Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:34])[CH2:21][C:22]2[C:31](I)=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([F:33])[CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:35]1(B(O)O)[CH2:37][CH2:36]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:34])[CH2:21][C:22]2[C:31]([CH:35]3[CH2:37][CH2:36]3)=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([F:33])[CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1cc(I)c(CC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1F
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C2CC2)c(CC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1F
Temperature: 100 °C

Procedure:
To a solution of methyl 4-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl)-2-fluoro-5-iodobenzoate (70 mg, 0.12 mmol), cyclopropylboronic acid (16 mg, 0.18 mmol), potassium phosphate (102 mg, 0.48 mmol) and tricyclohexylphosphine tetrafluoroborate (9 mg, 0.024 mmol) in toluene (2 mL) and water (0.1 mL) under a nitrogen atmosphere was added palladium acetate (8 mg, 0.037 mmol). The reaction mixture was heated to 100° C. for 18 hours then cooled to ambient temperature. The reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford the target compound (70 mg, crude) which was used in the next step without purification. LCMS (ESI): m/z: 486.9 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([OH:17])=[O:16])=[N:7]1.[CH3:18]O>>[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([O:17][CH3:18])=[O:16])=[N:7]1
Reactant: CO
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1n[nH]c2ccccc12

Procedure:
0.5 ml of concentrated sulphuric acid (95%) is added dropwise, at a temperature in the region of 20° C., to a solution of 9.13 g of 3-indazolecarboxylic acid in 100 ml of methanol. After refluxing for 20 hours, the reaction medium is concentrated under reduced pressure at a temperature in the region of 40° C. The aqueous residue obtained is extracted with dichloromethane. The organic phases are combined, washed with water until neutral, dried over magnesium sulphate and then concentrated under reduced pressure at a temperature in the region of 40° C. The yellow powder obtained is washed with ethyl ether. A white powder is obtained. The filtrate is concentrated under reduced pressure until a yellow powder is obtained. This yellow powder is washed again with ethyl ether until a white powder is obtained. The yellow filtrate is concentrated a third time under reduced pressure and the yellow powder collected is itself also washed with ethyl ether. All the fractions of white powder are combined. 7.08 g of methyl 3-indazolecarboxylate are thus obtained in the form of a white powder.
Reaction SMILES: C(N(CC)CC)C.[S:8](Cl)([CH3:11])(=[O:10])=[O:9].[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[C:22]2[CH2:25][CH2:26][OH:27])=[CH:17][CH:16]=1>ClCCl>[S:8]([O:27][CH2:26][CH2:25][C:22]1[C:23]2[C:18](=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[CH:24]=2)[CH:19]=[CH:20][CH:21]=1)(=[O:10])(=[O:9])[CH3:11]
Reactant: COc1ccc2cccc(CCO)c2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2cccc(CCOS(C)(=O)=O)c2c1
Temperature: -10 °C

Procedure:
In a 250-cm3 flask, 4 g of 2-(7-methoxy-1-naphthyl)ethanol are dissolved in 100 cm3 of dichloromethane, and 3.3 cm3 of triethylamine are added. The mixture is cooled in an ice bath at -10° C. and 2.75 g of mesyl chloride are then added dropwise and with stirring. The mixture is left stirring for 30 minutes. The aqueous phase is extracted with 3 times 50 cm3 of dichloromethane, and the organic phase is washed with 3 times 20 cm3 of 1N hydrochloric acid solution and then with water, dried over potassium carbonate and evaporated. The oily residue is recrystallized.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])[CH:9]=[N:10][C:5]2=[C:4]([O:23]C)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>O.Cl>[CH3:22][C:13]1[C:14]([C:18]([F:21])([F:19])[F:20])=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:8]1[C:6]2=[N:7][C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:3][C:4]([OH:23])=[C:5]2[N:10]=[CH:9]1
Reactant: C1COCCN1
Reactant: COc1cc(Cl)nc2c1ncn2Cc1cccc(C(F)(F)F)c1C
Agent: Cl
Solvent: O
Product: Cc1c(Cn2cnc3c(O)cc(N4CCOCC4)nc32)cccc1C(F)(F)F
Yield: 17.77 %

Procedure:
5-chloro-7-(methyloxy)-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (45 mg, 0.126 mmol) was suspended in 1.5 mL of morpholine in a microwave vial and the mixture was irradiated in a microwave oven at 130° C. for 45 min, then for additional 3 h, another 3 h and then additional 12 h. Product is slowly forming (as observed by LC/MS) going through the formation of the 7-hydroxy derivative first. The mixture was then irradiated for 3 h at 200° C., to provide complete conversion to the desired product. An additional aliquot of 5-chloro-7-(methyloxy)-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (60 mg, 0.169 mmol) was suspended in morpholine (1.5 mL) and irradiated in a microwave oven at 200° C. for 3 h. The reaction was not completed, so it was irradiated again in the microwave at 200° C. for 150 min. The two reaction mixtures were combined and diluted with water and 1 N HCl was added to pH 4-5. The precipitate formed was collected by filtration, washed with water and dried. The solid was dissolved in DMSO and purified by Reverse phase-HPLC (25 to 80% AcCN in water plus 0.1% TFA). Two peaks closely eluted on the HPLC and were isolated for the product. The slower retention time peak presented 2% impurity so it was kept separated. The collected fractions were neutralized by the addition of NaHCO3 sat sol and the solvent volume was reduced to ½-⅓ of the original. The precipitates were collected washed with water and dried in a vacuum oven at 45° C. for 5 h to give 3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(4-morpholinyl)-3H-imidazo[4,5-b]pyridin-7-ol (21 mg, 0.052 mmol, 17.77% yield) which was submitted for testing, and the less pure sample of 3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(4-morpholinyl)-3H-imidazo[4,5-b]pyridin-7-ol (18 mg, 0.046 mmol, 15.54% yield), which was stored as is. MS (ES+) m/e 393 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (br. s., 1H), 7.99 (s, 1H), 7.62 (d, J=8.08 Hz, 1H), 7.34 (t, J=7.83 Hz, 1H), 7.26 (d, J=7.58 Hz, 1H), 6.07 (s, 1H), 5.41 (s, 2H), 3.57-3.76 (m, 4H), 3.24-3.40 (m, 4H), (CH3 peak under DMSO peak).
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].[Cl:25][C:26]1[N:31]=[N:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(N(CC)CC)C>C(=O)(O)[O-].[Na+].C(Cl)Cl>[Cl:25][C:26]1[N:31]=[N:30][C:29]([S:32]([N:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=3)[CH2:18][CH2:19]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Cl)nn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Cl)nn1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 24 h
Yield: 34.2 %

Procedure:
To a 20 mL vial was added 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (0.35 g, 0.87 mmol, Example 91), 6-chloropyridazine-3-sulfonyl chloride (0.20 g, 0.96 mmol, Archiv der Pharmazie and Berichte der Deutschen Pharmazeutischen Gesellschaft 1966, 229, 646), CH2Cl2 (10 mL) and triethylamine (0.61 mL, 4.4 mmol). After 24 h at room temperature, an additional 100 mg of 6-chloropyridazine-3-sulfonyl chloride was added and the solution was stirred for an additional hour. The reaction was diluted with saturated aqueous sodium bicarbonate and CH2Cl2. This was stirred for 5 min and then the solution was transferred onto a phase separation cartridge (Radleys Discovery Technologies, Essex, UK) with the organic phase being collected and passed through a plug of Na2SO4. The collected solution was purified by silica gel chromatography (0 to 70% EtOAc in hexanes). The resulting oil was dissolved in EtOAc/heptanes, concentrated and dried under reduced pressure to afford 2-(4-(4-((6-chloropyridazin-3-yl)sulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.15 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][OH:13])=[CH:5][CH:4]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([C:9]#[C:10][CH2:11][CH2:12][O:13][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCC#Cc1ccc(C(F)(F)F)cc1
Product: CS(=O)(=O)OCCC#Cc1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 1G], 4-(4-trifluoromethyl-phenyl)-but-3-yn-1-ol and methanesulfonyl chloride gave the title compound as light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[C:16]#[C:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20].CC(O)=O>[Fe].CCO>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:16]#[C:17][Si:18]([CH:19]([CH3:21])[CH3:20])([CH:22]([CH3:23])[CH3:24])[CH:25]([CH3:26])[CH3:27]
Reactant: CC(C)[Si](C#Cc1cc([N+](=O)[O-])ccc1OCc1cccc(F)c1)(C(C)C)C(C)C
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)[Si](C#Cc1cc(N)ccc1OCc1cccc(F)c1)(C(C)C)C(C)C

Procedure:
To a flask was charged with (2-(2-(3-fluorobenzyloxy)-5-nitrophenyl)ethynyl)triisopropylsilane (compound 23.1, 472 mg, 1.11 mmole), Fe (309 mg), HOAc (4 mL) and EtOH (10 mL). The reaction mixture was refluxed for 3 h and the solvent was removed. Methylene was added and washed with aqueous NaHCO3. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 30% EtOAc in Hexane to give the desired product as yellow crystalline. LCMS ESI(+) m/z: 398 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24](OC)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2ccc3c(c2)OCCc2cc(C(=O)N(C)c4ccccc4Cl)sc2-3)CC1

Procedure:
Following Example 47 and General Procedure C, methyl 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate 138 and N-methylpiperazine gave 202. MS: (ESI+) 496.2
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[C:11]([C:23]([O:25][CH3:26])=[O:24])[NH:10][N:9]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+].[CH3:30]I>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[C:11]([C:23]([O:25][CH3:26])=[O:24])[N:10]([CH3:30])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: COC(=O)c1[nH]nc(-c2ccc(Br)cc2)c1OCc1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(OCc2ccc(OC)cc2)c(-c2ccc(Br)cc2)nn1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 3-(4-bromophenyl)-4-(4-methoxybenzyloxy)-1H-pyrazole-5-carboxylate T-11 (10 g, 24 mmol) in anhydrous N,N-dimethylformamide (100 mL) cooled in an ice bath was added lithium hydroxide monohydrate (3 g, 71 mmol) and methyl iodide (10 g, 70 mmol). The reaction mixture was stirred at room temperature for 3 hours. The crude product was diluted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over sodium sulfate. Solvent was evaporated under reduced pressure. The crude solid product was washed with hexane to afford the desired methyl 3-(4-bromophenyl)-4-(4-methoxybenzyloxy)-1-methyl-1H-pyrazole-5-carboxylate T-12 (7 g, 16 mmol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC([O-])(C)C.[Na+].Br[C:48]1[CH:49]=[C:50]2[C:59](=[C:60]3[C:65]=1[CH:64]=[CH:63][CH:62]=[N:61]3)[NH:58][S:57](=[O:67])(=[O:66])[C:56]1[C:51]2=[CH:52][CH:53]=[CH:54][CH:55]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[N:1]1([C:48]2[CH:49]=[C:50]3[C:59](=[C:60]4[C:65]=2[CH:64]=[CH:63][CH:62]=[N:61]4)[NH:58][S:57](=[O:67])(=[O:66])[C:56]2[C:51]3=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=S1(=O)Nc2c(cc(Br)c3cccnc23)-c2ccccc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: O=S1(=O)Nc2c(cc(N3CCOCC3)c3cccnc23)-c2ccccc21
Yield: 27.2 %

Procedure:
In a similar fashion using route 58 general procedure 126, morpholine (37 μl, 0.42 mmol), Pd2(dba)3 (3 mg, 3 μmol), X-Phos (7 mg, 14 μmol), NaOtBu (67 mg, 0.69 mmol), 12-bromo-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 545 (100 mg, 0.28 mmol) and toluene (2 ml) gave the title compound (28 mg, 28%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]4[CH3:29])=[C:19]([N+:30]([O-])=O)[CH:18]=3)[O:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CCO.C([O-])(O)=O.[Na+]>[NH2:30][C:19]1[CH:18]=[C:17]([C:15]2[O:14][N:13]=[C:12]([C:10]3[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=3)[N:16]=2)[CH:22]=[CH:21][C:20]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[CH3:29]
Reactant: COC(=O)c1ccc(-c2noc(-c3ccc(N4CCCCC4C)c([N+](=O)[O-])c3)n2)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(-c2noc(-c3ccc(N4CCCCC4C)c(N)c3)n2)cc1F

Procedure:
Stannous chloride dihydrate (20.49 g; 90.82 mmol) was added to a suspension of methyl 2-fluoro-4-{5-[4-(2-methylpiperidin-1-yl)-3-nitrophenyl]-1,2,4-oxadiazol-3-yl}benzoate, obtained in step 1, (8 g; 18.16 mmol) in EtOH (80 mL) and the resulting mixture was stirred at reflux for 3 hours. The solution was diluted with a saturated aqueous solution of NaHCO3 and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4 and concentrated affording the title compound as a yellow solid. 1H NMR (DMSO, 400 MHz) δ 8.18-7.95 (m, 3H), 7.56-7.55 (d, J=1.77 Hz, 1H), 7.44-7.41 (m, 1H), 7.21-7.19 (d, J=8.38 Hz, 1H), 5.32 (br s, 2H), 3.94 (s, 3H), 3.21-2.92 (m, 2H), 1.88-1.22 (m, 7H), 0.88 (d, J=6 Hz, 3H). LC/MS (Method B): 411.4 (M+H)+; 417.2 (M−H)−. HPLC: Rt 4.47 min (Purity: 95.6%).
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5]CC)[O:2][CH2:3][CH3:4].Br[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:14].BrCC>>[CH2:9]([O:8][P:1]([CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:14])([O:2][CH2:3][CH3:4])=[O:5])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)CBr
Solvent: CCBr
Product: CCCCCCCCCCCCCCCCCCOC(=O)CP(=O)(OCC)OCC
Temperature: 100 °C
Yield: 98 %

Procedure:
100 parts by weight of triethyl phosphite and 235 parts by weight of octadecyl bromoacetate were put into a reactor equipped with a distillation tube, and the inside of the reactor was substituted by nitrogen. Subsequently, the reactor was heated at 100° C. to start a reaction. Since bromoethane as a by-product began to distill out immediately, the reaction was maintained until the distillation-out of bromoethane slowed down. When the distillation-out of bromoethane became moderate, the reactor was further heated at 150° C. to continue the reaction for 3 hours. The reaction mixture was cooled to room temperature to obtain a precipitate. The precipitate was collected by filtration and recrystallized with acetone to obtain a white plate-like crystal (yield of 98%, melting point of 28 to 31° C.).
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:8]=1)=[O:5].I[C:24]1[C:28]([CH:29]=[O:30])=[CH:27][N:26]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[N:25]=1.C([O-])(O)=O.[Na+].O>O1CCOCC1.CO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:29]([C:28]1[C:24]([C:9]2[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH:3]=[C:2]([CH3:1])[CH3:22])[CH:12]=[CH:11][CH:10]=2)=[N:25][N:26]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH:27]=1)=[O:30]
Reactant: CC(C)=CC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=Cc1cn(C2CCCCO2)nc1I
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CC(C)=CC(=O)Nc1cccc(-c2nn(C3CCCCO3)cc2C=O)c1
Yield: 72.7 %

Procedure:
To a solution of 3-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-2-enamide (0.261 g, 0.00098 mol) and 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde (0.250 g, 0.000817 mol) in 1,4-dioxane (8 ml) was added saturated NaHCO3 solution (8 mL). The reaction mixture was degassed using argon for 0.5 h. Tetrakis(triphenylphosphine) palladium (0.094 g, 0.000081 mol) was added under an argon atm. and the resultant suspension was heated for 8 h at 90° C. The reaction was poured into water (50 mL) extracted with EtOAc (40 mL×2). The combined extracts were washed with brine (50 mL) dried over sodium sulphate and concentrated under vacuum. The residue was purified by SGC using DCM:MeOH (0-1%) as eluent to obtain N-(3-(4-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)phenyl)-3-methylbut-2-enamide (0.210 g, Yield 73.43%). LCMS (ESI): RT=2.20 min, m/z=354.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C:9](=[O:12])[C:10]#[CH:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].I[C:14]1[CH:15]=[C:16]([O:20][CH3:21])[CH:17]=[CH:18][CH:19]=1.CCN(CC)CC.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O.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.[Cu]I>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([C:11]#[C:10][C:9]([N:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:1])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(I)c1
Reactant: C#CC(=O)N(C)CC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C)C(=O)C#Cc1cccc(OC)c1
Reaction time: 2 h
Yield: 34.5 %

Procedure:
To a solution of ethyl 2-(N-methylprop-2-ynoylamino)acetate (312 mg, 1.84 mmol) in THF (6 mL) was added 3-iodoanisole (475 mg, 0.24 mL, 2.03 mmol), dichlorobis(triphenylphosphine)palladium(II) (133 mg, 0.19 mmol), copper(I) iodide (36 mg, 0.19 mmol) and Et3N (279 mg, 0.39 mL, 2.76 mmol). The resulting mixture was stirred in dark for 2 h. A saturated NH4Cl solution (30 mL) was then added and the mixture was extracted with EtOAc (2×30 mL). The combined organic layers were washed with a saturated NaCl solution (60 mL), dried (Na2SO4) and concentrated under reduced pressure to give a dark oil, which was dissolved in EtOAc and filtered through a pad of silica gel. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (33% EtOAc/hex) to give ethyl 2-[3-(3-methoxyphenyl)-N-methylprop-2-ynoylamino]acetate (175 mg, 35%) as a light yellow oil: 1H NMR (CDCl3; a mixture of two rotomers) δ 1.30 (t, J=7.0 Hz, 3H), 3.10 (1.35H), 3.36 (s, 1.65H), 3.81 (s, 1.35H), 3.82 (s, 1.65H), 4.20-4.30 (m, 3.2H), 4.39 (s, 0.8H), 6.97-7.29 (m, 4H); HPLC ES-MS m/z (rel abundance) 276 (MH+, 100%).
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:26]1[CH:27]=[CH:28][C:29]([O:41][CH3:42])=[C:30]([S:32]([NH:35][C:36]([CH3:40])([CH3:39])[CH2:37][OH:38])(=[O:34])=[O:33])[CH:31]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:26]4[CH:27]=[CH:28][C:29]([O:41][CH3:42])=[C:30]([S:32]([NH:35][C:36]([CH3:39])([CH3:40])[CH2:37][OH:38])(=[O:34])=[O:33])[CH:31]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(Br)cc1S(=O)(=O)NC(C)(C)CO
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: COc1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and 5-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-2-methoxy-benzenesulfonamide (85 mg, 0.25 mmol) (Example B.7) according to general procedure II. Obtained as a yellow solid (61 mg, 42%). MS (ISP) 585.3 [(M+H)+]; mp 192–195° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[CH:15]=[CH:14][N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[C:10]2=[N:11][CH:12]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:36])(=O)=O)=CC=1>C1COCC1.CCCCCC>[F:36][C:7]1[CH:8]=[C:9]2[CH:15]=[CH:14][N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[C:10]2=[N:11][CH:12]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(F)cnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
2.5M Butyl lithium (4.4 mL, 10.8 mmol) was added dropwise to a stirred solution of 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (2.55 g, 7.23 mmol) in THF (65 mL) over 10 min at −78° C. under nitrogen in three necked flask. The resulting solution was stirred at −78° C. for 1 h and solid N-fluorobenzenesulfonimide (2.84 g, 9.03 mmol) was added in one portion and stirred at −78° C. for 2 h. The solvent was evaporated and the crude material was dissolved in water (50 mL) and extracted with EtOAc (3×25 mL). The organic extract was dried and concentrated under reduced pressure to give a residue which was suspended in hexane (5 mL) and filtered. The filtrate was chromatographed (Biotage HPFC) on silica gel eluting with hexane to give 5-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.06 g, 50.2%) as a viscous oil.; Mass Spec.; MS 293 (M+1); 1H NMR(CDCl3,500 MHz) 8.11(d,1H), 7.51(dd,1H), 7.34(d,1H), 6.50(d,1H), 1.84(q,3H), 1.10(d,18H).