Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OCCN1C=NC(C2C=CC(C3C=NN4C=CC(N5[C@@H](C(C)C)COC5=O)=NC=34)=CC=2)=N1.[OH:33][CH2:34][CH2:35][N:36]1[C:40]([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:48]=[N:49][N:50]4[CH:55]=[CH:54][C:53]([N:56]5[CH:60]([CH:61]([CH3:63])[CH3:62])[CH2:59][O:58][C:57]5=[O:64])=[N:52][C:51]=34)=[CH:43][CH:42]=2)=[N:39][CH:38]=[N:37]1>C(#N)C.O>[OH:33][CH2:34][CH2:35][N:36]1[C:40]([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:48]=[N:49][N:50]4[CH:55]=[CH:54][C:53]([N:56]5[C@@H:60]([CH:61]([CH3:62])[CH3:63])[CH2:59][O:58][C:57]5=[O:64])=[N:52][C:51]=34)=[CH:43][CH:42]=2)=[N:39][CH:38]=[N:37]1
Reactant: CC(C)C1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncnn4CCO)cc3)c2n1
Agent: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(CCO)n4)cc3)c2n1
Solvent: O
Solvent: CC#N
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncnn4CCO)cc3)c2n1
Yield: 11 %

Procedure:
A crude mixture of (S)-3-(3-(4-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one and S)-3-(3-(4-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidin -5-yl)-4-isopropyloxazolidin-2-one was prepared as described in Example 58. (S)-3-(3-(4-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidin -5-yl)-4-isopropyloxazolidin-2-one (6 mg, 11%) was isolated as the minor product by reverse phase preparative HPLC (5%-95% acetonitrile/water) as described in Example 58. LCMS (APCI+) m/z 434.6 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15]>CC(C)=O>[CH3:15][C:14]([CH3:16])=[CH:13][CH2:12][S:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)=CCSc1ccc(Br)cc1

Procedure:
A mixture of 12.8 g (67.7 mmol) of 4-bromothiophenol (Compound 40) and 2.7 g (67.7 mmol) of sodium hydroxide in 50 ml acetone was heated at reflux under argon for 2.5 hours. The refluxing mixture was then treated dropwise with a solution of 10.0 g (67.1 mmol) of 4-bromo-2-methyl-2-butene (Compound 45) in 10 ml acetone and the mixture heated at reflux for a further 24 hours. The mixture was then cooled and solvent removed in-vacuo. The residue was treated with 50 ml water and extracted with 3×75 ml ether. The ether extracts were combined and washed successively with 3×30 ml of 5% NaOH, 50 ml of water and 50 ml of saturated NaCl and then dried (MgSO4). Solvent was then removed in-vacuo and the residual oil purified by kugelrohr distillation (70 degrees C., 0.1 mm) to give the title compound as a colourless oil. PMR (CDCl3 ): & 1.58 (3H, s), 1.70 (3H, s) 3.5 (2H, d, J-7.0 Hz), 5.27 (1H, t, J-7.0 Hz), 7.17 (2H, d, J-8.3 Hz), 7.36 (2H, d, J-8.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[C:7]2[CH:16]=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:8]=2[N:9]=[C:10](SC)[N:11]=1>C(OCC)(=O)C.CO.C(Cl)Cl.[Ni]>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[C:7]2[CH:16]=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: CCc1cc2c(OCC(=O)OC)nc(SC)nc2n1Cc1cccc(Cl)c1
Agent: [Ni]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1cc2c(OCC(=O)OC)ncnc2n1Cc1cccc(Cl)c1
Yield: 85 %

Procedure:
A solution of 186 mg (0.458 mmol) of [[2-(methylthio)-6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester in 4 mL of ethyl acetate and 1 mL of methanol was heated to reflux and treated with 1.05 g of Raney Ni in portions over 3 hours. The reaction was diluted with 2 mL of methylene chloride and the solids were removed by filtration through a filter aid. The reaction mixture was dried with sodium sulfate and concentrated to provide 140 mg (85%) of [[6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a solid. nmr (500 MHz, CDCl3) δ1.29 (t, J=7.4 Hz, 3H), 2.62 (q, J=7.4 Hz, 2H), 3.80 (s, 3H), 5.09 (s, 2H), 5.42 (s, 2H), 6.41 (s, 1H), 6.88 (d, J=6.9 Hz, 1H),. 7.04 (s, 1H), 7.21 (m, 2H), 8.38 (s, 1H)
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH:16]=[N:17][OH:18])[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:19]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]([S:26]([CH3:25])(=[O:28])=[O:27])=[N:17][OH:18])[N:15]=2)=[O:9])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Nc1nc(C=NO)cs1)N(C1CCCCC1)C1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)C(=NO)c1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of 1,1-dicyclohexyl-3-[4-(hydroxyimino-methyl)-thiazol-2-yl]-urea (0.15 mmol) in DCM (4 mL) was added methansulfonyl chloride (0.15 mmol) and DIEA (0.15 mL). The mixture was stirred at rt for 2 h and quenched with water (10 mL). The reaction mixture was extracted with ethyl acetate (3×10 mL). The combined organic extracts was washed with water (2×30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica, EtOAc/hexanes 1:4 to EtOAc/hexanes 1:1) to give the desired product in 30% yield.
Reaction SMILES: Cl[C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[O:3].[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([CH2:22][NH:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]([CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[C:2]([N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)=[O:3])=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Reactant: CCN(CC)CCNCc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)CCN(Cc1ccc(Cl)cc1)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
tert-Butyl 4-chlorocarbonyl-piperazine-1-carboxylate (245 mg, 0.99 mmol) was added to a solution of N1-(4-chlorobenzyl)-N2,N2-diethylethane-1,2-diamine (235 mg, 0.98 mmol) and N,N-diisopropylethylamine (0.54 mL, 2.94 mmol) in DCM (2 mL). The reaction mixture was allowed to stir at room temperature for 1 hour. The mixture was quenched with saturated NH4Cl (2 mL) and extracted with DCM (2×5 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography to give tert-butyl 4-(N-(4-chlorobenzyl)-N-(2-(diethylamino)ethyl)carbamoyl)piperazine-1-carboxylate (200 mg, 45%). 1H NMR (CDCl3, 400 MHz) δ□7.32 (d, J=8.4 Hz, 2 H), 7.19 (d, J=8.4 Hz, 2 H), 4.42 (s, 2 H), 3.45-3.40 (m, 4 H), 3.25-3.20 (m, 4 H), 3.18 (t, J=6.8 Hz, 2 Hz), 2.56 (t, J=6.8 Hz, 2 H), 2.49 (q, J=7.2 Hz, 4 H), 1.46 (s, 9 H), 0.99 (t, J=7.2 Hz, 6 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:7])[NH:5][N:6]=1.C([O:10][C:11](=O)[CH2:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C>CC(O)=O>[CH3:1][C:2]1[CH:3]=[C:4]2[NH:7][C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:11](=[O:10])[N:5]2[N:6]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: Cc1cc(N)[nH]n1
Solvent: CC(=O)O
Product: Cc1cc2[nH]c(-c3ccccc3)cc(=O)n2n1
Temperature: 25 °C

Procedure:
(prepared in a procedure analogous to that outlined in WO 2004/026229 A2) Step A: 5-Methyl-2H-pyrazol-3-ylamine (1 g, 0.0103 mol) was suspended in AcOH (7 ml), 3-oxo-3-phenylpropionic acid ethyl ester (1.95 ml, 1.1 eq) was added and the mixture heated at reflux for 3 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was stirred with EtOAc and the solid collected by filtration to give 1.83 g of 2-methyl-5-phenyl-4H-pyrazolo[1,5-a]pyrimidin-7-one. Step B: The product of step A (1.83 g) was dissolved in POCl3 (8.6 ml), pyridine (0.43 ml) was added and the mixture stirred for 3 days at rt. The resulting dark solution was diluted with Et2O and filtered. The filtrate was cooled to 0° C. and quenched with water; once the quench was complete, additional water was added and the organic layer removed. The aqueous layer was further extracted with Et2O, the combined organic layers were washed with NaHCO3 (sat), dried (Na2SO4), and concentrated under reduced pressure to give 1.92 g of 7-chloro-2-methyl-5-phenylpyrazolo[1,5-a]pyrimidine which was used without further purification. LCMS: MH+=244.1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10]
Reactant: OB(O)c1ccco1
Reactant: Cc1cc(C)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C)c(O)c(-c2ccco2)c1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
2-Bromo-4,6-dimethylphenol (500 mg, 2.49 mmol), furan-2-ylboronic acid (88 mg, 2.99 mmol), sodium carbonate (791 mg, 7.47 mmol) and Pd2(dppf)2Cl2 (406 mg, 0.49 mmol) were dissolved in dimethoxyethane/water 6 mL/3 mL, followed by stirring in microwave at 120° C. for 20 minutes. After the completion of the reaction, the reaction mixture was filtered using Celite. The filtrate was added with water, and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, and purified by column chromatography (ethyl acetate:hexane=1:3) to obtain 2-(furan-2-yl)-4,6-dimethylphenol (231 mg, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(O)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(Cl)c2)c1=O
Reactant: N
Product: CC(C)(O)CCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(Cl)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 459, substituting 2-(3-chloro-4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 473) in place of 2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 160 mg, 45%). mp 59-62° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.05 (s, 6H), 1.73 (t, 2H, J=6 Hz), 4.32 (s, 1H), 4.54 (t, J=6 Hz, 2H), 7.50 (s, 2H), 7.60 (t, J=9 Hz, 1H), 7.66 (m, 1H), 7.73 (d, J=9 Hz, 2H), 7.74 (d, J=9 Hz, 2H), 7.75 (m, 1H), 8.22 (s, 1H); MS (DCI/NH3) m/z 482 (M+H)+. Anal. calcd. for C21H21FClN3O5S: C, 52.33; H, 4.39; N, 8.71. Found: C, 52.30; H, 5.03; N, 8.10.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[C:9](N1C=CN=C1)(N1C=CN=C1)=[O:10].[CH:21]1([NH:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C1C=CN=CC=1)C.C1COCC1>[CH:28]1([N:27]([CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[C:9]([NH:1][C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)=[O:10])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Nc1ncc(C=O)s1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-Amino-5-formylthiazole (215 mg, 1.67 mmol), carbonyldiimidazole (275 mg, 1.70 mmol) and a catalytic amount of DMAP were heated together in 5 mL THF at 40° C. for 2 h. To this solution was added dicyclohexylamine (0.34 mL, 1.70 mmol) and the reaction mixture was stirred for an additional 6 h at room temperature. The reaction mixture was concentrated and the crude product was purified by flash chromatography (silica, CH2Cl2-EtOAc, 4:1) to obtain 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9]Br)[CH:3]=1.[O:11]1CCOCC1.C(=O)([O-])[O-].[Ca+2]>O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(CBr)c1
Reactant: C1COCCO1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: Cc1cc(Br)cc(CO)c1

Procedure:
A mixture of 1-bromo-3-(bromomethyl)-5-methylbenzene (40.0 g, 151 mmol), 1,4-dioxane (150 mL), water (150 mL) and calcium carbonate (37.9 g, 379 mmol) was heated for 16 h at reflux. The mixture was filtered and the filtrate was concentrated in vacuum, then diluted with CH2Cl2 (150 mL). The organic layer was washed with HCl (2N, 50 mL) and a solution of saturated sodium bicarbonate (50 mL), dried over (Na2SO4) and concentrated in vacuum to give 25.0 g of crude product (3-bromo-5-methylphenyl)methanol.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[CH3:6][CH:7]([CH3:15])[CH2:8][CH:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14].C(N(CC)CC)C.C1(C)C=CC=CC=1>CCCCCC>[CH3:6][CH:7]([CH3:15])[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([Si:2]([CH3:4])([CH3:3])[CH3:1])[C:10]1=[O:14]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)CC1CCNC1=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)CC1CCN([Si](C)(C)C)C1=O
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
TMSCl (2.2 mL, 18 mmol) is added dropwise to a solution of 3-(2-methylpropyl)-2-pyrrolidinone (2.25 g, 15.9 mmol), triethylamine (2.7 mL, 19 mmol), and toluene (16 mL) at room temperature. The mixture is heated at 40° C. for 3 hours and diluted with hexane (50 mL). After stirring for 10 minutes at 0° C., the mixture is filtered and the filtrate concentrated. Distillation (1 mm, 62°-68° C.) of the residue gives 2.40 g (71%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].Br[C:26]#[N:27]>C(#N)C>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:26]([NH2:27])=[N:24][C:8]=12)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Reactant: N#CBr
Solvent: CC#N
Product: CCC(CC)Nc1cc(C)nc2c1nc(N)n2-c1c(C)cc(C)cc1C

Procedure:
The title compound was prepared by reacting N4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine with BrCN in acetonitrile at room temperature overnight. The mixture was quenched with water and adjusted to pH 8.0 with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give crude material. The material was purified through silica gel column chromatography to give the title compound as a brown solid, mp. 158-160° C.; Anal. For C21H29N5 ¼H2O calc. C, 70.85; H, 8.35; N, 19.67; found: C, 71.07; H, 8.30; N, 19.63.
Reaction SMILES: [CH2:1]([O:3][CH:4](O)[CH3:5])[CH3:2].N1C(C)=CC=CC=1C.[F:15][C:16]([F:29])([F:28])[S:17]([O:20]S(C(F)(F)F)(=O)=O)(=[O:19])=[O:18].[Cl-].[NH4+]>C(Cl)Cl>[O:20]([CH2:2][CH2:1][O:3][CH2:4][CH3:5])[S:17]([C:16]([F:29])([F:28])[F:15])(=[O:19])=[O:18]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(C)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCOCCOS(=O)(=O)C(F)(F)F
Reaction time: 1 h
Yield: 67.6 %

Procedure:
In a round bottom flask containing a stirring bar was placed 9.0 g (100 mmol) of ethoxyethanol. The atmosphere in the flask was replaced with nitrogen by using a nitrogen bubbler. The flask was given 160 mL of methylene chloride and 23.3 mL (120 mmol) of 2,6-lutidine. The flask cooled with ice was given dropwise 20.2 mL (120 mmol) of trifluoromethanesulfonic acid anhydride over 20 minutes. After stirring for 1 hour, the reaction liquid was mixed with 20 mL of saturated solution of ammonium chloride. The resulting mixture was washed sequentially with 1N hydrochloric acid (100 mL), deionized water (100 mL), saturated solution of sodium hydrogen carbonate (100 mL), and saturated aqueous solution of sodium chloride (100 mL). The organic layer was separated and dried with anhydrous sodium sulfate. With the sodium sulfate filtered off, the solution was concentrated under reduced pressure. The residue underwent silica gel chromatography. Thus there was obtained 15.03 g (67.6% yields) of 2-ethoxyethyl triflate from the fraction in eluate of 20% ethyl acetate-hexane.
Reaction SMILES: C([C:3]1[N:4]([CH3:23])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])=[CH:10][CH:9]=2)[N:7]=1)#N.FC1C=C(F)C=CC=1OC1C=CC(C2N=CNC=2)=CC=1.[OH-].[K+].CI>>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[O:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[N:7]=[CH:3][N:4]([CH3:23])[CH:5]=2)=[CH:13][CH:12]=1
Reactant: Cn1cc(-c2ccc(Oc3ccc(F)cc3F)cc2)nc1C#N
Agent: Fc1ccc(Oc2ccc(-c3c[nH]cn3)cc2)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Product: Cn1cnc(-c2ccc(Oc3ccc(F)cc3F)cc2)c1

Procedure:
2-Cyano-4-[4-(2,4-difluorophenoxy)phenyl]-1-methyl-1H-imidazole. A mixture of crude 4-[4-(2,4-difluorophenoxy)phenyl]-1H-imidazole (prepared from 4.14 g of 2-bromo-1-[4-(2,4-difluorophenoxy)phenyl]ethanone and 35 mL of formamide as described above), solid KOH (2.57 g) and MeI (1 mL) was heated at reflux overnight. After filtration, the reaction was concentrated to dryness and the residue was purified by flash chromatography, affording 4-[4-(2,4-difluorophenoxy)phenyl]-1-methyl-1H-imidazole as a solid. A solution of 4-(dimethylamino)pyridine (1.34 g, 10.9 mmol) in 30 mL of dry DMF at −10° C. was added cyanogen bromide (5.0 M solution in MeCN; 2.1 mL, 10.5 mmol), giving a pale yellow precipitate. Solid 4-[4-(2,4-difluorophenoxy)phenyl]-1-methyl-1H-imidazole (1.39 g, 4.86 mmol) was added and the reaction was heated at 60° C. overnight. The reaction was allowed to cool to room temperature and added to water and EtOAc. The separated aqueous layer was extracted twice with EtOAc and the pooled organic layers were washed with water (3×), dried (Na2SO4), filtered and concentrated. The oily residue was purified by flash chromatography (gradient from 8.5/2.5 to 7/3 hexane/EtOAc) affording 713 mg of 2-cyano-4-[4-(2,4-difluorophenoxy)phenyl]-1-methyl-1H-imidazole as a solid, mp 109-110° C. (Rf 0.42, 7/3 hexane/EtOAc) along with 122 mg of 4-cyano-4-[4-(2,4-difluorophenoxy)phenyl]-1-methyl-1H-imidazole, mp 169-170° C. (Rf 0.32, 7/3 hexane/EtOAc). 1H NMR (2-cyano; CDCl3): δ7.65 (d, 2H, J=9.0 Hz), 7.16 (s, 1H), 7.06 (dt, 1H, J=9.3, 5.4 Hz), 6.93 (d, 2H, J=8.7 Hz), 6.98-6.80 (m, 2H), 3.65 (s, 3H). 1H NMR (4-cyano; CDCl3): δ7.69 (d, 2H, J=8.7 Hz), 7.27 (s, 1H), 7.09 (dt, J=8.7, 5.7 Hz), 6.96 (d, 2H, J=8.7 Hz), 7.00-6.82 (m, 2H), 3.90 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31](/[C:41](=[CH:45]\[CH:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)/[C:42](O)=[O:43])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31](/[C:41](=[CH:45]\[CH:46]2[CH2:47][CH2:48][CH2:49][CH2:50]2)/[C:42]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:43])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1
Reactant: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
A solution of triphenylphosphine (165 mg, 0.63 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (112 mg, 0.63 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-acrylic acid (123 mg, 0.37 mmol) in methylene chloride (3 mL). The reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (92.5 mg, 0.93 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (20 mL) and a 1N aqueous hydrochloric acid solution (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×15 mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-acrylamide (36 mg, 23%) as an amorphous solid: EI-HRMS m/e calcd for C19H19ClN6OS (M+) 414.1029, found 414.1029.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][S:18][CH2:19][S:20]([CH3:22])=[O:21].[OH-].[Na+]>O>[CH3:22][S:20]([C:19]([S:18][CH3:17])=[CH:12][C:11]1[CH:14]=[CH:15][CH:16]=[C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)=[O:21]
Reactant: CSCS(C)=O
Reactant: O=Cc1cccc(C(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSC(=Cc1cccc(C(=O)c2ccccc2)c1)S(C)=O
Temperature: 95 °C
Reaction time: 1.17 h

Procedure:
m-Benzoylbenzaldehyde (902 mg) was added to 1 ml of FAMSO, and 60 mg of sodium hydroxide was added. The mixture was stirred at 95° C. for 70 minutes in an atmosphere of argon. Water (20 ml) was added, and the reaction mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on a silica gel column using methylene chloride as an eluant to afford 1.035 g of 1-methylsulfinyl-1-methylthio-2-(m-benzoylphenyl)ethylene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]3[S:18][C:19]4[CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH2:23][C:24]=4[C:11]=23)[CH:5]=[CH:6][C:7]=1[F:8].Cl.O1CCOCC1>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]3[S:18][C:19]4[CH2:20][NH:21][CH2:22][CH2:23][C:24]=4[C:11]=23)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc(F)c(Cl)c4)c23)C1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: N#Cc1cnc2sc3c(c2c1Nc1ccc(F)c(Cl)c1)CCNC3
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 105.4 %

Procedure:
tert-Butyl 4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-5,8-dihydrothieno[2,3-b:5,4-c′]dipyridine-7(6H)-carboxylate from Example 54A (250 mg, 0.365 mmol) was dissolved in 2-propanol (2 mL), and 4 M gaseous hydrogen chloride in dioxane (0.18 mL, 0.72 mmol) was added. The mixture was stirred at 80° C. for 1.5 h. The solvent was removed, and the residue was treated with 1 M aqueous sodium hydroxide solution (5 mL). The precipitate was collected by suction filtration, washed with water and dried in vacuo to yield 138 mg (99%) of the title compound.