Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:11][OH:12])[O:7][C@H:6]1[N:13]1[C:23]2[N:22]=[C:20]([NH2:21])[NH:19][C:17](=[O:18])[C:16]=2[N:15]=[CH:14]1)[CH2:2][CH3:3].C[Si](Cl)(C)C.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31].[NH4+].[OH-]>N1C=CC=CC=1.O>[C:29]([NH:21][C:20]1[NH:19][C:17](=[O:18])[C:16]2[N:15]=[CH:14][N:13]([C:23]=2[N:22]=1)[C@@H:6]1[O:7][C@H:8]([CH2:11][OH:12])[C@@H:9]([OH:10])[C@H:5]1[O:4][CH2:1][CH2:2][CH3:3])(=[O:33])[CH:30]([CH3:32])[CH3:31]
Reactant: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Reactant: CC(C)C(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2'-O-Propylguanosine (3.6 gm) in pyridine (50 ml) was cooled in an ice bath and trimethylsilyl chloride (8.4 ml, 6 eq.) was added. The reaction mixture was stirred for 30 min and isobutyryl chloride (5.8 ml, 5 eq.) was added. The solution was stirred for 4 hours during which it was allowed to warm to room temperature. The solution was cooled, H2O added (10 ml) and the solution was stirred for an additional 30 mins. Concentrated NH4OH (10 ml) was added and the solution evaporated in vacuo. The residue was purified by silica gel chromatography using 10% MeOH/CH2CL2 to elute the product. Product-containing fractions were evaporated to yield 2.5 g of product as a foam. An analytical sample was re-chromatographed on silica and eluted with CH2Cl2 →6% MeOH/CH2Cl2. 1H NMR (DMSO-d6) δ 0.75 (t 3, CH3) 1.13 [d, 6, CH(CH3)2 ], 1.4 (m, 2, CH2), 2.75 [m, 1, CH(CH3)2 ], 3.52 (m, 6, OCH2), 3.36 and 3.6 (ABX, 2, H-5'), 3.95 (m, 1), 4.26 (m, 1), 4.33 (m, 1), 5.07 (t, 1, 5'-OH), 5.18 (d, 1, 3'-OH), 5.9 (d, 1, H-1'), 8.25 (s, 1, H-8), 11.65 (br s, 1, NH) and 12.1 (br s, 1, NH). Anal. Calcd. for C17H25N5O6.1/2H2O: C, 50.49; H, 6.48; N, 17.32. Found: C, 50.81; H, 6.62; N, 17.04.
Reaction SMILES: [K].[C:2]([O:5][C:6]1[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=O)=[O:28])=[CH:23][CH:22]=2)=[CH:15][C:7]=1[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9])(=[O:4])[CH3:3].CN(C)C=O.S(Cl)([Cl:38])=O.[OH-].[Na+]>ClCCl.O>[C:2]([O:5][C:6]1[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([Cl:38])(=[O:30])=[O:28])=[CH:23][CH:22]=2)=[CH:15][C:7]=1[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9])(=[O:4])[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc(C=Cc2ccc(S(=O)(=O)O)cc2)cc1C(=O)OCC(C)C
Agent: [K]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)Oc1ccc(C=Cc2ccc(S(=O)(=O)Cl)cc2)cc1C(=O)OCC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Isobutyl 2-acetyloxy-5-[2(4-sulfophenyl)ethenyl]benzoate potassium salt (36.1 g, 0.08 mol) was suspended in dichloromethane. Dimethylformamide (20 ml) and thionyl chloride (20 ml) were added, and the mixture refluxed with stirring for 3 h. After cooling to room temperature, water (15 ml) was added. By careful addition of 5M sodium hydroxide, the pH of the aqueous phase was adjusted to about 7. The phases were separated and the organic phase washed with water. The solution was dried (MgSO4), treated with activated carbon and filtered. After evaporation of the solvent, the solid residue was recrystallized from a toluene and petroleum ether mixture. Yield 19.5 g (57%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:6]=1.[C:14]([CH2:16][C:17](O)=[O:18])#[N:15].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:14]([CH2:16][C:17]([NH:11][CH2:10][CH2:9][C:8]1[CH:12]=[CH:13][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=1)=[O:18])#[N:15]
Reactant: COCOc1ccc(CCN)cc1
Reactant: N#CCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCOc1ccc(CCNC(=O)CC#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.9 %

Procedure:
4-Methoxymethoxyphenethylamine (1.58 g, 8.7 mmol) and cyanoacetic acid (0.82 g, 9.6 mmol) were dissolved in dimethylformamide (10 ml) and under ice-cooling and stirring diethylphosphoric cyanide (1.51 ml, 9.6 mmol) and triethylamine (1.34 ml, 9.6 mmol) were sequentially added. After stirring at room temperature for 24 hours, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was distilled out under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=19:1) to yield 2-cyano-N-(4-methoxymethoxyphenethyl)acetamide (0.97 g, 45%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])[CH:36]=1)[C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44])[CH:36]=1)[C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCCCCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1ccc(N(Cc2cnn(CCCCCCC(=O)O)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Ethyl 7-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(6-isopropylpyridin-3-yl)amino]methyl}pyrazol-1-yl)heptanoate (2.0 g) was dissolved in ethanol (100 mL), and 1 mol/L-aqueous sodium hydroxide solution (6.60 mL) was added. The mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1 mol/L-hydrochloric acid (6.60 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 7-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(6-isopropylpyridin-3-yl)amino]methyl}pyrazol-1-yl)heptanoic acid (1.80 g). By the reaction and treatment of this compound in the same manner as in Example 139, 7-(4-{[N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(6-isopropylpyridin-3-yl)amino]methyl}pyrazol-1-yl)heptanoic acid hydrochloride (0.84 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[S:10]1[CH:14]=[CH:13][N:12]=[C:11]1[NH2:15].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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.C(Cl)(Cl)Cl.[Pd].[Pd]>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][C:11]2[S:10][CH:14]=[CH:13][N:12]=2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: Nc1nccs1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2nccs2)nc(Cl)n1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To the mixture of 2,4-dichloro-6-methylpyrimidine (507.7 mg), 1,3-thiazol-2-amine (345.0 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (289.1 mg) and K3PO4 (936.3 mg) in dioxane (20 ml) was added Pd2(dba)3 CHCl3 (255.9 mg). And the suspension was stirred at 85° C. overnight. The mixture was cooled to room temperature. The insoluble material was filtered off and washed with EtOAc. The filtrate was poured into saturated aqueous solution of NaHCO3 and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4 and concentrated. The residue was purified with silica gel column chromatography (eluent: CHCl3/MeOH=98/2˜90/10) to give 2-chloro-6-methyl-N-(1,3-thiazol-2-yl)pyrimidin-4-amine as an orange solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:8][CH2:9][NH2:10])[CH3:2].C(N1CCC[C@H]1CC#N)(=O)C>>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[CH2:8][CH2:9][NH2:10])[CH3:2]
Reactant: CCN1CCC[C@H]1CCN
Agent: CC(=O)N1CCC[C@H]1CC#N
Product: CCN1CCC[C@@H]1CCN

Procedure:
Prepared by proceeding in a similar manner to Intermediate 136, starting from ((S)-1-acetylpyrrolidin-2-yl)acetonitrile (Intermediate 142) and used without further characterisation.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].C[O-].[Na+].[CH:16](OC)=[O:17].C1(C)C=CC=CC=1>C1(C)C=CC=CC=1.O>[OH:17][CH:16]=[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC=O
Reactant: COC(=O)Cc1ccccc1C
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C(=CO)c1ccccc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
To a three neck flask (1000 mL), 50 g of methyl 2-o-tolylacetate and 600 mg of toluene were added, and then 54.3 g of sodium methoxide was further added with stiffing. The mixture was cooled with an ice-water bath to less than 10° C., and then a mixture of methyl formate (65 mL) and toluene (50 mL) was dripped. After that, the ice-water bath was removed and the temperature was raised slowly to room temperature. The solution was allowed to react with stirring for 12 hrs, and then dumped into 1000 mL of water, shaken, standed for demix. The organic layer was extracted with 500 mL of water twice. The water layer was combined, acidized with 6M hydrochloric acid to pH value of 4-5, extracted with ethyl acetate, dried with anhydrous magnesium sulfate, and distilled under vacuum condition to yield 55.9 g of light red oily product with a yield of 95%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[NH2:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2]>[O-2].[O-2].[Mn+4]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[NH2:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(CO)cc1OC
Agent: [Mn+4]
Agent: [O-2]
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(C=O)cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.3 %

Procedure:
7.60 g (87.4 mmol) of manganese dioxide were added to a solution of 1.98 g (4.36 mmol) of N-(2-t-butyl-5-carbamoylphenyl)-3-(4-hydroxymethyl-2-methoxyphenyl)octanamide (prepared as described in Example 109), and the resulting mixture was stirred at room temperature for 6 hours. At the end of this time, the reaction mixture was filtered using a Celite (trade mark) filter aid to remove the oxidizing agent used. The filtrate was then concentrated by evaporation under reduced pressure, to give 1.88 g (yield 95%) of the title compound as a foam-like substance.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:20]=[C:19]([NH2:21])[CH:18]=[CH:17][CH:16]=2)[CH2:10][C:9]1([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:20]=[C:19]([NH:21][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:25]=3[Cl:24])[CH:18]=[CH:17][CH:16]=2)[CH2:10][C:9]1([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: CC1(C)CC(Oc2cccc(N)n2)CCN1Cc1ccccc1
Solvent: C1COCCO1
Product: CC1(C)CC(Oc2cccc(NC(=O)c3ccc(F)cc3Cl)n2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 11.5 %

Procedure:
Combine 6-(1-benzyl-2,2-dimethyl-piperidin-4-yloxy)-pyridin-2-ylamine (preparation 66, 0.537 g, 1.72 mmol), 1,4-dioxane (20 mL) and 2-chloro-4-fluoro-benzoyl chloride (0.20 g, 1.04 mmol), stir and heat to reflux. After 1.5 hr., cool to ambient temperature and concentrate. Dissolve the residue in methanol (10 mL) and load on an SCX column (10 g); wash with methanol (2×50 mL); elute product with 2M ammonia/methanol (2×50 mL). Concentrate the eluent. Purify the crude mixture by silica gel flash chromatography eluting with 9:1 hexane:ethyl acetate to obtain the title compound (0.056 g 11.5%). Mass spectrum (electrospray): m/z=468.2 (M+1); 1H NMR (CDCl3): 8.3 (bs, 1H), 7.8 (m, 2H), 7.6 (dd, 1H), 7.3 (m, 6H), 7.1 (m, 1H), 6.5 (d, 1H), 5.1 (m, 1H), 3.9 (d, 1H), 3.2 (d, 1H), 2.65 (m, 1H), 2.4 (m, 1H), 2.0 (m, 2H), 1.7 (m, 1H), 1.6 (m, 1H), 1.3 (s, 3H), 1.2 (s, 3H).
Reaction SMILES: C([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([B:18]3[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.[Br-].C([O-])([O-])=O.[Na+].[Na+].CC#[N:36]>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]>[CH3:25][C:20]1([CH3:26])[C:21]([CH3:24])([CH3:23])[O:22][B:18]([C:14]2[CH:13]=[C:12]3[C:17](=[N:16][CH:15]=2)[N:8]([C:6]([NH2:36])=[O:5])[CH2:9][CH2:10][CH2:11]3)[O:19]1
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CC1(C)OB(c2cnc3c(c2)CCCN3C(N)=O)OC1(C)C

Procedure:
To a solution of crude 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (175 mg, 0.63 mmol) in MeCN (9.0 mL) is added bromide 2 (1.0 eq.) and saturated aqueous Na2CO3 solution (4.0 mL). Then Pd(dppf)Cl2 (23 mg, 0.031 mmol) is added under N2 atmosphere and the mixture is microwaved at 120° C. The progress of the reaction is monitored and after the reaction is completed, the solid is filtered and the filtrate is concentrated. The residue is partitioned between DCM and water. The organic layer is separated and washed with water and brine, dried over Na2SO4 and concentrated to give the crude product. Purification by column chromatography affords the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[CH3:16][O:17]C1C=CC(C=O)=CC=1.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9]([O:17][CH3:16])=[CH:8][CH:7]=1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(C=O)cc1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1ccc(OC)cc1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester but using 4-methoxybenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: [CH:1]1([C:6]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:7]2[CH2:31][C:30]([CH3:33])([CH3:32])[C:10]3[CH:11]=[C:12]4[C:20](=[CH:21][C:9]=3[C:8]2([CH3:35])[CH3:34])[CH2:19][C:18]2[CH:17]=[C:16]3[C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][C:25]([CH3:27])([CH3:26])[C:15]3=[CH:14][C:13]4=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.CCCCCC.[Li]CCCC.Cl[Si:60]([CH3:63])([CH3:62])[CH3:61]>C1COCC1>[CH3:61][Si:60]([CH3:63])([CH3:62])[C:3]1[CH:4]=[CH:5][CH:1]([C:6]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:7]2[CH2:31][C:30]([CH3:32])([CH3:33])[C:10]3[CH:11]=[C:12]4[C:20](=[CH:21][C:9]=3[C:8]2([CH3:34])[CH3:35])[CH2:19][C:18]2[CH:17]=[C:16]3[C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][C:25]([CH3:27])([CH3:26])[C:15]3=[CH:14][C:13]4=2)[CH:2]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CC(C(c1ccccc1)(c1ccccc1)C1C=CC=C1)C2(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CC(C(c1ccccc1)(c1ccccc1)C1C=CC([Si](C)(C)C)=C1)C2(C)C
Yield: 60.8 %

Procedure:
In a 30 ml Schlenk flask purged with nitrogen, 0.92 g (1.48 mmol, 1 eq) of 1-(cyclopentadienyl)-1-(1,1,4,4,7,7,10,10-octamethyl-1,2,3,4,7,8,9,10-octahydrodibenzo(b,h)-fluorenyl)diphenylmethane was placed at room temperature. Then, 20 ml of dehydrated THF was added, and the mixture was stirred by a magnetic stirrer to give a solution. The solution was cooled with an ice bath (light orangy brown solution). To the solution, 1.0 ml (1.63 mmol, 1.10 eq) of a hexane solution of n-BuLi was dropwise added. Then, the ice bath was removed, and the solution was stirred at room temperature for 18 hours (dark red solution). The solution was cooled with an ice bath, and to the solution, 1.05 ml (8.28 mmol, 5.59 eq) of chlorotrimethylsilane was dropwise added by a syringe (dark brown solution). The ice bath was removed, and the solution was stirred at room temperature for 3 hours. The resulting dark brown solution was poured into 50 ml of a diluted hydrochloric acid solution to perform quenching. After the soluble component was extracted with 30 ml of diethyl ether, the organic phase was washed with 50 ml of a saturated saline solution. The organic phase was dried over MgSO4, then the MgSO4 was filtered off, and from the filtrate the solvent was vacuum distilled off by a rotary evaporator to obtain a yellowish brown amorphous product. The amorphous product was purified by silica gel column chromatography (developing solvent: hexane:dichloromethane=19:1) to obtain 0.62 g a light yellow amorphous product (yield: 61%)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>CCOCC.C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:25][CH:22]1[CH2:24][CH2:23]1
Reactant: OCc1ccccc1Br
Reactant: NC1CC1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Brc1ccccc1CNC1CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a THF solution (0.15 M) of 2-bromobenzyl alcohol (1 eq.) was added triethylamine (1.6 eq.). The reaction mixture was cooled to 0° C. before methanesulfonyl chloride (1.3 eq.) was added dropwise. The resulting solution was then allowed to warm slowly to RT. After 1.5 h, cyclopropylamine (5 eq.) was added to the now cloudy suspension. After another 18 h, the reaction mixture was diluted with ether and quenched with 1 N aq. NaOH. The organic extract was separated, washed with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 4:1 (v/v) Hex:EtOAc→1:4 (v/v) Hex:EtOAc) afforded the title compound as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10].S(Cl)([Cl:23])=O.Cl>Cl.C(N(CC)CC)C.C(Cl)(Cl)Cl>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([Cl:23])=[O:10]
Reactant: O=C(O)c1cccnc1Oc1cccc(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1cccnc1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
There were combined 14.1 grams (0.05 mole) 2-(3-trifluoromethylphenoxy)nicotinic acid, 0.1 grams triethylamine hydrochloride and 150 milliliters of chloroform. The mixture was stirred and heated to reflux. Then, 6.5 grams (0.055 mole) thionyl chloride was slowly added. After addition was complete the reaction mass was heated under reflux until hydrogen chloride evolution had ceased (about 30 minutes); it was then cooled to room temperature, filtered, and the solvent removed under vacuum producing 10.0 grams (66.7% of theoretical yield) of 2-(3-trifluoromethylphenoxy)nicotinoyl chloride. The structure was confirmed by infrared spectral analysis.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[C:17]([CH2:24][CH3:25])[CH:16]=1>C(Cl)Cl>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][O:23][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11])=[C:17]([CH2:24][CH3:25])[CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCc1cc(Br)ccc1CCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCc1cc(Br)ccc1CCO[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
Imidazole (2.1 g, 30.6 mmol) followed by tert-butylchlorodimethylsilane (2.5 g, 16.8 mmol) were added to a solution of 36B (3.5 g, 15.3 mmol) in CH2Cl2 (100 mL). The reaction mixture was stirred for 2 h then washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (0% to 30% EtOAc in hexanes) to yield 46A (4.3 g, 82%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm −0.02 (s, 6 H) 0.86 (s, 9 H) 1.20 (t, J=7.42 Hz, 3 H) 2.63 (q, J=7.51 Hz, 2 H) 2.79 (t, J=7.15 Hz, 2 H) 3.74 (t, J=7.15 Hz, 2 H) 7.22 (dd, J=7.97, 1.92 Hz, 1 H) 7.29 (d, J=2.20 Hz, 1 H).
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.Cl[CH2:26][C:27]1[N:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][C:28]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1.[NH:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[C:44]1[C:52]([O:54][CH2:55][CH3:56])=[O:53]>>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:28]2[N:29]=[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]3[C:27]=2[CH2:26][N:43]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]=[C:44]2[C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:37][CH:38]=1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: CCOC(=O)c1cc2ccccc2n1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and ethyl 1H-indole-2-carboxylate. M/e+ 430 for C25H21ClN3O2 (M+H)+; 1H-NMR (400 MHz, CD3OD) δ 8.13 (d, J=6.6 Hz, 1H), 7.70 (dd, J=8.4, 2.2 Hz, 2H), 7.55 (d, J=9.1 Hz, 1H), 7.42 (d, J=8.4, 2.5 Hz, 2H), 7.33 (d, J=8.4 Hz, 1H), 7.25 (t, J=6.6 Hz, 1H), 7.10 (t, J=6.6 Hz, 1H), 6.79 (m, 1H), 6.67 (m, 1H), 6.61 (m, 2H), 5.03 (s, 2H), 4.44 (q, J=6.9 Hz, 2H), 1.39 (t, J=6.9 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1([NH:8][C:9]2[C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:22][C:23]1[CH:24]=[C:25]([CH:29](OS(C)(=O)=O)[CH3:30])[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:24]=[C:25]([CH:29]([N:5]2[CH2:6][CH2:7][C:2]([NH:8][C:9]3[C:10]4[C:17]5[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=5[S:15][C:11]=4[N:12]=[CH:13][N:14]=3)([CH3:1])[CH2:3][CH2:4]2)[CH3:30])[CH:26]=[CH:27][CH:28]=1
Reactant: CC1(Nc2ncnc3sc4c(c23)CCCC4)CCNCC1
Reactant: CC(OS(C)(=O)=O)c1cccc(F)c1
Product: CC(c1cccc(F)c1)N1CCC(C)(Nc2ncnc3sc4c(c23)CCCC4)CC1

Procedure:
The title compound was prepared (97 mg, 81%) from (4-methyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine (150 mg, 0.28 mmol) and methanesulfonic acid 1-(3-fluoro-phenyl)-ethyl ester (61.1 mg, 0.28 mmol) by following the procedure described for preparation 12. 1H NMR (400 MHz, CDCl3): 8 (ppm) 8.38 (s, 1H), 7.20 (s, 1H), 6.89-6.79 (m, 3H), 3.91 (q, 1H), 2.80-2.74 (m, 4H), 2.20-2.09 (M, 2H), 1.90 (m, 2H), 1.89-1.85 (m, 4H), 1.55 (m, 4H), 1.31 (s, 3H); MS (SEI): m/z: Calculated: 424.2; Observed: 425.2 (M++1).