Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][NH:16][CH2:15][CH2:14]3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc3c(c2)CCNC3)c1=O
Reaction time: 0.33 h

Procedure:
Compound 258a (2.18 g, 5 mmol) was suspended in dioxane (10 mL). Saturated hydrogen chloride in dioxane (20 mL) was added dropwise. The reaction mixture was stirred for 20 minutes and concentrated under reduced pressure to afford 258b, which was used without further purification in the next step. LC/MS: m/z 335 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)O[CH2:11]2)=[CH:4][CH:3]=1>ClC1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][CH2:9][CH:10]3[CH:11]([C:4]=2[CH:3]=1)[C:16]1[CH:17]=[C:18]([Br:21])[CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13]3
Reactant: Brc1ccc(CCC2(CCc3ccc(Br)cc3)CO2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: Brc1ccc2c(c1)C1c3cc(Br)ccc3CCC1CC2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
37 ml (337 mmol) of titanium tetrachloride are added dropwise to a solution of 48 g (118 mmol) of 1,1-di-(p-bromophenylethyl)epoxyethane in 250 ml of chlorobenzene, and the mixture is stirred at 80° C. for 18 h. The reaction mixture is carefully poured into 100 ml of ice-water, the phases are separated, and the aqueous phase is extracted three times with 70 ml of chloroform. The combined organic phases are washed with 100 ml of saturated NaCl solution and 100 ml of NaHCO3 solution and dried over sodium sulfate, the solvent is stripped off, and the residue is recrystallised from ethanol. Yield: 43 g (110 mmol), 94%.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].Br[CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C1COCC1>[CH2:1]([N:4]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCNCCC
Reactant: CCOC(=O)C(Br)C(=O)OCC
Solvent: C1CCOC1
Product: CCCN(CCC)C(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
Dipropylamine (22.3 g, 0.22 mol) was added to a stirred solution of diethyl bromomalonate (47.8 g, 0.20 tool) in THF (400 mL) and the solution was stirred for 18 hours at room temperature. The precipitate of dipropylamine hydrobromide was filtered off and washed with THF. The THF phase was evaporated and the residual oil was partitioned between ethyl acetate (200 mL) and sodium hydroxide solution (10 mL of 4 N). The ethyl acetate phase was separated, washed with water (2-10 mL), and the solvent was removed under reduced pressure. The residual oil was dissolved in an equal volume of hexane and was applied to a silica gel column (420 g) which was eluted initially with ethyl acetate:hexane (1:20). The concentration of ethyl acetate in the eluant was increased slowly until all the diethyl (dipropylamino)malonate was eluted from the column. Fractions containing the compound as determined by TLC and GC were pooled and the solvent was removed to give diethyl (dipropylamino)malonate as an oil in 80-90% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][C:16]([CH3:20])=[CH:17][CH2:18]Br.Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:18][CH:17]=[C:16]([CH3:20])[CH3:15])[CH:3]=1
Reactant: Sc1cccc(Br)c1
Reactant: CC(C)=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=CCSc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-bromothiophenol (5.0 g) in 60 mL of DMF was treated with 3.75 g of ground potassium carbonate and 3.2 mL of 3,3-dimethylallyl bromide. The reaction mixture was stirred at room temperature for two hours, poured onto 75 mL of ice-water, acidified to pH 2.0 with 10% HCl and extracted with three 75 mL portions of ether. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by short path distillation (T=170° C. at 950 mTorr) to give 5.651 g of 1-bromo-3-(3-methyl-but-2-enylsulfanyl)-benzene as a colorless liquid.
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]2[C:7]3[C:12]([CH2:13][CH2:14][C:3]=12)=[CH:11][CH:10]=[C:9]([O:15][CH3:16])[CH:8]=3.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O.C(Cl)(Cl)Cl.C(Cl)Cl.CO>[N:17]1([C:2]2[O:6][N:5]=[C:4]3[C:7]4[C:12]([CH2:13][CH2:14][C:3]=23)=[CH:11][CH:10]=[C:9]([O:15][CH3:16])[CH:8]=4)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: COc1ccc2c(c1)-c1noc(Cl)c1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2c(c1)-c1noc(N3CCNCC3)c1CC2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A stirred mixture of 3-chloro-8-methoxy-4,5-dihydronaphth[1,2-c]isoxazole (2.0 g, 8.51 mmol), piperazine (7.0 g, 80.6 mmol) and K2CO3 (2.4 g, 17.1 mmol) in 8.0 ml of N-methylpyrrolidinone under N2 was lowered into an oil bath preheated to 150° C. The mixture was heated while stirring under N2 for 20 minutes. At that time TLC [CH2Cl2 ] showed no starting material remained. The mixture was removed from the heating bath and allowed to cool to room temperature. Upon dilution of the reaction mixture with H2O, a solid precipitated which was collected and dried in vacuo to provide pure product, mp of 86°-88° C., homogeneous by TLC [silica, 1:1 CH3OH:CH2Cl2, Rf=0.37]. The IR (CHCl3), NMR (CDCl3) and Mass Spectrum (M+ =285, EI, 70 eV) were consistent with the structure. The yield was 1.932 g (6.78 mmol, 79.66%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([O:15][CH3:16])=[C:7](CC=O)[C:6]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:3])[CH3:2].[CH3:24][Si](I)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:9][C:8]2[O:15][CH:16]=[CH:24][C:7]=2[C:6]=1[C:20]([CH3:21])([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)I
Reactant: COc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1CC=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1c(C(C)(C)C)cc2occc2c1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Acetoxy-3,5-di-tert-butyl-2-formylmethylanisole (16 g) was dissolved in dichloromethane (100 ml) and trimethylsilyl iodide (7.1 ml) was added dropwise to the solution under cooling with ice. After stirring the mixture at room temperature for 1 h, a saturated aqueous solution of sodium thiosulfate was added and the mixture was subjected to extraction with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 5-acetoxy-4,6-di-tert-butylbenzofuran quantitatively (14.3 g) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:16][CH2:17][C:18]([NH:20][CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1)=[O:19].C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[F:13][C:12]([F:15])([F:14])[C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][N:3]=[C:2]2[NH:16][CH2:17][C:18]([NH:20][CH:21]2[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]2)=[O:19])=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc2ccnc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CN)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2nccc3ccc(C(F)(F)F)cc23)C1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
Into a 8 mL sealed tube, was placed 1-chloro-7-(trifluoromethyl)isoquinoline (as prepared in the previous step, 433 mg, 1.87 mmol, 1.00 equiv), tert-butyl 3-(2-aminoacetamido)azetidine-1-carboxylate (prepared as described in Example 1, Step E) (460 mg, 2.01 mmol, 1.18 equiv), Pd(OAc)2 (15 mg, 0.07 mmol, 0.05 equiv), Cs2CO3 (1500 mg, 4.60 mmol, 1.77 equiv), BINAP (30 mg, 0.05 mmol, 0.04 equiv) and toluene (2 mL). The reaction mixture was stirred for 12 h at 100° C. in an oil bath. The solids were filtered off. The resulting mixture was concentrated under vacuum. The residue was purified by chromatography over a silica gel column with ethyl acetate:retroleum ether (1:3). The title compound was obtained as an off white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][N:5]2[C:6](=[O:8])[CH:7]=1.S(Cl)([Cl:19])(=O)=O.C([O-])(O)=O.[Na+]>ClC(Cl)C>[Cl:19][C:7]1[C:6](=[O:8])[N:5]2[CH:9]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[S:11][C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: COC(=O)c1cn2c(=O)cc(C)nc2s1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)c1cn2c(=O)c(Cl)c(C)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
7-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester (5.5 g; m.p. 146°-148° C.), prepared according to Example 1, was reacted with sulfuryl chloride (3.6 g) in dichloroethane (150 ml) under stirring at room temperature for 30 minutes. The reaction mixture was poured into ice water containing NaHCO3 : the organic phase was separated and evaporated in vacuo to dryness: crystallization from methanol gave 6-chloro-7-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester (4.28 g), m.p. 218°-220° C., which was reacted with benzaldehyde (3.5 g) in methanol (150 ml) in the presence of sodium methoxide (2.68 g) under stirring at reflux temperature for 24 hours. The precipitate was filtered and dissolved in a mixture of dimethylformamide and formic acid; the solution was diluted with ice water and the precipitate was filtered and washed with water until neutral. Crystallization from CH2Cl2 -methanol gave 3.1 g of 6 -chloro-7-trans-(2-phenyl-ethenyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, m.p. 265°-270° C. dec.,
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31]Br)[CH2:26][CH2:25]2)=[C:20](/[CH:34]=[CH:35]\[CH3:36])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:37]1[C:41]2[CH:42]=[C:43]([C:46]3([CH3:53])[NH:50][C:49](=[O:51])[NH:48][C:47]3=[O:52])[CH:44]=[CH:45][C:40]=2[CH2:39][CH2:38]1>>[CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31][N:48]3[C:47](=[O:52])[C:46]([C:43]4[CH:44]=[CH:45][C:40]5[CH2:39][CH2:38][O:37][C:41]=5[CH:42]=4)([CH3:53])[NH:50][C:49]3=[O:51])[CH2:26][CH2:25]2)=[C:20]([CH:34]=[CH:35][CH3:36])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)CC1
Reactant: CC1(c2ccc3c(c2)OCC3)NC(=O)NC1=O
Product: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc4c(c3)OCC4)C2=O)CC1

Procedure:
(Z)-1-(4-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-2-(prop-1-en-1-yl)phenyl}piperazin-1-yl)-2-bromoethanone and 5-(2,3-dihydrobenzofuran-6-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Example 14-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[CH2:10][C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7]1)(=[O:3])[CH3:2].C(NC(C)C)(C)C.O.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[C:1]([S:4][CH2:5][C@H:6]1[CH2:10][C@H:9]([C:11]([O:13][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:12])[CH2:8][S:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC[C@H]1C[C@H](C(=O)O)CS1
Reactant: BrCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(=O)SC[C@H]1C[C@H](C(=O)OCc2ccccc2)CS1
Yield: 71 %

Procedure:
To a stirred solution of (2R,4R)-2-acetylthiomethyl-4-carboxytetrahydrothiophene (compound No. 13-2, 0.18 g) in dimethylformamide (4 ml), benzyl bromide dissolved in dimethylformamide (4 ml) and diisopropylamine (214 μl) were added and the mixture was stirred over night. Water was added to the mixture and extracted with diethylether. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 0.18 g (71%) of the titled compound (compound No. 14-1).
Reaction SMILES: [CH3:1]COC(/N=N/C(OCC)=O)=O.[C:13]([NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CO>[CH3:1][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N(C)C(=O)OC(C)(C)C)cc1
Yield: 85 %

Procedure:
The crude fluorous DEAD reagent 22 was then used in Mitsunobu reactions with N-Boc-p-toluenesulfonamide. Once again, the standard mode of addition gave complete conversion with MeOH and the product, N-methyl-N-boc-p-toluenesulfonamide was isolated in 85% yield after FSPE. However, the allyl alcohol gave only trace conversion of the starting material. The organic fraction after FSPE was mostly starting material. These results are summarized in Table 7.
Reaction SMILES: [CH3:1]N(C)C=O.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:30][C:31](=[O:41])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40].CI>O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:30]([CH3:1])[C:31](=[O:41])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40]
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)OCc4ccccc4C)c(Cl)c3)c2cc1OC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(N(C)C(=O)OCc4ccccc4C)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (11 mg), and 2-methylbenzyl N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (62 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of methyl iodide (77 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (57 mg, yield 89%).
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][C:11](I)=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH:2]=[CH2:3].C[Sn](C)(C)[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=1.[Li+].[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.[Cu]I>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][C:11]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=2)=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH:2]=[CH2:3]
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)ccn1
Reactant: C=CCn1ccnc1-c1sc(I)cc1-c1ccc(Cl)cc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Product: C=CCn1ccnc1-c1sc(-c2ccnc(NC(C)=O)c2)cc1-c1ccc(Cl)cc1Cl
Temperature: 90 °C
Reaction time: 5 h
Yield: 50.6 %

Procedure:
1-allyl-2-[3-(2,4-dichlorophenyl)-5-iodo-2-thienyl]-1H-imidazole (4) (2.00 g, 4.34 mmol), N-[4-(trimethylstannyl)pyridin-2-yl]acetamide (2.59 g, 8.67 mmol), tetrakis(triphenylphosphine)palladium (0.25 g, 0.22 mmol), CuI (0.25 g, 1.30 mmol), and LiCl (0.55 g, 13.0 mmol) were weighed into a round bottom flask, equipped with reflux condenser, and the flask was purged with Argon. To this mixture was added 1,4-dioxane (100 mL) and the resulting suspension was stirred for 5 hrs at 90° C. The reaction was cooled to room temperature and concentrated in vacuo. To the solid residue was added EtOAc and DCM then the suspension was filtered through a Celite pad. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (SiO2, elution with 45% CH3CN: 50% DCM: 5% MeOH) to give crude product which was further purified by column chromatography (SiO2, elution with 4-7% MeOH in DCM) to provide 1.03 g of product (51%). LC/MS (FA) ES+ 471. 1H NMR (400 MHz, d6-DMSO) δ: 10.6 (s, 1H), 8.39 (s, 1H), 8.36 (d, J=5.3 Hz, 1H), 7.86 (s, 1H), 7.73 (d, J=2.3 Hz, 1H), 7.49 (dd, J=1.8, 5.3 Hz, 1H), 7.42 (dd, J=2.2, 8.3 Hz, 1H), 7.19-7.23 (m, 2H), 7.03 (d, J=1.1 Hz, 1H), 5.54-5.65 (m, 1H), 5.02-5.07 (m, 1H), 4.79-4.86 (m, 1H), 4.28-4.32 (m, 2H), 2.12 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15](C3C=CN=C(C(OC)=O)C=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].BrC1C=CN=C(C(OC)=O)C=1.C([O:49][CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][N:60]2[CH:64]=[C:63](Br)[CH:62]=[N:61]2)[CH:54]=1)(=O)C>>[CH3:1][C:2]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:63]3[CH:62]=[N:61][N:60]([CH2:59][C:55]4[CH:56]=[CH:57][CH:58]=[C:53]([O:52][CH2:51][CH2:50][OH:49])[CH:54]=4)[CH:64]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: CC(=O)OCCOc1cccc(Cn2cc(Br)cn2)c1
Reactant: COC(=O)c1cc(-c2cccc3c2CCCN3C(=O)CCCOc2cccc(C)c2C)ccn1
Agent: COC(=O)c1cc(Br)ccn1
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(OCCO)c5)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to methyl 4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)picolinate except that methyl 4-bromopicolinate was replaced with 2-(3-((4-bromo-1H-pyrazol-1-yl)methyl)phenoxy)ethyl acetate. LCMS, [M+H]+=540.4.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16](=O)[NH:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[CH:5][CH:4]=1)[CH3:2].P(Cl)(Cl)([Cl:28])=O.N>O>[Cl:28][C:16]1[C:17]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[O:11][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1ccc(-c2c(-c3ccccc3F)oc3nc[nH]c(=O)c23)cc1
Agent: N
Solvent: O
Product: CCc1ccc(-c2c(-c3ccccc3F)oc3ncnc(Cl)c23)cc1
Temperature: 25 °C

Procedure:
Stir a suspension of 20.0 g (0.06 mol) 5-(4-ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4(3H)-one in 100 ml (165 g, 1.07 mol) phosphoryl chloride for 1 h at 120° C. After cooling to room temperature, add the reaction solution dropwise to a mixture of 330 ml water and 610 ml 25% aqueous ammonia solution, stirring vigorously; a temperature rise to 55-65° C. is observed. Leave the reaction mixture to cool to room temperature. After extracting twice with 500 ml dichloromethane each time, wash the organic phase with satd. aqueous sodium chloride solution, dry over sodium sulphate and filter. Concentrate the filtrate by vacuum evaporation. Mix the residue with 150 ml petroleum ether, filter, wash with ice-cooled petroleum ether and dry under vacuum. 18.7 g (90% purity, 80% of theor.) of the title compound is obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:25]=[C:24]4[C:20]([CH:21]=[CH:22][NH:23]4)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.[H-].[Na+].C([O:32][C:33](=[O:37])/[CH:34]=[CH:35]/[CH3:36])C>CN(C)C=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:25]=[C:24]4[C:20]([CH:21]=[CH:22][N:23]4[CH:35]([CH3:36])[CH2:34][C:33]([OH:37])=[O:32])=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3cc[nH]c3c2)cc1
Reactant: C/C=C/C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3ccn(C(C)CC(=O)O)c3c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 6.6 %

Procedure:
To 6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indole (37 mg, 0.10 mmol, 1 eq.) was added dimethylformamide (1 ml), sodium hydride (8 mg of 60% dispersion, 0.2 mmol, 2 eq.) and (E)-but-2-enoic acid ethyl ester (0.025 ml, 0.2 mmol, 2 eq.). The reaction was stirred at room temperature for 18 hr and heated at 50° C. for 2 hr. To the reaction was added more (E)-but-2-enoic acid ethyl ester (0.050 ml, 0.4 mmol, 4 eq.) and the reaction heated at 80° C. for 22 hr. The reaction was partitioned between ethyl acetate (10 mL) and aqueous citric acid (10 mL), the organic layer separated and washed with brine (saturated NaCl), dried over magnesium sulfate, filtered, evaporated under reduced pressure. The crude material was dissolved in dimethylsulfoxide and purified by HPLC with a 50-100% acetonitrile in water gradient to yield 3-[6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-butyric acid as white solid (3 mg, 6%). LC-MS (ES) calculated for C26H23F2NO4, 451.2; found m/z 452 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[CH3:10])[C:5]2[N:15]([CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]3)[CH:16]=[N:17][C:4]=2[CH:3]=1.[Cl-].[Li+].CC1(C)CCCC(C)(C)N1[Mg]Cl.[Br:40]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[Br:40][C:16]1[N:15]([CH2:18][C@H:19]2[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]2)[C:5]2[C:6]([O:8][CH:9]([CH:11]3[CH2:12][CH2:13][CH2:14]3)[CH3:10])=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[N:17]=1
Reactant: CC(Oc1nc(Cl)cc2ncn(C[C@H]3CC[C@H](C)CC3)c12)C1CCC1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: CC1(C)CCCC(C)(C)N1[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(Oc1nc(Cl)cc2nc(Br)n(C[C@H]3CC[C@H](C)CC3)c12)C1CCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 6-chloro-4-(1-cyclobutylethoxy)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine (3.5 g, 11.73 mmol) in THF (20 mL) was added 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex (1.0 M in THF/Toluene, 29.8 mL, 29.84 mmol) at −78° C. The resulting solution was stirred 2.5 hours and then 1,3 dibromo-5,5 dimethyl hydantoin (8.5 g, 29.84 mmol) in THF (20 mL) was added dropwise at −78° C. The reaction was stirred for 30 minutes then slowly warmed to room temperature over a period of 2 hours. The reaction was quenched with saturated NH4Cl solution (50 mL) at 0° C. and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 8-10% EtOAc/petroleum ether) to yield 2-bromo-6-chloro-4-(1-cyclobutylethoxy)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine. MS ES/APCI calc'd. for C20H27BrClN3O [M+H]+ 440. found 440.