Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[CH2:7][O:8][Si](C(C)(C)C)(C)C.C([Li])CCC.[CH3:24][S:25]SC.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:18][O:17][C:5]1[CH:4]=[CH:3][C:2]([S:25][CH3:24])=[CH:16][C:6]=1[CH2:7][OH:8]
Reactant: COc1ccc(Br)cc1CO[Si](C)(C)C(C)(C)C
Reactant: CSSC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(SC)cc1CO
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a solution of Example 170A (2.91 g, 8.75 mmol) in 20 mL of tetrahydrofuran at −78° C. was added 1.6 M n-butyllithium in hexanes (7.1 mL, 11.4 mmol). The reaction was stirred at −78° C. for 10 min, then 1.5 mL of dimethyldisulfide was added. The reaction was warmed to ambient temperature and stirred for 2 h, then concentrated in vacuo. The residue was taken up in 50 mL of diethyl ether, then extracted with water (2×15 mL), 2 M NaOH(aq.) (1×15 mL), and brine (1×15 mL), dried over MgSO4, filtered, and concentrated in vacuo to an oil. This was taken up in 15 mL of tetrahydrofuran and treated with 2.0 g (ca. 7 mmol) of tetrabutylammonium fluoride hydrate. The reaction was stirred at ambient temperature for 1 h, then concentrated in vacuo. The residue was taken up in 30 mL of diethyl ether, then extracted with water (2×10 mL), 2M NaOH(aq.) (1×10 mL), and brine (1×10 mL), dried over MgSO4, filtered, and concentrated in vacuo to an oil. The product was purified via silica gel chromatography, eluting with a 20-40% ethyl acetate in hexanes gradient to give 1.23 g (76%) of the alcohol. The product was about 90% pure by 1H NMR analysis.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH2:8]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:40]([O:42][C:43]([CH:45]1[CH2:50][CH2:49][CH:48](O)[CH2:47][CH2:46]1)=[O:44])[CH3:41].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:40]([O:42][C:43]([CH:45]1[CH2:50][CH2:49][CH:48]([O:19][C:16]2[CH:15]=[CH:14][C:13]([C:12](=[O:20])[NH:11][CH:2]3[CH:3]4[CH2:9][CH:7]5[CH2:6][CH:5]([CH2:10][CH:1]3[CH2:8]5)[CH2:4]4)=[CH:18][CH:17]=2)[CH2:47][CH2:46]1)=[O:44])[CH3:41]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(Oc2ccc(C(=O)NC3C4CC5CC(C4)CC3C5)cc2)CC1
Temperature: 0 °C
Reaction time: 48 h
Yield: 31.9 %

Procedure:
To a stirred solution of N-adamantan-2-yl-4-hydroxy-benzamide (6 g, 22.11 mmol) in dry THF (100 mL) was added triphenyl phosphine (8.7 g, 33.17 mmol) and 4-hydroxy cyclo-hexane carboxylic acid ethyl ester (4.57 g, 26.53 mmol). The reaction mixture was cooled to 0° C. and DEAD (5.22 mL, 33.17 mmol) was added dropwise from an addition funnel over a period of 30 min. The reaction was gradually brought to room temperature and stirring continued for 48 hrs. The solvent was removed under vacuum and ether (100 mL) was added and cooled to 0° C. The solid formed was filtered off and the clear filtrate concentrated and purified by column chromatography (Gyan-flash). Desired fractions were collected and the solvent evaporated. The residue was crystallised from diethyl ether and filtered off affording 3 g (32%) of 4-[4-(adamantan-2-ylcarbamoyl)-phenoxy]-cyclohexane carboxylic acid ethyl ester as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[NH:31]1[CH2:34][CH:33]([C:35]([OH:37])=[O:36])[CH2:32]1>>[Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:31]5[CH2:34][CH:33]([C:35]([OH:37])=[O:36])[CH2:32]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:29])([F:28])[F:30])[CH:3]=1
Reactant: O=C(O)C1CNC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Br)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CC(C(=O)O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Br)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(4-Bromo-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylic acid was prepared from 5-[1-(4-Bromo-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and azetidine-3-carboxylic acid following General Procedure C.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20]Cl)[CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1>CC(=O)CC.O>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][O:46][C:43]3[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=3)[CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCCl)cc12
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCOc3ccc(F)cc3)cc12
Yield: 68.8 %

Procedure:
A mixture of 6-(3-chloro-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 101A) (125 mg, 0.29 mmol), potassium carbonate (120 mg, 0.87 mmol), potassium iodide (48 mg, 0.29 mmol) and 4-fluorophenol (65 mg, 0.58 mmol), in butanone (3.5 ml) was heated in a sealed tube at 130° C. for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were washed with, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography over silica gel (gradient cyclohexane/dichloromethane: 0-100%) to yield the title compound (100 mg, 69%) as a yellow solid.
Reaction SMILES: Br[CH:2]=[C:3]([CH3:5])[CH3:4].[Mg].[CH3:7][C:8]1[C:9]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]([C:9]1[C:8]([CH3:7])=[CH:13][CH:12]=[CH:11][N:10]=1)([OH:15])[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: COc1ccccc1C(=O)c1ncccc1C
Reactant: CC(C)=CBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1C(O)(C=C(C)C)c1ncccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.4 %

Procedure:
9.23 g of 1-bromo-2-methylprop-1-ene were added dropwise to 2.5 g of magnesium turnings covered with tetrahydrofuran while heating. 7.76 g of 2-methoxyphenyl 3-methyl-2-pyridyl ketone were added while heating to reflux. After 4 hours the mixture was allowed to cool to room temperature. Saturated ammonium chloride solution was added and the resulting mixture was extracted with diethyl ether. The organic extract was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution. There were obtained 5.75 g of 1-(2-methoxyphenyl)-3-methyl-1-(3-methyl-2-pyridyl)-2-buten-1-ol in the form of an oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:3]=1.[CH2:23]([O:27]C=C)[CH2:24]CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:23]([C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:3]=1)(=[O:27])[CH3:24]
Reactant: C=COCCCC
Reactant: COC(=O)c1ccc2c(Br)nn(CC(=O)OC(C)(C)C)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccc2c(C(C)=O)nn(CC(=O)OC(C)(C)C)c2c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A solution of methyl 3-bromo-1-(2-tert-butoxy-2-oxoethyl)-1H-indazole-6-carboxylate (1.00 g, 2.71 mmol), n-butyl vinylether (1.75 mL, 13.5 mmol), palladium acetate (61 mg, 0.27 mmol), triphenylphosphine (142 mg, 0.54 mmol) and triethylamine (0.45 mL, 3.25 mmol) in dry CH3CN (10 mL) was heated at 100° C. under microwave irradiation for 7 h. Then, the mixture was further heated at 120° C. for 5 h under microwave irradiation. The solvent was evaporated, and the residue was then treated with 4N HCl/dioxane with stirring at RT for 16 h. Volatiles were evaporated and the residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to give after lyophilization of the pure fractions the title compound. MS (LC-MS): 333 [M+H]+, 355 [M+Na]; tR (HPLC conditions k): 3.83 min.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:8]([CH3:20])[CH:7]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>O1CCCC1>[CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:29](=[O:31])[CH3:30])[S:13]([C:16]([F:19])([F:17])[F:18])(=[O:15])=[O:14])=[C:8]([CH3:20])[CH:7]=1)(=[O:4])=[O:5]
Reactant: CC(=O)Cl
Reactant: Cc1cc(S(=O)(=O)N(C)C)ccc1NS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N(c1ccc(S(=O)(=O)N(C)C)cc1C)S(=O)(=O)C(F)(F)F
Yield: 76.7 %

Procedure:
To a solution of N,N-dimethyl-3-methyl-4-(trifluoromethanesulfonamido)benzenesulfonamide (1.5 g) and triethylamine (0.65 g) in tetrahydrofuran (40 ml), acetyl chloride (0.51 g) was added, and the resultant mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and solidified with water. The solidified product was recrystallized from a mixture of ethanol and toluene to give 1.29 g of N,N-dimethyl-3-methyl-4-(N-acetyl-N-trifluoromethanesulfonylamino)benzenesulfonamide (Compound No. 86). M.P., 148°-148.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Br:15][C:16]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:17]=1[CH:18]=[CH:19][C:20](O)=O>>[Br:15][C:16]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1cc2c(cc1Br)OCO2
Product: CCn1c(=O)c2[nH]c(/C=C/c3cc4c(cc3Br)OCO4)nc2n(CC)c1=O
Yield: 36.8 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 3.77 g (13.9 mmol) of 2-bromo-4,5-methylenedioxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylsulfoxide/water to give 2.01 g (yield 38%) of Compound 158 as a yellow powder.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:38]([O:42][C:43](Cl)=[O:44])[CH:39]([CH3:41])[CH3:40].CCOCC>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([O:21][C:43](=[O:44])[O:42][CH2:38][CH:39]([CH3:41])[CH3:40])[CH:15]=[CH:14]3)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CC(C)COC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)COC(=O)Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Reaction time: 0.17 h
Yield: 73.2 %

Procedure:
Dissolve the compound of Example 3 (120 mg, 0.23 mmol) in dichloromethane (3 mL) and add isobutylchloroformate (38 μL, 0.30 mmol) dropwise. After stirring for 10 minutes, pour the reaction into vigorously stirred ether (10 mL) and filter. Dissolve the solids in dichloromethane (10 mL) and wash with saturated aqueous sodium bicarbonate. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with methanol in dichloromethane (4%) to give 104 mg of the title compound (73%): mass spectrum (ion spray): m/z=618.4 (M+H).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:22]([NH:24][C@H:25]([C:27](O)=[O:28])[CH3:26])=[O:23])[C@H:18]([CH2:20][CH3:21])[CH3:19])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH2:30]([O:32][CH:33]([O:45][CH2:46][CH3:47])[CH2:34][C@@H:35]([NH2:44])[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH3:31]>>[CH2:46]([O:45][CH:33]([O:32][CH2:30][CH3:31])[CH2:34][C@@H:35]([NH:44][C:27](=[O:28])[C@H:25]([CH3:26])[NH:24][C:22](=[O:23])[C@H:17]([C@H:18]([CH2:20][CH3:21])[CH3:19])[NH:16][C:14](=[O:15])[C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[NH:4][C:1](=[O:3])[CH3:2])[CH2:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH3:47]
Reactant: CCOC(C[C@@H](N)CC(=O)OC(C)(C)C)OCC
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(C)=O)C(=O)N[C@@H](C)C(=O)O
Product: CCOC(C[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(C)=O)[C@@H](C)CC)OCC

Procedure:
0.24 g (0.6 mmol) of acetyl-L-tyrosyl-L-isoleucyl-L-alanine (Example 7, Step A2) and 0.16 g (0.6 mmol) of (3R)-3-amino-4-t-butoxycarbonyl-butyraldehyde diethyl acetal (Example 1, Step B4) are coupled and the end product is isolated according to the method described in Example 1, Step 1, using proportional amounts of reagents and solvents.
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:17]([O:24][CH3:25])=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([CH3:14])[C:6]1=[O:15].[CH2:26]([O:33][C:34]1[C:39](B(O)O)=[CH:38][CH:37]=[CH:36][N:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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>[CH2:26]([O:33][C:34]1[C:39]([C:2]2[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:17]([O:24][CH3:25])=[CH:16][C:3]=2[CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N:7]([CH3:14])[C:6]2=[O:15])=[CH:38][CH:37]=[CH:36][N:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1cc(Cn2c(=O)n(C)c3ccccc32)c(Br)cc1C(C)(C)C
Reactant: OB(O)c1cccnc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(Cn2c(=O)n(C)c3ccccc32)c(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Yield: 78 %

Procedure:
step 2—A sealed tube containing 96 (100 mg, 0.25 mmol), 2-benzyloxy-pyridin-3-yl boronic acid (85 mg, 0.37 mmol), Na2CO3 (80 mg, 0.74 mmol) and Pd(PPh3)4 (29 mg, 0.025 mmol) in a mixture of MeOH (1.5 mL) and DCM (0.5 mL) was irradiated on a microwave synthesizer at 100° C. for 30 min. The reaction mixture was diluted with DCM, filtered through a pad of CELITE, and the filtrate was concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 30% EtOAc/hexanes to afford 99 mg of 1-[2-(2-benzyloxy-pyridin-3-yl)-4-tert-butyl-5-methoxy-benzyl]-3-methyl-1,3-dihydro-benzoimidazol-2-one (98).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:21]1[S:25][C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[C:29]#[N:30])=[N:23][CH:22]=1)CCC>>[CH3:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6]2[N:7]=[C:2]([C:21]3[S:25][C:24]([C:26]4[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=4)[C:29]#[N:30])=[N:23][CH:22]=3)[CH:3]=[CH:4][CH:5]=2)[N:14]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(-c2cccc(C#N)c2)s1
Reactant: Cc1ccnc(Nc2cccc(Br)n2)n1
Product: Cc1ccnc(Nc2cccc(-c3cnc(-c4cccc(C#N)c4)s3)n2)n1

Procedure:
By following essentially the same procedure in preparative example 019 and starting with N-(6-bromopyridin-2-yl)-4-methylpyrimidin-2-amine (215 mg 0.81 mmol) and 3-(5-(tributylstannyl)thiazol-2-yl)benzonitrile (656 mg, 1.38 mmol), the 3-(5-(6-(4-methylpyrimidin-2-ylamino)pyridin-2-yl)thiazol-2-yl)benzonitrile was obtained and purified by dry flash chromatography over SiO2 eluting with DCM/MeOH (5%)/NEt3 (0.5%), by precipitation in DCM/MeOH and by trituration with Et2O (119 mg, 39%). 1H NMR (300 MHz, DMSO-d6) δ 9.60 (br s, 1H), 8.62 (s, 1H), 8.43 (d, J=5.0 Hz, 1H), 8.38 (d, J=2.3 Hz, 1H), 8.31-8.23 (m, 2H), 8.01-7.95 (m, 1H), 7.86 (t, J=8.0 Hz, 1H), 7.75 (t, J=7.9 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 6.89 (d, J=5.0 Hz, 1H), 2.42 (s, 3H). (APCI+) m/z 371 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[CH2:8]([O:12][C:13]1[CH:38]=[CH:37][C:16]([CH2:17][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:15][CH:14]=1)[CH2:9][CH2:10][CH3:11].[CH:39]([CH:41]1[CH:46]2[CH2:47][CH2:48][N:43]([CH2:44][CH2:45]2)[CH2:42]1)=O.O>O1CCCC1>[CH2:8]([O:12][C:13]1[CH:14]=[CH:15][C:16](/[CH:17]=[CH:39]\[CH:41]2[CH:46]3[CH2:47][CH2:48][N:43]([CH2:44][CH2:45]3)[CH2:42]2)=[CH:37][CH:38]=1)[CH2:9][CH2:10][CH3:11]
Reactant: O=CC1CN2CCC1CC2
Reactant: CCCCOc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1ccc(/C=C\C2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium-tert-butoxide (2.46 g) was added to a stirred, ice-cooled suspension of (4-butoxybenzyl)-triphenylphosphonium bromide (10.1 g) in dry tetrahydrofuran (300 ml) under an atmosphere of argon. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to -10° C. and a solution of 3-formylquinuclidine (750 mg) in dry tetrahydrofuran (20 ml) was added dropwise over 15 minutes. The reaction mixture was stirred at room temperature overnight and water (1.0 ml) was then added. The tetrahydrofuran was evaporated and the residue was triturated several times with ether and filtered. The ether extracts were combined and evaporated to give an oil which was purified by flash column chromatography, using 10% methanol in dichloromethane containing 1% 0.880 ammonia as eluent, to give Z-3-[2-(4-butoxyphenyl)vinyl]-quinuclidine (Rf=0.3). This was dissolved in ether and an excess of a solution of hydrogen chloride in ether added to give a solid which was collected by filtration. There was thus obtained Z-3-[2-(4-butoxyphenyl)vinyl]quinuclidine hydrogen chloride as a colourless solid, m.p. 146°-149° C. (220 mg); microanalysis, found: C, 68.2; H, 8.4; N, 4.2%; C19H27NO.HCl.0.75H2O requires: C, 68.06; H, 8.8; N, 4.18%; NMR (DMSO-d6): 0.9-0.97(3H, t), 1.35-1.49(2H, m), 1.66-2.16(8H, m), 2.82-2.95(1H, m), 3.08-3.3(4H, m), 3.41-3.58(1H, t), 3.9-4.03(2H, t), 5.65-5.78(1H, d of d), 6.43-6.53(1H, d, J=11 Hertz), 6.9-7.0(2H, d) and 7.16-7.26(2H, d); m/Z 286 (M+H).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2.C[O:24][B:25](OC)[O:26]C>CCOCC>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[C:13]([B:25]([OH:26])[OH:24])[CH:14]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.5 %

Procedure:
A 2.5M solution of n-butyllithium in hexane (4.4 ml, 11 mmol) was slowly added to a stirred solution of 3-bromoquinoline (2.08 g, 10 mmol) in anhydrous ether (20 ml), under nitrogen, at −75° C. After a further 20 minutes at −75° C., trimethylborate (1.46 ml, 13 mmol) was added, whereupon the red colour changed to yellow. The reaction mixture was allowed to warm to room temperature and quenched with water, followed by 1M aqueous sodium hydroxide solution (10 ml). The resulting mixture was stirred for 30 minutes and then glacial acetic acid added until a pH ˜5-6 was attained, which generated a gummy precipitate. Diisopropyl ether was added to this mixture, stirring continued for 1 hour and then the clear aqueous and organic phases were decanted from the solid and discarded. The solid residue was dissolved in ethyl acetate and the solution washed with water, dried (MgSO4) and evaporated under reduced pressure to give the title compound as a pale yellow solid (580 mg, 34%). Found: C, 62.74; H, 4.11; N, 7.92. C9H8BNO2 requires C, 62.49; H, 4.66; N, 8.10%. δ(DMSOd6): 7.59 (t,1H), 7.76 (t,1H), 7.98 (m,2H), 8.42 (brs,2H,exchangeable), 8.70 (s,1H), 9.18 (s,1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([OH:17])=O)[S:14][C:5]=3[C:4]=2[CH:3]=1.C(Cl)(=O)C([Cl:21])=O.CN(C)C=O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([Cl:21])=[O:17])[S:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2c(s1)-c1cc(Br)ccc1OC2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc2c(s1)-c1cc(Br)ccc1OC2
Reaction time: 2 h

Procedure:
To a suspension of 8-bromo-4H-thieno[3,2-c]chromene-2-carboxylic acid 3bp (1.50 g, 4.82 mmol, 1 equiv) in dichloromethane (45 mL) at 24° C. was sequentially added oxalyl chloride (3.1 mL, 6.3 mmol, 1.3 equiv, 2.0 M in dichloromethane) and N,N-dimethylformamide (56 μL, 0.72 mmol, 0.15 equiv), as in General Procedure B. After 2 hr, the clear yellow solution was concentrated in vacuo (˜20 mm Hg) to afford crude 4bp.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[CH3:7][C:8]1[N:9]=[CH:10][O:11][C:12]=1[C:13](=[O:16])[CH2:14][CH3:15]>>[O:4]1[CH:5]=[CH:6][C:2]([C:13]([C:12]2[O:11][CH:10]=[N:9][C:8]=2[CH3:7])([OH:16])[CH2:14][CH3:15])=[CH:3]1
Reactant: CCC(=O)c1ocnc1C
Reactant: Brc1ccoc1
Product: CCC(O)(c1ccoc1)c1ocnc1C

Procedure:
Starting with 3-bromofuran and 4-methyl-5propionyloxazole and following the general method of Example 4 the title compound was prepared.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2.[NH2:20][CH2:21][CH2:22][CH2:23][OH:24]>ClCCl>[O:24]([CH2:23][CH2:22][CH2:21][NH2:20])[Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](C)(C)OCCCN
Temperature: 25 °C
Reaction time: 6 h

Procedure:
tert-Butyldimethylsilyl chloride (14.7 g, 97.5 mmol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (14.6 ml, 97.5 mmol) was added to a solution 3-amino-1-propanol (7.45 ml, 97.5 mmol) in dichloromethane (100 ml) at 0° C. under argon. After 6 hours stirring at room temperature, the mixture was quenched with water and washed successively with 10% hydrochloric acid, saturated sodium bicarbonate solution and brine. Evaporation of the dried (magnesium sulfate) organic phase gave the title amine. 1 (HNMR(CDCl3): -0.03 (s, 6H), 0.81 (s, 9H), 1.61 (p, 2H, J=6.1 Hz), 2.20 (br, 2H), 2.75 (t, 2H, J=6.8 Hz) and 3.63 (t, 2H, J=6.12 Hz).