Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5](/[CH:11]=[C:12](\[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)/[C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1C=CC2N(O)N=[N:33]C=2C=1.[NH:37]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][C:39](O)=[O:40]>CN(C)C=O.O.C(N(CC)CC)C>[NH2:2][C:3]1[CH:4]=[C:5](/[CH:11]=[C:12](\[C:15]2[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)/[C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:42]([NH:37][CH2:38][C:39]([NH2:33])=[O:40])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(N)=O

Procedure:
Seven-hundred milligrams (1.86 mmols) of (E)-3-(3-amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-enenitrile hydrochloride, 478 mg of WSCI, 375 mg of HOBt.H2O and 486 mg of Boc-Gly were dissolved in 100 ml of N,N-dimethylformamide, and 0.35 ml of triethylamine were added thereto. The mixture was reacted at 50° C. for 3.5 hours. Seven-hundred milliliters of water were added thereto, and the resulting mixture was extracted with ethyl acetate. Subsequently, the ethyl acetate layer was washed three times with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified using a silica-gel column (eluent, ether), and then dissolved in a small amount of dichloromethane. Diethyl ether was added thereto for crystallization to obtain 1.71 mmols of the final product in a yield of 92%.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:8][C:9](=[O:16])[O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[N:4][O:5][C:6]=1[CH3:7].[C:17]([O:25][CH3:26])(=[O:24])[CH:18]([CH2:20][CH:21]([CH3:23])[CH3:22])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O.CN(C=O)C>[Br:1][C:2]1[C:3]([N:8]([C:9]([O:10][CH2:11][C:12]([Cl:14])([Cl:13])[Cl:15])=[O:16])[C@H:18]([C:17]([O:25][CH3:26])=[O:24])[CH2:20][CH:21]([CH3:23])[CH3:22])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: COC(=O)C(O)CC(C)C
Reactant: Cc1onc(NC(=O)OCC(Cl)(Cl)Cl)c1Br
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1noc(C)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dry degassed DMF solution (50 mL) of 2,2,2-trichloroethyl 4-bromo-5-methylisoxazol-3-ylcarbamate (2.67 g, 7.58 mmol), DL methyl leucate (2.31 g, 15.8 mmol), and triphenyl phosphine (4.11 g, 15.7 mmol) was added diisopropyl azodicarboxylate (3.1 ml, 15.7 mmol) at 0° C. over 2 hours. The reaction was allowed to warm to room temperature while stirring overnight. Water was added and the product was extracted with ether (2×) then ethyl acetate (2×), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (20% ethyl acetate/hexane) to afford methyl N-(4-bromo-5-methylisoxazol-3-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([CH2:13][C@@H:14]([OH:17])[CH2:15][CH3:16])[N:11]=[C:10]([NH:18][C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([O:29][CH3:30])[CH:20]=3)[N:9]=2)[CH:5]=[C:4]([CH3:31])[N:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([CH2:13][C@@H:14]([O:17][C:32](=[O:34])[CH3:33])[CH2:15][CH3:16])[N:11]=[C:10]([NH:18][C:19]3[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[C:21]([O:29][CH3:30])[CH:20]=3)[N:9]=2)[CH:5]=[C:4]([CH3:31])[N:3]=1
Reactant: CC[C@H](O)Cn1nc(Nc2cc(OC)cc(C(F)(F)F)c2)nc1-c1cc(C)nc(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Product: CC[C@@H](Cn1nc(Nc2cc(OC)cc(C(F)(F)F)c2)nc1-c1cc(C)nc(Cl)c1)OC(C)=O
Temperature: 25 °C

Procedure:
N,N-Dimethyl-4-pyridinamine (0.1222 g, 0.001 mol) was added to a solution of intermediate D7 (9.117 g, 0.020 mol) in acetyl acetate (378 ml). The reaction mixture was stirred at reflux for 30 minutes. Subsequently, the mixture was cooled to room temperature and the solvent was evaporated in vacuo. The residue was redissolved in CH2Cl2. This organic solution was washed with a saturated sodium bicarbonate solution, washed with brine, and was subsequently dried (MgSO4), filtered and the solvent was evaporated in vacuo. The obtained yellow oil was purified by reversed-phase high-performance liquid chromatography (Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8 μm, 250 g, I.D. 5 cm). A gradient with 3 mobile phases was applied. Phase A: a 0.25% NH4HCO3 solution in water; phase B: methanol; phase C: CH3CN). The desired fractions were collected. The solvent was evaporated and co-evaporated with methanol. The product was crystallized from DIPE/heptane. The white crystals were filtered off and dried in vacuo. Yield: 3.677 g of intermediate D8 (37%; 5-enantiomer).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[N:23](COCC[Si](C)(C)C)[C:22]([CH3:32])=[C:21]([C:33]([NH:35][CH:36]4[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N)CN>O1CCCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:32])=[C:21]([C:33]([NH:35][CH:36]4[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c2ncnc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: C1CCOC1
Solvent: O
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A solution of tert-butyl 4-{[(4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidin-7-yl)carbonyl]amino}piperidine-1-carboxylate from example D.d1 (3.74 g; 5.5 mmol), tetrabutylammonium fluoride trihydrate (5.21 g; 16.5 mmol) and ethane-1,2-diamine (0.50 g; 8.25 mmol) in tetrahydrofurane (40 mL) is heated to gentle reflux until the starting material is completely consumed according to LC-MS. The crude is purified by column chromatography on silica gel (ethyl acetate/cyclohexane—1:1 to 2:1) to yield the title compound as colorless solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[C:25]3[CH:21]([CH2:22][N:23]([C:26]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)=[O:27])[N:24]=3)[CH2:20][CH2:19][C:18]=2[CH:39]=1.Cl[C:41]([O:43][CH3:44])=[O:42]>CCCCCC.C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[C:25]3[C:21]([C:41]([O:43][CH3:44])=[O:42])([CH2:22][N:23]([C:26]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:31][CH:30]=4)=[O:27])[N:24]=3)[CH2:20][CH2:19][C:18]=2[CH:39]=1
Reactant: COC(=O)Cl
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CC2CCc3cc(Cl)ccc3C2=N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COC(=O)C12CCc3cc(Cl)ccc3C1=NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of 50 ml of THF and 6.7 ml of diisopropylamine was cooled under N2 to -78° C. and then 17.5 ml of 2.5 M n-butyllithium in hexane was added. After 5 min. a solution of 7.8 g of the title compound of Example 4 in 15 ml of THF was added dropwise and the dark red solution that formed was stirred at -78° C. for an additional 15 min. After this time a solution of 4.6 ml of methyl chloroformate in 10 ml of THF was added dropwise and the red color dissipated rapidly. The reaction was warmed to room temperature and after 1 hr quenched with 5% aqueous sodium bicarbonate. The reaction mixture was partitioned between ether and 5% aqueous sodium bicarbonate. The ether extracts were dried over magnesium sulfate and concentrated to 14.1 g of a yellow oily solid. The crude product was triturated with ether and the resulting white precipitate was filtered and dried to afford 5.56 g of the title compound as a white solid, m.p. 234° C. to 236° C. 1H NMR(CDCl3) δ 2.1 (m, 1H), 2.75 (m, 1H) 2.95 (m, 2H), 3.71 (s, 3H), 3.75 (d, 1H, J=6Hz), 4.59 (d, 1H, J=6Hz), 7.25 (m, 2H), 7.57 (d, 2H), 7.66 (d, 2H), 7.94 (d, 1H), 8.18 (d, 1H),
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:18]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: COc1ccc(C(=O)Nc2ccc(C(=O)CCC(=O)O)cc2)cc1
Yield: 12.2 %

Procedure:
In a manner similar to that described in Example 3, 4-methoxy-benzoyl chloride (0.057 g, 0.00033 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.010 g of 4-[4-(4-methoxy-benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+328.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1Br.[CH2:14]([N:16]1[C:20]([OH:21])=[CH:19][CH:18]=[N:17]1)[CH3:15].C(N(CC)CC)C.[C]=O.[O:31]1CCOC[CH2:32]1>>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:32]([C:19]1[CH:18]=[N:17][N:16]([CH2:14][CH3:15])[C:20]=1[OH:21])=[O:31]
Reactant: C1COCCO1
Reactant: CCn1nccc1O
Reactant: Cc1c(S(C)(=O)=O)ccc(Br)c1Cl
Agent: [C]=O
Solvent: CCN(CC)CC
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C)c2Cl)c1O
Temperature: 150 °C
Reaction time: 9 h
Yield: 43 %

Procedure:
1.42 g of 2-chloro-4-methanesulfonyl-3-methylbromobenzene, 2.24 g of 1-ethyl-5-hydroxypyrazole, 10 ml of triethylamine, 0.175 g of dichloro(bistriphenylphosphine)palladium and 50 ml of dry 1,4-dioxane were charged into a 100 ml stainless steel autoclave equipped with a rotary stirrer, and the interior of the autoclave was substituted by carbon monoxide. Then, carbon monoxide was injected under a pressure of 20 kg/cm2. Then, the reaction temperature was raised to 150° C. under stirring, and the reaction was continued for 9 hours. The reaction mixture was left to cool and treated in the same manner as in Example 2-1 to obtain 0.60 g of the desired product (yield: 43%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>CN(C)C=O>[Cl:9][CH2:10][C:11]([NH:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1)=[O:12]
Reactant: Nc1ccc(Cl)nn1
Reactant: O=C(Cl)CCl
Solvent: CN(C)C=O
Product: O=C(CCl)Nc1ccc(Cl)nn1

Procedure:
3-Amino-6-chloropyridazine (10.4 g) was dissolved in N,N-dimethylformamide (200 mL). Chloroacetyl chloride (7.48 mL) was added thereto, and the resultant mixture was stirred at room temperature for 1 hour. The solvent was distilled away under reduced pressure, and ethyl acetate and saturated aqueous sodium hydrogencarbonate were added to the residue. The precipitated solid was recoverd by filtration, followed by washing with ethyl acetate and water, to thereby give the title compound (9.39 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[ClH:12].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: NCCCCCn1ccnc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: Cl
Product: O=S(=O)(NCCCCCn1ccnc1)c1ccc(Cl)cc1

Procedure:
The compound of this Example, mp 157°-161° C., was obtained when 1H-imidazole-1-pentanamine was reacted with 4-chlorobenzenesulfonyl chloride by the procedure of Example 20.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][CH:21]([CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1)[CH2:22][N:23]1[C:28](=[O:29])[C:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:33][CH:32]=2)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]2[N:48]=[C:49]([CH3:51])[N:50]=[C:24]12)(C(C)(C)C)(C)C>O.C(OCC)(=O)C>[CH:52]1([CH:21]([OH:20])[CH2:22][N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:44][C:4](=[O:7])[O:5][N:3]=4)=[CH:35][CH:36]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[C:49]([CH3:51])[N:50]=[C:24]23)[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O[Si](C)(C)C(C)(C)C)C2CCCCC2)c2nc(C)nn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(O)C2CCCCC2)c2nc(C)nn12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogen carbonate (2.1 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C. for 30 min, 4′-{[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclohexylethyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.76 g) was added, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, and dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 3.1 mL) was added and the mixture was stirred at 70° C. for 5 hr. The reaction mixture was extracted with ethyl acetate and water, and the organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.6 g, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[CH3:12])[CH2:21][CH2:22]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Br)c(F)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Yield: 85.1 %

Procedure:
Using 4-bromo-3-fluorobenzoic acid (5 g) and 1-(2,4-dimethylphenyl)piperazine (4 g) and by the reaction and treatment in the same manner as in Preparation Example 109, the title compound (7 g) was obtained.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:43][O:44][C:45]1[CH:64]=[CH:63][C:48]([C:49]([C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([C:59]([O:61][CH3:62])=[O:60])[CH:52]=2)=O)=[CH:47][C:46]=1[C:65]([O:67][CH3:68])=[O:66]>C1COCC1>[CH3:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[C:49]([C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([C:59]([O:61][CH3:62])=[O:60])[CH:52]=1)[C:48]1[CH:63]=[CH:64][C:45]([O:44][CH3:43])=[C:46]([C:65]([O:67][CH3:68])=[O:66])[CH:47]=1
Reactant: COC(=O)c1cc(C(=O)c2ccc(OC)c(C(=O)OC)c2)ccc1OC
Reactant: CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCCCCC=C(c1ccc(OC)c(C(=O)OC)c1)c1ccc(OC)c(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
n-Hexyltriphenylphosphonium bromide (0.427 g, 1 mmol) was dried by azeotropic distillation from a benzene solution and then stirred in dry THF (10 mL) under nitrogen atmosphere. Sodium bis(trimethylsilyl)amide (1 M in THF, 1 mL, 1 mmol) was added and the ylide produced was stirred under nitrogen at 0° C. for 30 min. Intermediate 35 (0.276 g, 0.77 mmol) was added as a solution in THF (10 mL) under nitrogen. The mixture was stirred at rt overnight and partitioned between 1 N HCl (100 mL) and ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, and evaporated to afford an oil which was chromatographed on SiO2 (230-400 mesh, 50 g), eluting with hexanes/ethyl acetate (4:1) to give the product (36) (0.15 g, 46%) as an oil: 1H NMR (CDCl3, 300 MHz) δ 7.63 (d, J=2.3 Hz, 1H), 7.56 (d, J=2.2 Hz, 1H), 7.20 (dt, J=2.3 Hz, 1H), 6.94 (d, J=8.6 Hz, 1H), 6.82 (d, J=8.7H, 1H), 5.96 (t, J=7.5 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 3.83 (s, 6H), 2.05 (q, J=7.3 Hz, 2H), 1.39 (t, J=7.2 Hz, 2H), 1.22 (m, J=1.9 Hz, 2H), 0.83 (t, J=6.7 Hz, 3H); IR (neat) 2927, 2853, 1732, 1606, 1500, 1435, 1263 cm−1. Anal. (C25H30O6) C, H.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH3:32][C:33]1[N:37]([CH2:38][C:39](O)=[O:40])[N:36]=[C:35]([C:42]([F:45])([F:44])[F:43])[CH:34]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[C:26]([Si:23]([CH3:24])([CH3:25])[O:22][CH2:21][C:20]([N:12]1[C:13]2[C:18]([F:19])=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:39](=[O:40])[CH2:38][N:37]3[C:33]([CH3:32])=[CH:34][C:35]([C:42]([F:45])([F:44])[F:43])=[N:36]3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:31])[CH3:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(F)(F)F)nn1CC(=O)Nc1cncc(C(=O)c2cn(C(C)(C)CO[Si](C)(C)C(C)(C)C)c3c(F)cncc23)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 29, 35 mg, 79.1 μmol), (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (22 mg, 106.9 μmol) and DIPEA (48 μL, 276.8 μmol) in THF (3 mL), T3P (166 μL, 276.8 μmol) was added and the mixture stirred at 25° C. for 18 hours. The reaction was evaporated under reduced pressure, the residue partitioned between water and ethyl acetate, the organic extracts washed with saturated sodium bicarbonate solution, dried over sodium sulphate, evaporated in vacuo and triturated with pentane-ether to afford the title compound as an off white solid (70%, 37 mg).
Reaction SMILES: B([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[Cl:14])(O)O.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23].[F-].[Cs+].O>O1CCOCC1.CC(OC)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:14][C:5]1[CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:12]=[CH:13][C:4]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23]
Reactant: COC(=O)c1ccc(B(O)O)c(Cl)c1
Reactant: FC(F)(F)c1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)c(Cl)c1

Procedure:
A mixture of methyl 4-borono-3-chlorobenzoate (Combi-Blocks BB-3530, 1.5 g, 7.0 mmol), 2-bromobenzotrifluoride (1.9 g, 8.4 mmol), cesium fluoride (3.2 g; 21.0 mmol) and bis(triphenylphosphine)palladium(II) chloride (98 mg, 0.14 mmol) was prepared in dioxane (15 mL) and water (7.5 mL) under nitrogen atmosphere, and then heated at 90° C. for 30 minutes. The reaction mixture was diluted with MTBE (30 mL) and washed with water and brine. The aqueous layers were extracted with MTBE (30 mL). The combined organic layers were dried (MgSO4) and concentrated under vacuum. After two purifications by flash chromatography (silica, heptane/DCM, then heptane/EtOAc), the title compound was obtained as a yellow oil. HPLC (Method A) Rt 5.3 min (Purity: 99.7%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([C:20]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)([O:23][CH3:24])[CH2:21][CH3:22])[CH:17]=[CH:18][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH:55]=[CH:56][CH2:57]O)[CH:50]=1.C(O)=CC>O1CCCC1>[N:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH:55]=[CH:56][CH2:57][O:13][C:14]2[CH:15]=[C:16]([C:20]([C:25]3[S:26][CH:27]=[CH:28][N:29]=3)([O:23][CH3:24])[CH2:21][CH3:22])[CH:17]=[CH:18][CH:19]=2)[CH:50]=1
Reactant: CCC(OC)(c1cccc(O)c1)c1nccs1
Reactant: OCC=Cc1cccnc1
Agent: CC=CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(OC)(c1cccc(OCC=Cc2cccnc2)c1)c1nccs1
Reaction time: 2 h
Yield: 29.8 %

Procedure:
Diethyl azodicarboxylate (0.38 ml) was added dropwise to a mixture of 2-[1-(3-hydroxyphenyl)-1-methoxypropyl]thiazole (0.37 g), triphenylphosphine (0.57 g), 3-(3-pyridyl)prop-2-en-1-ol (0.27 g) and tetrahydrofuran (7 ml) which had been cooled to 0°-5° C. in an ice-bath. The mixture was stirred at this temperature range for 2 hours and then at ambient temperature for 4 hours. Further portions of diethyl azodicarboxylate (0.1 ml), triphenylphosphine (0.14 g) and the propenol (0.045 g) were added and the mixture was stirred at ambient temperature for 18 hours. The mixture was partitioned between ethyl acetate (40 ml) and dilute aqueous hydrochloric acid (40 ml). The aqueous layer was separated and basified by adding potassium carbonate portionwise. The resulting solution was extracted with ethyl acetate (3×20 ml). The combined extracts were dried (Na2SO4) and evaporated. The residue was purified by column chromatography eluting with toluene/ethyl acetate (2/3 v/v) to give 2-[1-[3-(3-(3-pyridyl)prop-2-en-1-yloxy)phenyl]-1-methoxypropyl]thiazole as a colourless oil (0.162 g).