Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].Br[CH2:10]/[CH:11]=[C:12](/[C:23]1[N:28]=[C:27]([O:29][CH3:30])[C:26]([Cl:31])=[CH:25][CH:24]=1)\[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1.O>O1CCCC1>[C:19]([C:16]1[CH:15]=[CH:14][C:13](/[C:12](/[C:23]2[CH:24]=[CH:25][C:26]([Cl:31])=[C:27]([O:29][CH3:30])[N:28]=2)=[CH:11]\[CH2:10][N:5]2[CH2:6][CH2:7][O:3][C:4]2=[O:8])=[CH:18][CH:17]=1)([CH3:20])([CH3:21])[CH3:22]
Reactant: COc1nc(/C(=C/CBr)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reactant: O=C1NCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(/C(=C/CN2CCOC2=O)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A suspension of sodium hydride (purity: 60%, 60 mg) in tetrahydrofuran (1.0 mL) was added to a solution of 2-oxazolidinone (153 mg) in tetrahydrofuran (1.0 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 6-[(1E)-3-Bromo-1-(4-tert-butylphenyl)prop-1-en-1-yl]-3-chloro-2-methoxypyridine obtained in Reference Example 4-5 (303 mg) was added thereto, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:2) to give 3-[(2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-yl]-1,3-oxazolidin-2-one as a light brown powder (298 mg, 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:13][N:12]2[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:28]=2)=O)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C=O.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:10])[N:11]3[CH2:15][CH:14]([O:16][C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH2:13][N:12]3[C:25]=2[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([O:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:28]=2)=[CH:4][CH:3]=1
Reactant: O=C(OC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)c2ccnc(Oc3ccccc3)n2)C1)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(OC1Cn2c(-c3ccnc(Oc4ccccc4)n3)c(-c3ccc(F)cc3)c(=O)n2C1)N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A solution of morpholine-4-carboxylic acid 1-[2-(4-fluorophenyl)acetyl]-2-(2-phenoxypyrimidine-4-carbonyl)-pyrazolidin-4-yl ester, 42, (154 mg, 0.287 mmol) in dimethylformamide (3 mL) is added dropwise to a −10° C. suspension of sodium hydride (16.4 mg of a 60% dispersion in mineral oil, 0.410 mmol) in tetrahydrofuran (3 mL). After 1 hour at −10° C., the reaction was warmed to 0° C. for 2 hours. The orange-colored solution is then quenched by slowly adding saturated NH4Cl (400 μL). The cooling bath is removed, and the solution allowed to warm to room temperature. The reaction mixture is concentrated in vacuo and the resulting residue is dissolved in THF (25 mL) and filtered through a pad of Celite. The filtrate is concentrated in vacuo and the residue purified by Prep HPLC to afford 47 mg (32% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.46 (d, J=4.9 Hz, 1H), 7.47-7.18 (m, 9H), 7.08 (t, J=8.7 Hz, 2H), 6.89 (d, J=4.9 Hz, 1H), 5.66 (m, 1H), 4.16 (m, 2H), 4.02 (d, J=12.9 Hz, 1H), 3.87 (dd, J=12.9, 5.1 Hz, 1H), 3.79-3.30 (m, 8H); HRMS m/z calcd for C27H25FN5O5 (MH+) 518.1840, found 518.1815.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:21][C:22]1[N:27]=[C:26]([NH:28]N)[CH:25]=[CH:24][CH:23]=1.C(O)(=O)C>CCO>[Cl:21][C:22]1[N:27]=[C:26]([N:28]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccncc2)ccc1=O
Reactant: NNc1cccc(Cl)n1
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1ccn(-c2ccncc2)nc1-c1ccnn1-c1cccc(Cl)n1
Yield: 11.6 %

Procedure:
A solution of 3-((E)-3-dimethylamino-acryloyl)-1-pyridin-4-yl-1H-pyridazin-4-one (A-1; 0.075 g; 0.3 mmol) in EtOH (2 ml) was treated with (6-chloropyridin-2-yl)-hydrazine (0.048 g; 0.3 mmol) in a sealed tube and irradiated at 100° C. for 30 min. Acetic acid (0.5 ml) was added and the mixture again irradiated at 100° C. for 15 min. The solvent of the reaction mixture was removed and the crude product purified by preparative HPLC yielding 0.0122 g (12%) of the final product. MS: M=351.1 (M+H)−
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16](O)=[O:17])=[CH:11][C:10]=2[S:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.S(Cl)(Cl)=O.[CH3:23][C:24]1[N:28]([CH2:29][CH2:30][OH:31])[C:27]([N+:32]([O-:34])=[O:33])=[CH:26][N:25]=1>>[CH3:23][C:24]1[NH:28][C:27]([N+:32]([O-:34])=[O:33])=[CH:26][N:25]=1.[O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([O:31][CH2:30][CH3:29])=[O:17])=[CH:11][C:10]=2[S:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=C(O)c1ccc2c(=O)c3ccccc3sc2c1
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc2c(=O)c3ccccc3sc2c1
Product: Cc1ncc([N+](=O)[O-])[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
The reaction mixture of 9-oxo-9H-thioxanthene-3-carboxylic acid (288 mg, 1.0 mmol) and thionyl chloride (2 ml) was refluxed for 2 h. The excessive thionyl chloride was evaporated under the vacuum. The residue was dissolved in 3 ml of pyridine. To this solution, metronidazole (125 mg, 0.70 mmol) was added. After the mixture was stirred at room temperature for 4 h, then pyridine was removed in vacuo. The residue was dissolved in dichloromethane (50 ml). The organic layer of dichloromethane was washed with 5% Na2CO3, H2O, and brine, and then dried over MgSO4. The solvent was removed, and the residue was recrystallized from C2H5OH-CHCI3 to give 151 mg 2-methyl-5-nitro-1H-imidazole-1-ethyl 9-oxo-9H-thioxanthene-3-carboxylate. m.p.: 128-130° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:40])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([C:31]([OH:33])=[O:32])[N:28]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:40])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([C:31]([OH:33])=[O:32])[N:28]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(=O)O)n(-c3ccccc3)n2)CC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(C(=O)O)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 50 mg of 4-{(S)-4-tert-Butoxycarbonyl-2-[(5-carboxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 3 ml of DCM, 0.1 ml of TFA was added at RT. After 4 h 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:10]1[CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: BrBr
Reactant: CCOC(=O)c1ccc(-c2ccc(OC)cc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ccc(OC)c(Br)c2)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A solution of bromine (14.6 g, 91.3 mmol) in carbon tetrachloride (100 mL) is added to a stirred mixture of 4′-Methoxy-[1,1′-biphenyl]4-carboxylic acid, ethyl ester (23.4 g, 91.3 mmol) and silica gal (100 g of particle size 0.040-0.063 mm; Merck 1.09385) in carbon tetrachloride (350 mL). The mixture is stirred at 20° C. for 4 h after which the silica gel is removed by filtration. The filtrate is washed with aqueous sodium hydrogen carbonate (200 mL of 1 M) followed by aqueous sodium thiosulphate (50 mL of 2 M), dried (Na2SO4), filtered and evaporated to dryness under reduced pressure to give the crude product which is recrystallised from ether-cyclohexane to give 3′-bromo4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid, ethyl ester as a colourless crystalline solid, m.p. 114-115° C.
Reaction SMILES: [CH3:1][C:2]1[NH:20][C:5]2=[N:6][C:7]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:24]=1[CH3:33].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[CH3:1][C:2]1[N:20]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[C:24]=2[CH3:33])[C:5]2=[N:6][C:7]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Reactant: COC(=O)c1cc(N2CCOCC2)nc2[nH]c(C)nc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(N2CCOCC2)nc2c1nc(C)n2Cc1cccc(C(F)(F)F)c1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
A mixture of methyl 2-methyl-5-morpholino-3H-imidazo[4,5-b]pyridine-7-carboxylate (207 mg, 0.75 mmol), 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (285 mg, 1.125 mmol) and Na2CO3 (239 mg, 2.25 mmol) in DMF (10 mL) was stirred at 80° C. for 3 h. TLC showed no methyl 2-methyl-5-morpholino-3H-imidazo[4,5-b]pyridine-7-carboxylate left. It was cooled to room temperature and poured into water (50 mL) and filtered. The solid was dissolved with DCM (150 mL) and it was washed with brine (100 mL×3) and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the desired product as a brown solid (320 mg, 95%); LC/MS: MS (ES+) m/e 449 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.40 (s, 3H), 2.51 (s, 3H), 3.41 (t, J=4.8 Hz, 4H), 3.68 (t, J=4.8 Hz, 4H), 3.92 (s, 3H), 5.50 (s, 2H), 6.90 (d, J=7.8 Hz, 1H), 7.07 (s, 1H), 7.28 (t, J=7.5 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:2]=1.O[N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C=O)C>[CH2:16]1[C:17](=[O:18])[N:13]([O:10][C:9](/[CH:8]=[CH:7]/[C:3]2[CH:4]=[CH:5][CH:6]=[N:1][CH:2]=2)=[O:11])[C:14](=[O:19])[CH2:15]1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)C=Cc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(/C=C/c1cccnc1)ON1C(=O)CCC1=O

Procedure:
A solution of 3-(3-pyridyl)acrylic acid (500 mg: commercially available from Aldrich Chemical Company), N-hydroxysuccinimide (463 mg), and EDCl (707 mg) in methylene chloride (20 mL) and DMF (10 mL) was stirred at ambient temperature for 18 hours. The product was isolated as described in Example 3a to yield 740 mg of the title compound as a white solid. MS (Cl/NH3) m/e 247 (M+H)+. 1H NMR(CDCl3, 300 MHz) δ2.87 (br s,4H), 7.15 (d,J=16 Hz,1H), 7.48-7.53 (m,1H), 8.02 (d,1H), 8.31 (dt,J=9 Hz,1H), 8.66 (dd,J=6 Hz,1H), 8.99 (d,J=2 Hz,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=O)C(C(O)=O)=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.CN(C=O)C.[C:31](Cl)(=O)[C:32]([Cl:34])=[O:33].C(Cl)[Cl:38]>>[Cl:38][C:13]1[C:31]([C:32]([Cl:34])=[O:33])=[CH:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Reactant: ClCCl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (200 mg, 0.41 mmol) from Step A in methylene chloride was added a drop of DMF (cat.) and oxalyl chloride (0.18 mL, 2.0 mmol). The reaction was stirred at rt for 1 h and then evaporated to dryness. The acid chloride was dissolved in methylene chloride and used directly in the subsequent amide formation.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([CH3:15])[CH:3]=1.[CH:16](B1OC(C)(C)C(C)(C)O1)=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[CH3:15][C:4]1[CH:3]=[C:2]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH2:16])[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC1(C)OB(C=Cc2ccccc2)OC1(C)C
Reactant: Cc1cc(Br)ccc1C(=O)OC(C)(C)C
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: O
Solvent: C1COCCO1
Product: C=C(c1ccccc1)c1ccc(C(=O)OC(C)(C)C)c(C)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
To a solution of tert-butyl 4-bromo-2-methylbenzoate (2 g, 7 mmol) in dioxane/water (50 mL, 4:1) was added styrylboronic acid pinacol ester (1.64 g, 7 mmol), tetrakis(triphenylphosphine)palladium (0.7 mmol, 0.904 g), sodium carbonate (21 mmol, 2.3 g). The mixture was stirred at 90° C. under nitrogen gas atmosphere for 18 hours. LC-MS showed the start material has been consumed. Then evaporated the solvent and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=30:1) to give tert-butyl 2-methyl-4-(1-phenylvinyl)benzoate (1.8 g, 91%).
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]([CH2:22][CH2:23][CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14][C:13]=3[CH:21]=2)=[O:7])=[CH:4][CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[CH:40])=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CCOCC>[CH:25]1([CH2:24][CH2:23][CH2:22][N:8]([C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14][C:13]=3[CH:21]=2)[C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([C:40]#[C:39][C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)=[CH:31][CH:30]=2)[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CC1(C)OC(=O)c2ccc(N(CCCC3CCCC3)C(=O)c3ccc(Br)cc3)cc2O1
Reactant: C#Cc1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1(C)OC(=O)c2ccc(N(CCCC3CCCC3)C(=O)c3ccc(C#Cc4ccc(F)cc4)cc3)cc2O1
Yield: 83.7 %

Procedure:
A solution of 4-bromo-N-(3-cyclopentylpropyl)-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)benzamide (355 mg, 0.73 mmol), 4-fluorophenylacetylene (Apollo, 96 mg, 0.80 mmol), bis(triphenylphosphine)palladium(I) chloride (26 mg, 0.04 mmol), triphenylphosphine (38 mg, 0.15 mmol) and cuprous(I) iodide (7 mg, 0.04 mmol) in DMF (3 mL) and TEA (1 mL) was heated under microwave conditions at 120° C. for 25 min. The reaction mixture was then diluted with Et2O and the precipitate obtained was filtered off. Filtrate was then washed with an aqueous solution of HCl (1N) and brine. The organic layer was dried over MgSO4 and the solvents were removed under reduced pressure. Purification by flash chromatography on silicagel (EtOAc/c-Hex (10/90 to 20/80)) gave 321 mg (84%) of the title compound. HPLC, Rt: 5.67 min (purity: 97.9%). 1H NMR (CDCl3) δ: 7.78 (d, J=8.3 Hz, 1H), 7.44 (m, 2H), 7.31 (AB, J=8.4, Δ=12 Hz, 4H), 7.01 (t, J=8.5 Hz, 2H), 6.75 (dd, J=8.3, 2.1 Hz, 1H), 6.58 (d, J=2.1 Hz, 1H), 3.91 (t, J=7.7 Hz, 2H), 1.40-1.71 (m, 15H), 1.34 (m, 2H), 1.03 (m, 2H).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]([C:7](=[NH:9])[NH2:8])=[CH:3]1.[Cl:10][C:11]([SH:14])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:10][C:11]1[S:14][N:8]=[C:7]([C:4]2[CH:5]=[CH:6][S:2][CH:3]=2)[N:9]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1ccsc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Clc1nc(-c2ccsc2)ns1
Temperature: 25 °C
Yield: 63 %

Procedure:
To a solution of thiophene-3-carboximidamide hydrochloride (2.00 g, 12.3 mmol) and perchloromethyl mercaptan (1.32 ml, 12.3 mmol) in dichloromethane (40 ml) was added dropwise a solution of sodium hydroxide (2.46 g, 61.5 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.57 g (59.5%) of the desired product as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:21][CH:22]([F:34])[O:23][C:24]1[CH:25]=[C:26]([S:30]([Cl:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[ClH:33].[F:34][CH:22]([F:21])[O:23][C:24]1[CH:25]=[C:26]([S:30]([NH:20][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=2)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2)CC1
Product: Cl
Product: O=S(=O)(Nc1cccc(N2CCNCC2)c1)c1cccc(OC(F)F)c1

Procedure:
The compound was prepared as described for Example 1 by reaction of 4-(5-aminophenyl)-piperazine-1-carboxylic acid tert-butyl ester with commercially available 3-difluoromethoxybenzene sulfonylchloride followed by deprotection under acidic conditions.
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].Cl[C:9]1[C:10]2[CH:17]=[CH:16][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=2[N:12]=[CH:13][N:14]=1.[CH2:26]([O:28][CH:29]([N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1)[CH3:30])[CH3:27]>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.C(O)CC>[CH2:26]([O:28][CH:29]([N:31]1[CH:35]=[C:34]([C:9]2[C:10]3[CH:17]=[CH:16][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:33]=[N:32]1)[CH3:30])[CH3:27]
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
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: [K+]
Solvent: CCCO
Solvent: O
Product: CCOC(C)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 90 °C

Procedure:
To a reactor equipped with overhead stirring, condenser, thermowell, and nitrogen inlet was charged water (H2O, 1.5 L), potassium carbonate (K2CO3, 1047 g, 7.58 mol, 2.45 equiv), 4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a, 755 g, 2.66 mol), crude 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (14, 822 g based on 100% conversion, 3.09 mol, 1.16 equiv) made as described above, and 1-propanol (6 L) at room temperature. The resulting reaction mixture was degassed three timed backfilling with nitrogen each time before being treated with tetrakis(triphenylphosphine)palladium(0) (9.2 g, 0.008 mol, 0.0026 equiv) at room temperature. The resulting reaction mixture was heated to gentle reflux (about 90° C.) for 1-4 hours. When the reaction was deemed complete by HPLC, the reaction mixture was concentrated under reduced pressure to remove solvents. The residue was then cooled to room temperature, diluted with ethyl acetate (9 L) and water (4 L). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2×2.5 L). The combined organic layers were washed with water (2×2 L) and concentrated under reduced pressure to afford the crude 4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (15), which was directly used in the subsequent acid-promoted de-protection reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([CH:16]=1)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].O.[CH3:25][C:26]1(C)C(C)(C)OB(C=C)O1>COCCOC.CCOCC.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>[C:12]([Si:9]([O:8][CH2:7][C:6]1[CH:16]=[C:2]([CH:25]=[CH2:26])[CH:3]=[CH:4][C:5]=1[Cl:17])([CH3:11])[CH3:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1Cl
Reactant: C=CB1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOCC
Product: C=Cc1ccc(Cl)c(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.5 %

Procedure:
Pd(PPh3)4 (173 mg, 0.149 mmol) was added to a sol. of (5-bromo-2-chloro-benzyloxy)-tert-butyl-dimethyl-silane (1.00 g, 2.98 mmol) in DME (30 mL). The mixture was stirred at rt for 20 min, and K2CO3 (411 mg, 2.98 mmol), water (10 mL) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.53 mL, 2.98 mmol) were added. The mixture was heated rapidly to reflux, and stirred under reflux for 2 h. The mixture was allowed to cool to rt, and was diluted with Et2O (100 mL). The mixture was washed with water, and the aq. layer was extracted back with Et2O (3×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 5:95) yielded the title compound (822 mg, 98%). LC-MS: tR=1.22 min.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(C#N)cc1Oc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1ccc(O)c(Oc2ccccc2)c1
Yield: 88.8 %

Procedure:
The product of step 1 (1.07 g, 4.75 mmol) was taken up in a 1 M methylene chloride solution of boron tribromide (20 mL, 20 mmol). After heating at reflux overnight the reaction was quenched by the dropwise addition of methanol (ca., 5 mL), and briefly refluxed. The mixture was then concentrated and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was dried (sodium sulfate) and concentrated to afford crude product as a brown solid. Flash chromatography over silica (hexanes/ethyl acetate) afforded 0.891 g (89%) of product a as a near colorless, crystalline solid: 1H NMR (CDCl3) δ 7.42 (t, J=7.7 Hz, 2H), 7.32 (dd, J=8.3, 1.8 Hz, 1H), 7.23 (t, J=7.4 Hz, 1H), 7.12-7.01 (m, 4H), 6.29 (s, 1H) ppm.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1)#[N:2].[BrH:27]>[Pd].C(O)C>[BrH:27].[NH2:2][CH2:1][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=3)[CH2:10][C:11]([CH3:15])([CH3:16])[O:12]2)=[CH:7][CH:6]=1
Reactant: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(OCC#N)cc2O1
Agent: [Pd]
Agent: Br
Solvent: CCO
Product: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(OCCN)cc2O1

Procedure:
A solution of 7-cyanomethyloxy-2,2-dimethyl-4-(3-trifluoromethylphenyl) chroman (5.4g) and 10% palladium on charcoal (0.5g) in ethanol (75 ml) was hydrogenated at atmospheric pressure. The catalyst was removed by filtration and the filtrate evaporated under reduced pressure to give an oil which was treated with ethereal hydrogen bromide to give the title compound (4 g) as a very hygroscopic noncrystalline compound.