Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH:3]([N:7]1[CH:11]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][N:18](COCC[Si](C)(C)C)[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:9]=[N:8]1)[CH2:4][C:5]#[N:6].C1COCC1.C([O-])(O)=O.[Na+].C(O)C.[OH-].[NH4+]>Cl.O.C(OCC)(=O)C>[F:30][C:2]([F:1])([F:29])[CH:3]([N:7]1[CH:11]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][NH:18][C:14]=3[N:15]=[CH:16][N:17]=2)[CH:9]=[N:8]1)[CH2:4][C:5]#[N:6]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C(F)(F)F)c3)ncnc21
Agent: Cl
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#CCC(n1cc(-c2ncnc3[nH]ccc23)cn1)C(F)(F)F
Yield: 138 %

Procedure:
A solution of 4,4,4-trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (3.1 g, 0.0071 mol) from Step 1 in THF (35 mL, 0.43 mol) and 3.0 M HCl in water (35 mL) was heated to reflux overnight. The solvent was removed by rotary evaporation to give a greenish orange oil/glass. The oil was stirred with ethyl acetate and sat. NaHCO3 (50 mL). The aqueous phase was extracted with ethyl acetate. The organic layers were washed with brine and reduced by rotary evaporation to give an oil/glass residue. The residue was stirred in ethanol (20 mL, 0.3 mol) and 8.0 M ammonium hydroxide in water (10 mL) over a weekend. The solvent was removed by rotary evaporation to give a pale orange foam/solid. The crude was chromatographed with 0-7% MeOH/DCM, 0-0.7% NH4OH to give 3 g of a pale orange paste/solid. The solid was recrystallized from EtOH to give 1.6 g of an off-white crystals (74% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].Br[C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[C:40]#[N:41].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+].C(N(CC)CC)C>CC(=O)CC.O.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]>[C:40]([C:39]1[CH:38]=[C:37]([N:33]2[CH2:32][CH2:31][CH:30]([NH:29][C:27]([C:4]3[N:5]([CH3:26])[C:6]4[C:15]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[N:9]([CH2:16][C:17](=[O:24])[C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[C:8](=[O:25])[C:7]=4[C:3]=3[O:2][CH3:1])=[O:28])[CH2:35][CH2:34]2)[CH:44]=[CH:43][CH:42]=1)#[N:41]
Reactant: N#Cc1cccc(Br)c1
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1c(C(=O)NC2CCN(c3cccc(C#N)c3)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Yield: 7.4 %

Procedure:
A solution of the compound of Example 77 (300 mg, 0.59 mmol), 3-bromobenzonitrile (143 mg, 1.2 mmol), tris(dibenzylideneacetone)dipalladium (0) (54 mg, 0.059 mmol), x-phos (56 mg, 0.12 mmol), sodium tert-butoxide (142 mg, 1.5 mmol) and triethylamine (0.082 mL, 0.59 mmol) in 2-butanone (4.0 mL) was stirred under microwave irradiation at 130° C. for 40 min. The reaction mixture was diluted with water, and extracted twice with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/hexane=40/60-100/0) and recrystallized from ethyl acetate-hexane to give the title compound (25 mg, 7.4%) as a white solid.
Reaction SMILES: C[Si](O[Si](C)(C)C)(C)C.[CH2:10]([OH:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19].C([Li])CCC.[CH:26](/B(C1CCCCC1)C1CCCCC1)=[CH:27]\[CH2:28][CH2:29][CH2:30][CH3:31].C([Sn](Cl)(CCCC)CCCC)CCC.S(=O)(=O)(O)O.[OH-].[Na+].OO>C1COCC1.C(O)(=O)C>[CH2:10]([OH:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCC/C=C/B(C1CCCCC1)C1CCCCC1
Reactant: C#CCCCCCCCCO
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CC(=O)O
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: C1CCOC1
Product: CCCC/C=C/C=C\CCCCCCCCO
Reaction time: 0.5 h
Yield: 8 %

Procedure:
A solution of 88.7 g (392.5 mmol) of the trimethylsilyl ether of 9-decyn-1-ol (from Example 1) in 100 ml of THF is cooled to -70°. To this is added, dropwise, 245.3 ml (392.5 mmol) of n-butyllithium (1.6 in hexane), after which the mixture is warmed to -40° and poured into the hexenyldicyclohexylborane solution from above. This mixture is stirred at 0° for 30 min. and then cooled to -35°. Tri-n-butyltin chloride (128 g, 124 ml) is added, and the mixture is allowed to warm to ~20° and stirred for 1.5 hours. Acetic acid (186 ml) is then added dropwise and the mixture is stirred overnight at 50°. 2 N sulfuric acid (80 ml) is then added. After 30 min., the mixture is cooled and 392.5 ml of 6 N sodium hydroxide is added, followed by the addition, in portions, of 94.2 ml of 30% hydrogen peroxide at ~30°. The reaction mixture is worked up by dilution with water and extraction with hexane. The hexane layer is washed with concentrated aqueous sodium bisulfite and with brine, dried, and stripped of solvent and cyclohexanol under vacuum (0.05 mm). The crude product is chromatographed on a column of silica gel, eluting with hexane, then 10% ether/hexane and finally 20% ether/hexane. Recrystallization from 400 ml of hexane (3X) at -60° gives (9Z, 11E)-9,11-hexadecadien-1-ol containing about 8% of the E, E isomer. This product is further purified by dissolving it in 150 ml THF, adding a solution of 3 g of tetracyanoethylene in 80 ml of THF and stirring the mixture overnight at room temperature. The THF is stripped under vacuum and the product is purified by chromatography on a column of silica gel, eluting with hexane, then 10% ether/hexane and finally 20% ether/hexane. Low temperature recrystallization (-60°) from hexane (3X 500 ml) yields the product (9Z, 11E)-9,11-hexadecadien-1-ol.
Reaction SMILES: ClC(Cl)(Cl)C([C:5]1[N:9]2[C:10]([CH2:14][N:15]([C:27](OC(C)(C)C)=[O:28])[CH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)=O.I[Si](C)(C)C.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(Cl)(Cl)Cl>[F:25][C:23]([F:24])([F:26])[S:20]([NH:19][CH2:18][CH2:17][CH2:16][N:15]1[CH2:14][C:10]2[N:9]3[C:5](=[CH:6][N:7]=[C:8]3[CH:13]=[CH:12][CH:11]=2)[C:27]1=[O:28])(=[O:21])=[O:22]
Reactant: CC(C)(C)OC(=O)N(CCCNS(=O)(=O)C(F)(F)F)Cc1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C1c2cnc3cccc(n23)CN1CCCNS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.8 %

Procedure:
To a solution of 1.16 g (2.00 mmol) of 3-trichloroacetyl-5-[N-tert-butoxycarbonyl-N-[3-(trifluoromethanesulfonamido)propan-1-yl]aminomethyl]imidazo[1,2-a]pyridine in 25 ml of chloroform was added dropwise 0.57 ml (4.00 mmol) of iodotrimethylsilane at room temperature. The reaction mixture was stirred for 15 minutes, which was then poured into ice-water, followed by neutralization with a saturated aqueous solution of sodium hydrogencarbonate. This solution was extractedith 150 ml of ethyl acetate. The organic layer was washed with 100 ml of a 1.0N aqueous solution of sodium thiosulfate, then with 100 ml of a saturated aqueous saline solution. The organic layer was dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=20:1) to give 397 mg of the desired compound (54.8%, pale yellow solid).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([C:14]1[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=1)[N:20]1[C:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=4)=[N:25][N:26]=[C:19]1[C:18](=[O:35])[NH:17]3)=[O:13])[CH2:7]2.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([C:14]1[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=1)[N:20]1[C:24]([C:27]4[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=4)=[N:25][N:26]=[C:19]1[C:18](=[O:35])[NH:17]3)=[O:13])[CH2:7]2
Reactant: COc1ccc(-c2nnc3c(=O)[nH]c4cc(C(=O)N5CCc6c(Cl)cccc6C5)ccc4n23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)[nH]c(=O)c1nnc(-c3ccc(O)cc3)n12)N1CCc2c(Cl)cccc2C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 4.6 %

Procedure:
To a mixture of 403 mg of 7-[(5-chloro-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]-1-(4-methoxyphenyl)[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one and 10 mL of dichloromethane was added 2.9 mL of a 1 M boron tribromide solution in dichloromethane, followed by stirring at the same temperature for 16 hours. The reaction liquid was poured into ice-water, followed by stirring for 5 minutes and extracting with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 97/3) and then further purified by preparative HPLC (acetonitrile/0.01% aqueous formic acid solution). The obtained solid was heated and washed with a mixed solvent of 3 mL of methanol and 1 mL of water to obtain 18 mg of 7-[(5-chloro-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]-1-(4-hydroxyphenyl)[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one as a white solid.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10]C1C2N=C(CCCC)N(CCN)C=2C2N=CC=CC=2N=1>>[CH:1]1([C:7]([NH2:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Reactant: O=C(Cl)C1CCCCC1
Product: NC(=O)C1CCCCC1

Procedure:
Using the general method of Example 92, cyclohexanecarbonyl chloride (94 μL, 0.7 mmol) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.2 g, 0.7 mmol) to provide 0.2 g of N12-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-1-cyclohexanecarboxamide as a white powder, m.p. 188-190° C. Analysis: Calculated for C22H30N6O: %C, 66.98; %H, 7.66; %N, 21.30. Found: %C, 66.72; %H, 7.57; %N, 21.48. HRMS (EI) calcd for C22H30N6O (M+) 394.2481 found 394.2475.
Reaction SMILES: C([O:4][C@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:24]=[C:23]([Sn:25]([CH3:28])([CH3:27])[CH3:26])[C:22](=[O:29])[NH:21][C:20]1=[O:30])(=O)C.C[O-].[Na+].CO>CO>[C@@H:6]1([N:19]2[CH:24]=[C:23]([Sn:25]([CH3:26])([CH3:28])[CH3:27])[C:22](=[O:29])[NH:21][C:20]2=[O:30])[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc([Sn](C)(C)C)c(=O)[nH]c2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[Sn](C)(C)c1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]c1=O
Temperature: 0 °C

Procedure:
250 mg (0.45 mmol) of the above product 6 as the starting material is dissolved in 15 mL of MeOH and cooled to 0° C. Then 5 mL of 0.01N NaOMe/MeOH is added with continuously stirring. After the starting material completely disappears, a cationic exchange resin (Dowex 500 WX8-400, H+form) is used to neutralize. After filtration, the solution is concentrated at reduced pressure at 30° C. to obtain a product (1-(β-D-arabinofuranosyl)-5-trimethylstannylpyrimidin-2,4(3H)-dione) 7. Its weight and yield are 140 mg and 80% respectively.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.Cl.[Cl:8][C:9]1[C:10]([F:35])=[C:11]([CH:32]=[CH:33][CH:34]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:30][CH3:31])=[C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:26]1[CH2:27][CH2:28][CH2:29][CH:24]([O:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][C:19]=2[O:30][CH3:31])[N:16]=[CH:15][N:14]=[C:13]3[NH:12][C:11]2[CH:32]=[CH:33][CH:34]=[C:9]([Cl:8])[C:10]=2[F:35])[CH2:25]1)=[O:4]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCNC1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(=O)CCl)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Chloroacetyl chloride (89 μl) was added to a solution of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline dihydrochloride (469 mg; prepared as described in Example 45) and diisopropylethylamine (700 μl) in methylene chloride (15 ml) that was cooled to 0° C. The mixture was stirred at room temperature for 2 hours to give 6-[1-(chloroacetyl)piperidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline; Mass Spectrum: (M+H)+ 479.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([O:9][CH2:10][CH2:11][OH:12])=[CH:7][C:6]([O:13][CH3:14])=[CH:5][C:4]=1[C@@H:15]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[NH:34])=[CH:31][CH:30]=1)[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:17]=1.C(=O)([O-])[O-].[K+].[K+].C1([O:50][C:51](=O)[O:52][CH2:53][C:54]([CH3:56])=[CH2:55])C=CC=CC=1.C(O)(=O)C>C(OCC)(=O)C.O.CS(C)=O>[CH3:56][C:54](=[CH2:55])[CH2:53][O:52][C:51](=[O:50])[N:34]=[C:33]([C:32]1[CH:31]=[CH:30][C:29]([NH:28][C@H:15]([C:4]2[CH:5]=[C:6]([O:13][CH3:14])[CH:7]=[C:8]([O:9][CH2:10][CH2:11][OH:12])[C:3]=2[F:2])[C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[N:23]=[CH:24][CH:25]=[CH:26][N:27]=3)[N:17]=2)=[CH:37][CH:36]=1)[NH2:35]
Reactant: COc1cc(OCCO)c(F)c([C@@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reactant: C=C(C)COC(=O)Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)COC(=O)N=C(N)c1ccc(N[C@@H](c2nn(-c3ncccn3)c(=O)[nH]2)c2cc(OC)cc(OCCO)c2F)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a mixture of 4-{[(R)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl](5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]amino}benzamidine hydrochloride (5.0 g, 9.41 mmol), potassium carbonate (2.6 g, 18.8 mmol), and dimethyl sulfoxide (15 mL), carbonic acid 2-methylallyl ester phenyl ester [CAS No. 138621-73-5] (1.57 g, 8.19 mmol) was added, and the resulting mixture was stirred at room temperature for 4 days. Ethyl acetate (100 mL) and water (200 mL) were added to the reaction solution, and the aqueous layer was collected. Acetic acid (1.62 mL, 28.2 mmol) was added dropwise to the aqueous layer with stirring, and the precipitated solid was filtered and sequentially washed with water (20 mL) and diethyl ether (20 mL). The solid obtained was suspended in ethyl acetate, filtered, and then dried under air flow. The dried solid was suspended in ethyl acetate (50 mL), and the suspension was stirred for 1 day. The suspension was filtered, and the solid obtained was washed with ethyl acetate and dried under air flow to obtain the captioned compound (4.87 g) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([OH:23])=O)[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][SH:36])=[CH:31][CH:30]=1>>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21](=[O:23])[S:36][CH2:35][C:32]4[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=4)[N:20]=3)[CH2:14][CH2:15]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1
Reactant: Fc1ccc(CS)cc1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)SCc3ccc(F)cc3)cs2)CC1

Procedure:
A solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 200 mg) is reacted analogously to Example I-227 with (4-fluorophenyl)methanethiol (78.0 mg). This gives, after chromatographic purification, S-(4-fluorobenzyl) 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbothioate (110 mg, 42%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8](Cl)=[N:9][N:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:9][N:10]=1)=[O:5])[CH3:2]
Reactant: Sc1ccccc1
Reactant: CCOC(=O)c1nnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1nnc(Sc2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of 5-chloro-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester (1.0 g, 5.2 mmol, 1 eq), and K2CO3 (1.44 g, 104 mmol, 2 eq) in CH3CN (50 mL), thiophenol (0.53 mL, 5.2 mmol, 1 eq) is added. The reaction is stirred overnight at room temperature. The reaction is filtered to remove the salts, and the filtrate is washed with CH3CN. The solvents are removed under reduced pressure, and the product is recrystallized from EtOH to give 5-phenylsulfanyl-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester (1.03 g, 74%). MS (ESI) for C11H10N2O2S2 m/z 267.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C(B(CC)[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)C>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>[CH3:10][CH:9]([CH3:11])[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH:3]=1)([C:13]1[N:14]=[CH:15][N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)[OH:12]
Reactant: CCB(CC)c1cccnc1
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)C(O)(c1cccc(-c2cccnc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 65.3 %

Procedure:
By the reaction in the same manner as in Example 4-(ii) using 1-(3-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.01 g), diethyl(3-pyridyl)borane (0.497 g) and tetrakis(triphenylphosphine)palladium(0) (0.170 g), the title compound (0.657 g) was obtained as a pale-yellow amorphous powder.
Reaction SMILES: [N:1]([C:4]1[C:9]([C:10]#[N:11])=[C:8]([O:12][CH:13]([CH3:15])[CH3:14])[N:7]=[C:6]([C:16]([NH:18][CH2:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=2[O:28][CH3:29])=[O:17])[CH:5]=1)=[N+]=[N-]>CO.[Pd]>[NH2:1][C:4]1[C:9]([C:10]#[N:11])=[C:8]([O:12][CH:13]([CH3:15])[CH3:14])[N:7]=[C:6]([C:16]([NH:18][CH2:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=2[O:28][CH3:29])=[O:17])[CH:5]=1
Reactant: COc1ccc(OC)c(CNC(=O)c2cc(N=[N+]=[N-])c(C#N)c(OC(C)C)n2)c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(OC)c(CNC(=O)c2cc(N)c(C#N)c(OC(C)C)n2)c1
Yield: 100.4 %

Procedure:
The azide from Example 102C (10 mg, 0.025 mmol) was hydrogenated in MeOH under a hydrogen balloon with cat. 10% Pd/C for 1 hour. The reaction mixture was filtered through a celite plug and washed with MeOH. The combined filtrate was evaporated and pumped in vacuo to provide the titled compound as a white solid (9.3 mg, 100% yield). 1H NMR (300 HZ, DMSO-d6) δ 8.81 (t, J=6.3 Hz, 1H), 7.30 (broad s, 2H), 7.04 (s, 1H), 6.93 (d, J=8.8 Hz, 1H), 6.79 (dd, J=8.8, 3.1 Hz, 1H), 6.71 (d, J=3.1 Hz, 1H), 5.53 (quintet, J=6.4 Hz, 1H), 4.41 (d, J=6.4 Hz, 2H), 3.79 (s, 3H), 3.65 (s, 3H), 1.31 (d, J=6.4 Hz, 6H). MS (m/e) 371 (M+H)+, 393 (M+Na)+.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[N:22]1([CH2:28][CH2:29][O:30][C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)CN)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CO>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([CH2:14][C:33]4[CH:36]=[CH:37][CH:38]=[C:31]([O:30][CH2:29][CH2:28][N:22]5[CH2:23][CH2:24][O:25][CH2:26][CH2:27]5)[CH:32]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Reactant: NCc1cccc(OCCN2CCOCC2)c1
Solvent: CO
Product: O=c1c2sc(-c3ccc(Cl)cc3)cc2ncn1Cc1cccc(OCCN2CCOCC2)c1
Temperature: 25 °C

Procedure:
5-(4-Chlorophenyl)-3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester (0.164 g, 0.508 mmol), 3-(2-morpholin-4-yl-ethoxy)-benzylamine (0.100 g, 0.423 mmol) and MeOH (1.5 mL) were heated by MW at 120° C. for 15 minutes. The reaction mixture was allowed to cool to r.t., the precipitate filtered, washed with MeOH, and dried in vacuo to give the product. Yield: 0.110 g (45%). 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.63 (d, 2H, J=8.42 Hz), 7.45 (s, 1H), 7.41 (d, 2H, J=8.42 Hz), 7.25 (m, 1H), 6.81-6.94 (m, 3H), 5.17 (s, 2H), 4.06 (t, 2H, J=6.12 Hz), 3.70 (t, 4H, J=4.68 Hz), 2.75 (t, 2H, J=5.58 Hz), 2.53 (t, 4H, J=4.51 Hz). MS (ESI+) 481.92 (M+1H+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:19]=[C:18]([C:28]#[N:29])[N:17]=2)=[CH:12][C:11]=1[C:30]([F:33])([F:32])[F:31].C(N(C(C)C)CC)(C)C.Br[CH2:44][C:45]([NH2:47])=[O:46]>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:28]([C:18]1[N:19]=[C:20]([N:22]2[CH2:23][CH2:24][N:25]([CH2:44][C:45]([NH2:47])=[O:46])[CH2:26][CH2:27]2)[CH:21]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[C:11]([C:30]([F:31])([F:33])[F:32])[CH:12]=2)[N:17]=1)#[N:29]
Reactant: COc1ccc(-c2cc(N3CCNCC3)nc(C#N)n2)cc1C(F)(F)F
Reactant: NC(=O)CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cc(N3CCN(CC(N)=O)CC3)nc(C#N)n2)cc1C(F)(F)F
Temperature: 65 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
4-(4-Methoxy-3-trifluoromethyl-phenyl)-6-piperazin-1-yl-pyrimidine-2-carbonitrile trifluoroacetic acid salt (50 mg), diisopropylethylamine (40 mg) and 2-bromoacetamide (22 mg) were dissolved in acetonitrile (2 ml) and the mixture was stirred at 65° C. overnight. Mixture was partitioned between ethyl acetate (10 ml) and water (10 ml), organics were dried and evaporated under reduced pressure to afford a white solid. Purification by prep-HPLC afforded 18 mg of 2-{4-[2-Cyano-6-(4-methoxy-3-trifluoromethyl-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-acetamide trifluoroacetic acid salt as a white solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:22])[CH:6]([O:17][CH2:18][C:19](=[O:21])[NH2:20])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1>CO>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH:6]([O:17][CH2:18][C:19](=[O:21])[NH2:20])[C:5]([OH:22])=[O:4])=[CH:8][CH:9]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)C(OCC(N)=O)c1ccc(C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1ccc(C(OCC(N)=O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1N aqueous sodium hydroxide solution (16 ml) was added to a solution of 4-tert-butyl carbamoylmethoxyphenylacetic acid methyl ester (2.8 g, 0.010 mol) in methanol (10 ml) and the reaction stirred at room temperature for 5 hours. The reaction mixture was then concentrated under reduced pressure, the residue suspended in 1N aqueous hydrochloric acid (20 ml) and extracted with diethyl ether (2×25 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=1.Cl[C:19]1[CH:20]=[C:21]2[N:28](C(OC(C)(C)C)=O)[C:27]([CH3:37])([CH3:36])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=1)[CH2:16][O:17][C:19]1[CH:20]=[C:21]2[NH:28][C:27]([CH3:37])([CH3:36])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1
Reactant: OCc1ccc(Oc2ccnc(F)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CC1(C)Cn2c(cc(OCc3ccc(Oc4ccnc(F)c4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((2-fluoropyridin-4-yl)oxy)phenyl)methanol and tert-butyl 7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.