Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:16]=[CH:17]/[C:18]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][CH:21]=2)=[O:19])[CH:6]=[C:7]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[C:8]=1[O:9][CH3:10].[C:31](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:16]=[CH:17]/[C:18]([C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:28])=[O:29])=[CH:22][CH:21]=2)=[O:19])[CH:6]=[C:7]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[C:8]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(/C=C/C(=O)c2ccc(NS(C)(=O)=O)cc2)cc(-c2cccs2)c1OC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1cc(/C=C/C(=O)c2ccc(N(C)S(C)(=O)=O)cc2)cc(-c2cccs2)c1OC
Yield: 45.9 %

Procedure:
A solution of N-{4-[3E-(3,4-dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-phenyl}-methanesulfonamide (Ex-14, 90 mg, 0.20 mmol) in anhydrous DMF was treated with potassium carbonate (56.1 mg, 0.41). Methyl iodide (126.32 uL, 2.03 mmol) was added to the reaction mixture which was then refluxed for 1.5 hours under inert conditions. The reaction was diluted with water (25 mL) and extracted with diethyl ether (2×50 mL). The organic portion was dried over sodium sulfate, filtered, and concentrated to a yellow oil. The crude material was purified by silica gel chromatography (30–50% ethyl acetate/hexanes) to give 42 mg (45%) of the title compound as a yellow solid. 1H-NMR (CDCl3) δ 8.06 (d, 2H), 7.59 (d, 1H), 7.54 (m, 4H), 7.42 (m, 2H), 7.12 (m, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 3.40 (s, 3H), 2.89 (s, 3H). MS m/z=457 ([M]+, 100%).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)[CH:7]=[CH:6][N:5]=1.[CH2:17]([C:24]1[CH:29]=[C:28]([CH3:30])[N:27]=[C:26](Cl)[N:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O.O>[CH2:17]([C:24]1[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:16][CH:13]2[CH2:14][CH2:15][N:10]([C:8]3[CH:7]=[CH:6][N:5]=[C:4]([CH3:3])[N:9]=3)[CH2:11][CH2:12]2)[N:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1nccc(N2CCC(N)CC2)n1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Cc2ccccc2)nc(NC2CCN(c3ccnc(C)n3)CC2)n1

Procedure:
A solution of 1-(2-methyl-pyrimidin-4-yl)-piperidin-4-ylamine dihydrochloride (53 mg, 0.2 mmol), 4-benzyl-2-chloro-6-methylpyrimidin (48.1 mg, 0.22 mmol) and N,N-diisopropylethyl amine (120 L, 0.7 mmol) in N-methyl-pyrrolidinone (1 mL) was heated at 200° C. in a microwave oven for 1 hour. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with AcOEt/EtOH 9:1 (v/v) as eluent. The title compound was obtained as a light yellow solid (16 mg, 21%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:5].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:5][O:21]1)=[O:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C(=O)OC)c1ccccc1
Solvent: ClCCl
Product: COC(=O)C1(c2ccccc2)CO1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
The title compound was synthesized according to a literature method (Whitman Tetrahedron 1985, 41, 1183). To a mixture of 2-phenylacrylic acid methyl ester (7.92 g, 45 mmol) in 60 ml of methylene chloride was added mCPBA (13.1 g, 58.5 mmol) and the reaction was stirred at 45° C. overnight. The reaction mixture was then filtered and the solid was washed with methylene chloride. The filtrate was washed three times with 50 ml of equal parts solution consisting of saturated Na2S2O3 and saturated NaHCO3. The organic layer was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure to afford the title compound in greater than 95% purity according to 1H NMR (85% yield). 1H NMR (CDCl3, 300 MHz) δ: 7.50-7.30 (m, 5H), 4.22 (q, J=7.2 Hz, 2H), 3.40 (d, J,=7.1 Hz, 1H), 2.95 (d, J=7.1 Hz, 1H), 1.26 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH2:6]([OH:11])[CH:7]=[CH:8][CH2:9][OH:10].N1C=CC=CC=1>C1COCC1>[CH3:5][O:4][C:2](=[O:3])[O:10][CH2:9][CH:8]=[CH:7][CH2:6][O:11][C:2]([O:4][CH3:5])=[O:3]
Reactant: COC(=O)Cl
Reactant: OCC=CCO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)OCC=CCOC(=O)OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Combine methyl chloroformate (7.04 g, 80.0 mmol) in THF (70 mL) and add dropwise to a ice-water cold solution of 2-buten-1,4-diol (majority Z form) (19.7 g, 208 mmol) and pyridine (16.5 g, 208 mmol) in THF (150 mL). Warm the mixture to room temperature and stir for 20 hours. Remove the pyridine salt by filtration and concentrate the filtrate to a residue. Dissolve the residue with CH2Cl2 and wash sequentially with 1 N HCl and brine. Dry the organic layer over Na2SO4 and concentrate the solvent in vacuo to give a residue. Purification by chromatography using hexanes: EtOAc=12:1 as the eluents give the title compound: 1H NMR (CDCl3): δ5.82–5.79 (m, 2H), 4.75 (d, J=4.8 Hz, 4H), 3.79 (s, 6H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH2:14]([C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18](O)=O)[CH3:15].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[CH2:14]([C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]2[N:9]=1)[CH3:15]
Reactant: CCc1cnccc1C(=O)O
Reactant: CNc1ncc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: CCc1cnccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 15.6 %

Procedure:
A mixture of 0.40 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 0.41 g of 3-ethylisonicotinic acid, 0.44 g of WSC and 10 ml of pyridine was stirred for 2.5 hours at 120° C. The reaction mixture was cooled down to room temperature. Into the reaction mixture was poured water, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, then, concentrated under reduced pressure. To the residue was added a mixture of 0.60 g of p-toluenesulfonic acid monohydrate and 10 ml of toluene, and the mixture was stirred for 7 hours at 120° C. The reaction mixture was cooled down to room temperature. Into the reaction mixture was poured water, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.10 g of 2-(3-ethylpyridin-4-yl-)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as present active compound 217).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:8]=[N:7][C:6]=12.[CH3:15][O:16][C:17]([C:19]1[S:20][C:21]([CH3:33])=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:23]=1)=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C=O)C>[CH3:15][O:16][C:17]([C:19]1[S:20][C:21]([CH3:33])=[C:22]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:8]=[N:7][C:6]=23)[CH:23]=1)=[O:18]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)s1
Reactant: FC(F)Oc1cnc2c(Br)cnn2c1
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: CN(C)C=O
Product: COC(=O)c1cc(-c2cnn3cc(OC(F)F)cnc23)c(C)s1
Temperature: 85 °C
Yield: 66.5 %

Procedure:
To a flask containing DMF (40.6 mL) was added 3-bromo-6-(difluoromethoxy)pyrazolo[1,5-a]pyrimidine (1.07 g, 4.06 mmol), methyl-5-methyl-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-carboxylate (1.20 g, 4.27 mmol), palladium tetrakis (235 mg, 0.203 mmol), and 2 M sodium carbonate (aq) (6.10 mL, 12.2 mmol). The reaction mixture was sealed and degassed with N2 for 5 min. The reaction mixture was then heated to 85° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with dichloromethane. The organic layer was washed twice with saturated sodium bicarbonate (aq) twice and once with brine. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-80% EtOAc/Hex) to afford the title compound (0.916 g, 2.70 mmol). LRMS (APCI) calc'd for (C14H11F2N3O3S) [M+H]+, 340.1; found 340.0.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6])#[N:2].S(Cl)([Cl:14])=O>>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:14])=[O:6])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccccc1C(=O)O
Product: N#Cc1ccccc1C(=O)Cl

Procedure:
A mixture of 2-cyanobenzoic acid (2 g, 13.6 mmol) and 15 ml of thionyl chloride was refluxed overnight. Excess thionyl chloride was removed in vacuo and the resultant 2-cyanobenzoyl chloride obtained as such as an off white solid was used in the above acylation.
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:23][C:24]1[S:25][C:26]([CH2:29][OH:30])=[N:27][N:28]=1.Cl>N1C=CC=CC=1>[CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:23][C:24]2[S:25][C:26]([CH2:29][OH:30])=[N:27][N:28]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Nc1nnc(CO)s1
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CO)s2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 65 %

Procedure:
To a solution of p-dodecylbenzenesulfonyl chloride (200 mg, 0.58 mmol) in pyridine (3 mL) was added 2-amino-5-hydroxymethyl-1,3,4-thiadiazole (70 mg, 0.53 mmol). The reaction mixture was stirred at room temperature for 4.5 h, then 2 M HCl (8 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×20 mL). The organic extracts were washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (70-230 mesh) eluted with CH2Cl2:methanol 19:1 to give the product as a solid, mp 138-139° C., in 65% yield (151 mg, 0.34 mmol); 1H NMR (300 MHz, DMSO-d6) δ 0.84 (t, 3H, J=6.6 Hz), 1.22 (m, 18H), 1.54-1.57 (m, 2H), 2.64 (t, 2H, J=7.8 Hz), 4.57 (s, 2H), 6.05 (br, 1H), 7.35 (d, 2H, J=8.1 Hz), 7.67 (d, 2H, J=7.8 Hz); 13C NMR (75 MHz, DMSO-d6) δ 13.9, 22.1, 28.6, 28.7, 28.8, 29.0, 30.6, 31.3, 34.9, 58.4, 125.8, 128.9, 139.2, 147.5, 161.1, 167.5; MS (LCQ, ESI+) Calcd for C21H34N3O3S2 440.2, found 440.2 (M+H)+; HRMS (ESI+, m/z) Calcd for C21H34N3O352 440.2042, found 440.2029 (M+H)+.
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:44])([CH3:43])[C:35](=O)[C:36]([CH3:41])=[CH:37]N(C)C)=[CH:30][CH:29]=1.C(N(CC)CC)C>CN1CCCC1=O>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:35]2[C:36]([CH3:41])=[CH:37][N:26]=[C:24]([NH:23][C:13]3[CH:14]=[CH:15][C:16]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:11]([O:10][CH3:9])[CH:12]=3)[N:25]=2)([CH3:43])[CH3:44])=[CH:30][CH:29]=1
Reactant: CC(=CN(C)C)C(=O)C(C)(C)c1ccc(Cl)cc1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COc1cc(Nc2ncc(C)c(C(C)(C)c3ccc(Cl)cc3)n2)ccc1-n1cnc(C)c1
Reaction time: 2.5 h

Procedure:
The title compound was prepared in analogous manner as described in example 4c) from N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]guanidine dinitrate, 4-(4-chloro-phenyl)-1-dimethylamino-2,4-dimethyl-pent-1-en-3-one and triethylamine using 1-methyl-2-pyrrolidone as the solvent. The reaction was performed in a microwave oven at 200° C. for 2.5 h. The title compound was isolated as a yellow solid in 52% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:58])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:57])[CH:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].CO[C:61](=O)[NH:62]C(C(N1CCCC1C1NC(C2C=CC(Br)=CC=2)=CN=1)=O)C(C)C.COC(=O)N[CH:91](C(N1C(C2NC(C3C=CC4C(=CC=C(B5OC(C)(C)C(C)(C)O5)C=4)C=3)=CN=2)CC2(CC2)C1)=O)[CH:92](C)C.COC(=O)NC(C(N1CCCC1C1NC(C2C=CC3C(=CC=C(B4OC(C)(C)C(C)(C)O4)C=3)C=2)=CN=1)=O)C(C)C>>[CH3:56][O:55][C:53](=[O:54])[NH:52][CH:48]([C:47]([N:43]1[CH2:44][CH:45]([C:61]#[N:62])[CH2:46][CH:42]1[C:39]1[NH:38][C:37]([C:34]2[CH:33]=[CH:32][C:31]([C:26]3[CH:25]=[CH:24][C:23]4[C:28](=[CH:29][CH:30]=[C:21]([C:18]5[NH:17][C:16]([CH:12]6[CH2:13][C:14]7([CH2:92][CH2:91]7)[CH2:15][N:11]6[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:58])[CH:6]([CH3:8])[CH3:7])=[N:20][CH:19]=5)[CH:22]=4)[CH:27]=3)=[CH:36][CH:35]=2)=[CH:41][N:40]=1)=[O:57])[CH:49]([CH3:51])[CH3:50]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)C(C)C
Agent: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CC(C#N)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CC7(CC7)CN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C

Procedure:
Title compound was prepared according to the method employed to prepare [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example AZ), substituting (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester and [2-Methyl-1-(6-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-propyl]-carbamic acid methyl ester for [2-methyl-1-(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester. 1H NMR (DMSO-d6, 400 MHz) δ: 8.20-8.10 (m, 2H), 7.90-7.68 (m, 6H), 7.60-7.55 (m, 2H), 7.33-7.30 (m, 2H), 5.18 (m, 1H), 5.07 (m, 1H), 4.44 (m, 1H), 4.04-3.69 (m, 6H), 3.40-3.38 (m, 1H), 3.30 (s, 6H), 2.71 (m, 1H), 2.40-1.90 (m, 5H), 0.90-0.79 (m, 12H), 0.70-0.54 (m, 4H);
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[O:15][C:14]([CH3:16])=[N:13][C:12]=2[C:17]([O:19]CC)=[O:18])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[OH-].[Li+]>O1CCCC1.O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[O:15][C:14]([CH3:16])=[N:13][C:12]=2[C:17]([OH:19])=[O:18])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)c1nc(C)oc1CCc1cccc(CC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cccc(CCc2oc(C)nc2C(=O)O)c1

Procedure:
A solution of the product from step (vi) (19.0 g) and lithium hydroxide (5.6 g) in tetrahydrofuran (200 ml) and water (100 ml) was heated at reflux for 4 hours and concentrated under reduced pressure. The residue was suspended in water, acidified with 2N HCl and extracted with ethyl acetate. The combined extracts were washed with water and saturated brine. The organic phase was collected, dried (MgSO4) and solvent evaporated to give a brown solid. Purification was by flash chromatography, eluting with 50% ethyl acetate in dichloromethane with 0.5% acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([F:42])[C:30]=1[O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH2:5][CH:6](/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27])[CH2:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.[C:43]([C:47]1[CH:54]=[CH:53][C:50]([CH2:51]Br)=[CH:49][CH:48]=1)([CH3:46])([CH3:45])[CH3:44].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:43]([C:47]1[CH:48]=[CH:49][C:50]([CH2:51][O:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2/[CH:20]=[CH:19]/[CH:6]([CH2:5][C:4]2[CH:28]=[C:29]([F:42])[C:30]([O:31][Si:32]([CH:36]([CH3:38])[CH3:37])([CH:39]([CH3:41])[CH3:40])[CH:33]([CH3:34])[CH3:35])=[C:2]([F:1])[CH:3]=2)[CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=2)=[CH:53][CH:54]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c2)cc1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)Cc2cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c2)cc1

Procedure:
A solution of 1.3 g (2.19 mmol) of methyl E4-[3-(3,5-difluoro-4-triisopropylsilanyloxybenzyl)-5-(2-hydroxyphenyl)pent-4-enyl]benzoate in 20 ml of dry acetonitrile is mixed with 600 mg (2.62 mmol) of 4-tert-butylbenzyl bromide and 450 mg (3.28 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated. The resulting crude product is purified by preparative HPLC. 780 mg (48% of theory) of a colorless oil are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=O)[C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.[CH3:23][N:24]([CH3:27])[CH:25]=O.C1CN(C(O[N:40]2N=[N:47][C:46]3[C:41]2=C[CH:43]=[CH:44][CH:45]=3)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl.O>[CH3:23][N:24]1[C:27]2[CH:43]=[CH:44][CH:45]=[C:46]([NH:47][C:11]([C:8]3[C:6]4[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=4[S:10][CH:9]=3)=[O:13])[C:41]=2[N:40]=[CH:25]1
Reactant: c1ccc2c(c1)nnn2OC(N1CCCC1)=[N+]1CCCC1
Reactant: O=C(O)c1csc2cnc(Cl)nc12
Reactant: CN(C)C=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cn1cnc2c(NC(=O)c3csc4cnc(Cl)nc34)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.050 g (0.233 mmole) 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid, 0.0686 g (0.466 mmole) of 1-methyl-1H-benzol[d]imidazol-4-amine, 0.122 mL (0.699 mmole) of N,N-diisopropylethylamine and 1.55 mL of dimethylformamide was added 0.111 g (0.256 mmole) of O-(benzotriazol-1-yl)-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate. The mixture was stirred at room temperature for overnight. Water and dichloromethane were added. The aqueous layer was washed three times with dichloromethane. The combined organic layer was washed with aqueous sodium carbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (gradient 50:50-0:100) gave 0.042 g of 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid (1-methyl-1H-benzoimidazol-4-yl)-amide as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][NH2:25].[O:26]([CH2:33][CH:34]=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][N:25]=[CH:34][CH2:33][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1
Reactant: O=CCOc1ccccc1
Product: CC1=C(CCON=CCOc2ccccc2)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylsulfinylphenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with phenoxyacetaldehyde by the method of Example 1.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@@H:13]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:31]([O:32][CH3:33])=[CH:30][C:29]([CH2:34][O:35][CH2:36][CH3:37])=[CH:28][C:27]=2[O:38][CH3:39])=[CH:22][CH:21]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])O.[Na+].O.[F:46][C:47]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:48]=1[C:49](Cl)=[O:50]>C(OCC)(=O)C>[F:46][C:47]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:48]=1[C:49]([NH:12][C@@H:13]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([O:38][CH3:39])=[CH:28][C:29]([CH2:34][O:35][CH2:36][CH3:37])=[CH:30][C:31]=2[O:32][CH3:33])=[CH:22][CH:21]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:50]
Reactant: CCOCc1cc(OC)c(-c2ccc(C[C@H](N)C(=O)OCC)cc2)c(OC)c1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOCc1cc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(F)cccc3F)C(=O)OCC)cc2)c(OC)c1
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a mixture of ethyl (αS)-α-amino-4′-ethoxymethyl-2′,6′-dimethoxy(1,1′-biphenyl)-4-propionate p-toluenesulfonate (29.0 g), sodium hydrogen carbonate (15.2 g), water (290 ml) and ethyl acetate (290 ml) was added dropwise 2,6-difluorobenzoyl chloride (9.6 g) at 15° C. or below and the mixture was stirred for 30 minutes at the same temperature. The ethyl acetate layer was washed with saturated aqueous NaCl solution and dried over magnesium sulfate. The solvent was removed in vacuo. The residue was recrystallized from isopropanol-water to yield ethyl (αS)-α-[(2,6-difluorobenzoyl)amino]-4′-ethoxymethyl-2′,6′-dimethoxy(1,1′-biphenyl)-4-propionate (26.4 g).
Reaction SMILES: [OH-].[K+].O.[C:4]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH2:13])=[CH:10][CH:9]=1)(=O)[CH3:5].[CH2:16](Br)C=C>O1CCOCC1.C1(C)C=CC=CC=1>[CH2:4]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH2:13])=[CH:10][CH:9]=1)[CH:5]=[CH2:16]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: C=CCOc1ccc(C=C)cc1
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
To a 4-necked, nitrogen swept, 2 liter glass reaction vessel equipped with a mechanical stirrer, double-walled condenser, thermocouple and pressure compensating addition funnel is added 1,4-dioxane (600 mls), potassium hydroxide (112.0 g, 2.00 moles) and water (39 g). The mixture is stirred and cooled to 10° C. at which time 4-acetoxystyrene (162.0 g, 1.00 moles) is added over approximately 5 minutes. The mixture is stirred for a further 1.5 hour and cooled to 5° C. A solution of allylbromide (133.1 g, 1.10 moles) in 1,4-dioxane (50 mls) is added dropwise over 15 minutes and the reaction mixture is stirred for a further 1.5 hours, while the temperature is maintained between 5° and 10° C. The stirred mixture is gradually heated to 60° C. Heating and stirring are continued at this temperature for a further 2.5 hours. On cooling the mixture is filtered and most of the solvent is removed under reduced pressure. The residue obtained is dissolved in toluene (300 mls) and the solution washed with 4×300 ml portions of water, dried over sodium sulfate and the solvent distilled under reduced pressure to yield crude 4-allyloxystyrene in high yield.