Cl:4][Si:3]([Cl:6])([Cl:5])[CH2:1][CH2:2][SiH:8]([Cl:9])[Cl:7]
Reactant: C=C[Si](Cl)(Cl)Cl
Reactant: Cl[SiH2]Cl
Agent: [Co+2]
Agent: [Co]
Agent: [C-]#[O+]
Product: Cl[SiH](Cl)CC[Si](Cl)(Cl)Cl
Temperature: 0 °C
Yield: 108 %

Procedure:
Vinyltrichlorosilane (68.8 g, 426 mmol) and cobalt octacarbonyl (700 mg) were placed in a 100 mL rb flask and cooled in an ice bath to 0° C. Dichlorosilane (bp. 8° C., 44.3 g, 439 mmol) was then condensed into the flask, The system was allowed to warm up to room temperature during night. Distillation at 60 . . . 62° C./8 mbar gave 1,1,1,4,4-Pentachloro-1,4-disilabutane (120.8 g, 460 mmol) in 93% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C([Li])CCC.[C:15]([C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>O>[C:15]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:4][C:3]2[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=2[CH3:1])=[NH:24])=[CH:25][CH:26]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1ccc(C#N)cc1
Reactant: Cc1cccc(C)c1N
Agent: [Li]CCCC
Solvent: O
Product: Cc1cccc(C)c1NC(=N)c1ccc(C(C)(C)C)cc1
Reaction time: 1 h
Yield: 79.8 %

Procedure:
Procedure as described for Amidine I using the following amounts: 6.15 mL of 2,6-dimethylaniline (50.0 mmol); 26.0 mL of 2.0 M butyllithium (52.0 mmol), 8.50 mL of 4-t-butylbenzonitrile (50.0 mmol). After refluxing overnight, the solution was red-orange. Addition of water yielded a yellow solution with suspended solid. Solution was filtered, taken to dryness, resuspended in 100 mL of pentane and stirred vigorously for 1 hour. The resulting white solid was filtered and dried in vacuo yielding 11.19 g of white powder. The filtrate was concentrated to approximately 50 mL and cooled to −10° C. An additional 1.47 g of solid was isolated. Total yield 10.60 g (76%). 1H NMR (400 MHz, CDCl3): 7.87 (d, 2H), 7.50 (d, 2H), 7.04 (d, 2H), 6.90 (t, 1H), 4.56 (s, 2H), 2.15 (s, 6H), 1.36 (s, 9H). 13C {1H} NMR (100 MHz, CDCl3): 154.27, 153.01, 146.97, 133.12, 129.16, 128.53, 126.83, 125.88, 123.05, 35.21, 31.59, 18.17.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23][NH2:24]>>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23][NH:24][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: Cc1cccc(Cl)c1CN
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: Cc1cccc(Cl)c1CNc1nccc(-n2cnc3ccccc32)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 2-chloro-6-methylbenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (EI): m/e 350.3 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.66 (s, 1H); 8.40 (br s, 1H); 8.21 (s, 1H); 7.87 (d, J=7.6 Hz, 1H); 7.40 (m, 2H); 7.30 (d, J=8.0 Hz, 1H); 7.17 (m, 2H); 6.85 (d, J=5.5 Hz, 1H); 5.56 (br s, 1H); 4.90 (d, J=5.0 Hz, 2H); 2.51 (s, 3H).
Reaction SMILES: [CH3:1][C@:2]1([CH2:5][N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:4][O:3]1.[Cl:23][C:24]1[NH:25][CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[N:28]=1.C(=O)([O-])O.[Na+].O>C(#N)C>[Cl:23][C:24]1[N:25]([CH2:4][C@@:2]([CH3:1])([OH:3])[CH2:5][N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=3)[CH2:8][CH2:7]2)[CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[N:28]=1
Reactant: C[C@]1(CN2CCN(c3ccc(OC(F)(F)F)cc3)CC2)CO1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: C[C@](O)(CN1CCN(c2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 31.5 %

Procedure:
To a suspension of (S)-1-(2-methyloxiran-2-ylmethyl)-4-(4-trifluoromethoxyphenyl)piperazine (0.43 g, 1.37 mmol) and 2-chloro-4-nitro-1H-imidazole (0.22 g, 1.51 mmol) in acetonitrile (4 ml), sodium hydrogencarbonate (0.17 g, 2.06 mmol) was added followed by stirring under reflux for 9 hours. To the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) to afford (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethoxyphenyl)piperazin-1-yl]propan-2-ol (0.20 g, yield 31%) as a light yellow oil.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]([F:26])([F:25])[CH:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16]1.CI>O1CCCC1>[CH3:1][C:18]1([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16][CH:15]([C:14]([F:25])([F:26])[F:13])[CH2:20][CH2:19]1
Reactant: COC(=O)C1CCC(C(F)(F)F)CC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCC(C(F)(F)F)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 104.1 %

Procedure:
To a solution of diisopropylamine (22.0 mL, 124.0 mmol) in tetrahydrofuran (60 mL) was added n-BuLi (2.0 M solution in hexane, 59.0 mL, 95.0 mmol) at 0° C. and the reaction mixture was allowed to stir at same temperature for 20 minutes before cooled to −78° C. Methyl 4-(trifluoromethyl)cyclohexanecarboxylate (10.0 g, 48.0 mmol) in tetrahydrofuran (60 mL) was added dropwise at −78° C. The reaction mixture was stirred at same temperature for 2 hours and then neat methyl iodide (4.5 mL, 72.0 mmol) was added dropwise. After stirring at −78° C. for 1 hour, the reaction mixture was warmed to ambient temperature and stirred for 16 hours, before quenched with 25% aqueous ammonium chloride solution (100 mL) at 0° C. and extracted with ethyl acetate. The organic layer was washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound (11.2 g, 99%) as a brown colored oil: 1H NMR (300 MHz, CDCl3) δ 3.70 (s, 3H), 2.32-2.28 (m, 2H), 2.01-1.80 (m, 3H), 1.42-1.08 (m, 7H).