Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:28]=[CH:27][C:8]2[N:9]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:10]([CH2:12][CH:13]3[CH2:16][CH:15]([CH:17]=O)[CH2:14]3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][C:30]1([CH3:53])[O:34][C@@H:33]2[C@@H:35]([CH2:48][NH:49][CH:50]([CH3:52])[CH3:51])[CH2:36][C@@H:37]([N:38]3[C:42]4[N:43]=[CH:44][N:45]=[C:46]([NH2:47])[C:41]=4[CH:40]=[CH:39]3)[C@@H:32]2[O:31]1.S([O-])([O-])(=O)=O.[Mg+2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([C:5]1[CH:28]=[CH:27][C:8]2[N:9]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])[C:10]([CH2:12][CH:13]3[CH2:16][CH:15]([CH2:17][N:49]([CH2:48][C@@H:35]4[C@H:33]5[O:34][C:30]([CH3:53])([CH3:29])[O:31][C@H:32]5[C@H:37]([N:38]5[C:42]6[N:43]=[CH:44][N:45]=[C:46]([NH2:47])[C:41]=6[CH:40]=[CH:39]5)[CH2:36]4)[CH:50]([CH3:52])[CH3:51])[CH2:14]3)=[N:11][C:7]=2[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1ccc2c(c1)nc(CC1CC(C=O)C1)n2COCC[Si](C)(C)C
Reactant: CC(C)NC[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCCl
Product: CC(C)N(CC1CC(Cc2nc3cc(C(C)(C)C)ccc3n2COCC[Si](C)(C)C)C1)C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Reaction time: 8 h
Yield: 11.5 %

Procedure:
3-[(5-Tert-butyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl)methyl]cyclobutane-1-carbaldehyde (282.3 mg, 0.7 mmol), 7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-[(propan-2-ylamino)methyl]-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (243.41 mg, 0.7 mmol) and magnesium sulfate (127.22 mg, 1.06 mmol) were stirred in 1,2-dichloroethane (10 ml) for 15 mins. Sodium triacetoxyborohydride (179.21 mg, 0.85 mmol) was added, and the reaction stirred overnight. The reaction was quenched by the addition of sat. Na2CO3 (10 ml), and the solution was extracted with DCM (3×10 ml). The combined organics were dried (MgSO4) and concentrated. The crude material was purified by mass directed prep-HPLC (acidic method). After combining the fractions, a small amount of 7M NH3 in MeOH was added to basify the solution. After concentration, the residue was partitioned between water (5 ml) and DCM (5 ml), and the layers separated. The aqueous layer was extracted with DCM (2×3 ml) and the combined organics were dried (MgSO4) and concentrated to afford the title compound (58.7 mg, 11%) as a colourless gum: MS (ESI) for C41H63N7O3Si m/z 730.2 [M+H]+; LC purity 95% (UV), 100% (ELS), (ret. time, 1.65 min); 1H NMR (500 MHz, CHLOROFORM-d) δH 8.30 (s, 1H), 7.75 (s, 1H), 7.32 (s, 2H), 7.04 (d, J=3.6 Hz, 1H), 6.37 (d, J=3.6 Hz, 1H), 5.40-5.50 (m, 2H), 5.24 (br. s., 2H), 4.89-5.04 (m, 2H), 4.45 (d, J=5.2 Hz, 1H), 3.50 (s, 3H), 2.11-3.09 (m, 13H), 2.01 (s, 6H), 1.34-1.49 (m, 6H), 1.29 (s, 3H), 0.85-1.02 (m, 8H), −0.11-0.05 (m, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.Br[C:17]1[CH:22]=[CH:21][N:20]2[C:23]([C:26]([NH:28][C:29]3[CH:37]=[CH:36][CH:35]=[C:34]4[C:30]=3[C:31]([CH3:46])=[N:32][N:33]4[CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]=3)=[O:27])=[CH:24][N:25]=[C:19]2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O.CN(C=O)C.CC#N>CO.C(Cl)Cl.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>[CH3:46][C:31]1[C:30]2[C:34](=[CH:35][CH:36]=[CH:37][C:29]=2[NH:28][C:26]([C:23]2[N:20]3[CH:21]=[CH:22][C:17]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[CH:18][C:19]3=[N:25][CH:24]=2)=[O:27])[N:33]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]=2)[N:32]=1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(Br)ccn45)cccc32)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: CO
Solvent: CC#N
Solvent: O
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(-c6cnn(C)c6)ccn45)cccc32)n1
Temperature: 80 °C
Yield: 42.3 %

Procedure:
A dried flask equipped with a reflux condenser and a nitrogen line was charged with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (14.4 mg, 0.069 mmol), 7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 50, Steps A-B; 30 mg, 0.063 mmol), Pd(PPh3)4 (3.7 mg, 0.003 mmol), and potassium carbonate (44 mg, 0.32 mmol). To the flask was added a water:DMF:CH3CN (1:1:4.5; 0.16:0.16:1.0 mL) mixture, and the reaction mixture was degassed under nitrogen and heated at 80° C. for 5 hours. The reaction mixture was cooled and diluted with water. The resulting suspension was extracted with EtOAc and DCM. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to afford the crude product. The crude product was subjected to preparative thin-layer chromatography on silica with 8% MeOH/DCM as eluent to afford 12.7 mg of product as a yellow solid. MS (ES+APCI) m/z=477 (M+H) detected.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[C:17]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=3[Cl:29])(=[O:21])=[O:20])=[N:16][CH:15]=[C:14]([Cl:30])[N:13]=2)[CH:5]=1.O.[OH-].[Li+].Cl>O.CO>[Cl:30][C:14]1[N:13]=[C:12]([O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:31])=[O:2])[C:17]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[Cl:29])(=[O:20])=[O:21])=[N:16][CH:15]=1
Reactant: COC(=O)c1cccc(COc2nc(Cl)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(COc2nc(Cl)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-[6-chloro-3-(2,3-dichlorobenzenesulphonylamino)-2-pyrazinyloxymethyl]benzoic acid methyl ester (Example 104) (0.3 g) and lithium hydroxide hydrate (0.2 g) in water (5 mL) and methanol (5 mL) was stirred at room temperature. After 3 h, hydrochloric acid (2M) was added to acidify the mixture and the solid product was collected by filtration and dried (0.25 g).
Reaction SMILES: Br[C@H:2]1[CH2:22][N:5]2[C:6](=[O:21])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=3)[CH2:8][C@H:4]2[CH2:3]1.C([O-])([O-])=O.[K+].[K+].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([NH2:39])(=[O:38])=[O:37]>CN(C=O)C>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([NH:39][C@@H:2]1[CH2:22][N:5]2[C:6](=[O:21])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=3)[CH2:8][C@H:4]2[CH2:3]1)(=[O:38])=[O:37]
Reactant: O=C1N(c2ccc(OCC(F)(F)F)cc2)C[C@H]2C[C@@H](Br)CN12
Reactant: NS(=O)(=O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1N(c2ccc(OCC(F)(F)F)cc2)C[C@H]2C[C@H](NS(=O)(=O)c3ccccc3Cl)CN12
Temperature: 80 °C
Yield: 26.7 %

Procedure:
To a solution of (6R,7aR)-6-Bromo-2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-3-one (50 mg, 0.130 mmol) in DMF (3 mL) in a sealed tube, was added K2CO3 (27.3 mg, 0.197 mmol) and 2-Chloro-benzenesulfonamide (50.5 mg, 0.263 mmol) and heated to 80° C. for 12 h. All volatiles were removed under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified through biotage column chromatography (elution with 40% ethyl acetate in hexane) to afford 17 mg (26.5%) of the title compound as a white solid. LC-MS: 489 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26](=[O:39])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH:37][NH2:38])=[O:36])=[CH:30][CH:29]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26](=[O:39])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH:37][NH:38][C:18]([C@@H:13]2[CH2:12][CH2:11][C@@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:20])=[O:36])=[CH:30][CH:29]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)NN)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)cc1
Yield: 74.6 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and tert-butyl(4-(2-hydrazinyl-2-oxoethyl)phenyl)carbamate (682.6 mg, prepared following a procedure analogous to Reference Example 5 and Reference Example 6), 550.8 mg of the title compound was afforded (yield 74.6%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](Cl)=[N:8][C:4]=2[CH:3]=1.[F:12][C:13]([F:27])([F:26])[C:14]1[C:15]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([N:23]3[CH2:24][CH2:25][N:20]([C:15]4[C:14]([C:13]([F:27])([F:12])[F:26])=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:21][CH2:22]3)[NH:8][C:4]=2[CH:3]=1
Reactant: Clc1nc2cc(Br)ccc2[nH]1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Product: FC(F)(F)c1cccnc1N1CCN(c2nc3ccc(Br)cc3[nH]2)CC1

Procedure:
The benzoimidazole from step (b) above (0.115 g, 0.5 mmol) and 1-(3-trifluoromethylpyridin-2-yl)piperazine (0.231 g, 1 mmol, Maybridge) reacted under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 426 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24](=O)[CH3:25])[CH:19]=[CH:20][CH:21]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:24]([CH3:25])[CH2:23][CH2:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(=O)CCc1cccc(F)c1
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(F)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(3-fluoro-phenyl)-butan-2-one.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[O:14][C:13]([CH:15]=O)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1)=[O:22]>>[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][N:33]([CH2:15][C:13]3[O:14][C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:17])[F:18])[CH:5]=4)=[CH:11][CH:12]=3)[CH2:32][CH2:31]2)[CH:25]=1)=[O:22]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(-c2cccc(OC(F)(F)F)c2)o1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4cccc(OC(F)(F)F)c4)o3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 5-[3-(trifluoromethoxy)phenyl]-2-furaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 487.2 (M+H)+.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[H-].[Na+].[CH3:25]I.O>CN(C=O)C>[N:1]1[C:2]([C:10]2[CH:11]=[CH:12][C:13]([N:16]([CH3:25])[C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])=[CH:14][CH:15]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CI
Reactant: O=C(Nc1ccc(-c2cn3ccccc3n2)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)C(F)(F)F)c1ccc(-c2cn3ccccc3n2)cc1
Temperature: 25 °C

Procedure:
0.95 g (3.11 mmol) N-[4-(Imidazo[1,2-a]pyridin-2-yl)-phenyl]-2,2,2-trifluoro-acetamide (educt IV.2.c) is dissolved in 10 mL DMF. 0.14 g (3.73 mmol) NaH (60% in mineral oil) is added. Then 195 μL (3.11 mmol) methyl iodide is added and the mixture is stirred at RT over night. The mixture is poured into water. The precipitate is filtered off and dried in vacuo at 50° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38])[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[O:28]=[C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:29])[N:19]1[CH2:18][C@@H:17]([NH:16][C:7]([C:5]1[O:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)[CH:4]=1)=[O:9])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:39])([F:38])[F:40]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1oc(C(=O)O)cc1-c1ccnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1oc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.5 %

Procedure:
To a solution of 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (130 mg, 0.63 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (243 mg, 0.63 mmol)[prepared in Preparation 6] and diisopropylethylamine (0.55 ml, 3.15 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (324 mg, 0.69 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (190 mg, 0.23 mmol, 37% yield) as a clear oil: LCMS (ES) m/e 537 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1([C:23]([O:25][CH3:26])=[O:24])[NH:9][C:8](=[O:10])[C:7]2[S:11][C:12](Br)=[CH:13][C:6]=2[CH:5]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:75]1[CH2:80][CH2:79][O:78][CH2:77][CH2:76]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:1]([C:4]1([C:23]([O:25][CH3:26])=[O:24])[NH:9][C:8](=[O:10])[C:7]2[S:11][C:12]([N:75]3[CH2:80][CH2:79][O:78][CH2:77][CH2:76]3)=[CH:13][C:6]=2[CH:5]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[CH:2]=[CH2:3]
Reactant: C=CCC1(C(=O)OC)NC(=O)c2sc(Br)cc2C1c1ccc(Cl)c(Cl)c1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C=CCC1(C(=O)OC)NC(=O)c2sc(N3CCOCC3)cc2C1c1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Yield: 25.7 %

Procedure:
A mixture of methyl 5-allyl-2-bromo-4-(3,4-dichlorophenyl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-carboxylate (0.51 g, 1.1 mmol),tris(dibenzylideneacetone)dipalladium(0) (98.3 mg, 0.107 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (124 mg, 0.215 mmol) and cesium carbonate (1.29 g, 3.97 mmol) was evacuated and filled with argon, followed by addition of 1,4-dioxane (12 mL) and morpholine (0.281 mL, 3.22 mmol). The mixture was heated at 100° C. overnight. The mixture was then concentrated in vacuo and the residue was purified by silica gel chromatography. Final purification by HPLC afforded pure product as a white solid (0.136 g, 26%). LCMS (AA) ES+: 482, 484. 1H NMR (400 MHz, DMSO) δ 7.55 (d, J=8.4 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.22 (s, 1H), 7.07 (dd, J=8.4, 2.0 Hz, 1H), 5.98 (s, 1H), 5.70 (dt, J=17.0, 7.2 Hz, 1H), 5.06 (t, J=13.4 Hz, 2H), 4.41 (s, 1H), 3.66 (t, J=4.7 Hz, 4H), 3.41 (s, 3H), 3.19-3.05 (m, 4H), 2.68 (ddd, J=31.0, 13.9, 7.4 Hz, 2H).
Reaction SMILES: C(O[C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13]C(=O)C)=[C:7]([CH3:17])[C:6]=1[CH2:18][CH2:19][C:20](=[O:22])[CH3:21])(=O)C.C[C:24](P(OC)(O)=O)([C:26]([O-:28])=[O:27])C>>[OH:13][C:8]1[C:7]([CH3:17])=[C:6]2[C:5](=[C:10]([CH3:11])[C:9]=1[CH3:12])[O:22][C:20]([CH3:21])([CH2:24][C:26]([OH:28])=[O:27])[CH2:19][CH2:18]2
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: CC(=O)CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC(=O)O)O2

Procedure:
By the procedure described in Example 6, (±)-4-(2,5-diacetoxy-3,4,6-trimethylphenyl)butan-2-one was treated with the anion from trimethylphosphonoacetate. The crude (±)-methyl 5-(2,5-diacetoxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenoate thus obtained, upon saponification with base as in Example 6, yielded (±)-6-hydroxy-2,5,7,8-tetramethylchroman-2-acetic acid as a light tan powder, m.p. 169°-171.5°.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)OCC1.[CH2:13](Br)[CH:14]=[CH2:15]>>[CH2:15]([O:12][CH2:11][CH:8]1[CH2:7][CH2:6][C:5](=[O:1])[CH2:10][CH2:9]1)[CH:14]=[CH2:13]
Reactant: OCC1CCC2(CC1)OCCO2
Reactant: C=CCBr
Product: C=CCOCC1CCC(=O)CC1

Procedure:
The title compound was prepared as white solid from reaction of (1,4-dioxa-spiro[4.5]dec-8-yl)-methanol and allyl bromide (Aldrich) followed by de-protection using the procedure described in Example 34.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([CH3:11])[C:4]=1[CH3:12].ClC1C=C(C=CC=1)C(OO)=[O:18].[OH-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N+:6]([O-:18])=[C:5]([CH3:11])[C:4]=1[CH3:12]
Reactant: COc1cnc(C)c(C)c1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1c[n+]([O-])c(C)c(C)c1OC
Temperature: 20 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
6.3 g of 4,5-dimethoxy-2,3-dimethylpyridine are dissolved in 120 ml of methylene chloride, 20 g of m-chloroperoxybenzoic acid are added successively and the mixture is stirred first at 20° C. for 2 hours and then at 40° C. for 4 hours. After addition of 20 ml of 5N sodium hydroxide solution, the mixture is washed three times with a mixture of 5% strength sodium thiosulphate solution and 5% strength sodium carbonate solution, the aqueous phases are back-extracted twice with methylene chloride and the combined organic phases are dried over magnesium sulphate and concentrated. 4.6 g (66% of theory) of 4,5-dimethoxy-2,3-dimethylpyridine 1-oxide are obtained. The Rf value in methylene chloride/methanol 19:1 is 0.25.
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[CH:4]/[B:5]([OH:7])[OH:6].O[C:9]([C:12](O)([CH3:14])[CH3:13])([CH3:11])[CH3:10].S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[Cl:1][CH2:2]/[CH:3]=[CH:4]/[B:5]1[O:7][C:12]([CH3:14])([CH3:13])[C:9]([CH3:11])([CH3:10])[O:6]1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OB(O)/C=C/CCl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC1(C)OB(/C=C/CCl)OC1(C)C
Yield: 57.8 %

Procedure:
A solution of (E)-3-chloroprop-1-enylboronic acid (5 g, 41 mmol), pinacol (4.9 g, 41 mmol), and magnesium sulfate (15 g, 120 mmol) in methylene chloride (100 mL) was stirred at room temperature for 18 h. The reaction mixture was filtered through silica gel and the filter cake was washed with methylene chloride. The filtrate was concentrated to afford the desired product (4.8 g, 60%) as a colorless oil: ESI MS m/z 203 [C9H16BClO2+H]+.
Reaction SMILES: NC1C(Br)=C[C:5]([O:9]C)=C(Br)N=1.BrC1C(O)=CC=CN=1.[Br:20][C:21]1[C:26](OC)=[CH:25][CH:24]=[C:23]([N+:29]([O-:31])=[O:30])[N:22]=1>C(O)C>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([O:9][CH3:5])=[C:23]([N+:29]([O-:31])=[O:30])[N:22]=1
Reactant: COc1ccc([N+](=O)[O-])nc1Br
Reactant: COc1cc(Br)c(N)nc1Br
Agent: Oc1cccnc1Br
Solvent: CCO
Product: COc1ccc(Br)nc1[N+](=O)[O-]

Procedure:
Starting material -2-amino-6-bromo-5-methoxybromo-pyridine, was prepared in following manner: 2-bromopyridin-3-ol (Aldrich) was converted to 2-bromo-3-methoxy-6-nitropyridine as described in J. Med. Chem. 1981, 24, 39-42. Hydrogenation of 2-bromo-6-nitro-5-methoxypyridine in ethanol (Pt on C, 1 atm) gave the starting material as a reddish oil. This product was then condensed with cis/trans mixture of 2-(2-chloro-3-ethoxy-6-fluorophenyl)cyclopropylisocyanates, described in Example 53, in a manner analogous to the method in Example 7 to provide cis/trans (50:50) mixture of N-2-(2-Chloro-3-ethoxy-6-fluorophenyl)-cyclopropyl-N'-(6-bromo-5-hydroxypyrid-2-yl)-ureas. 1H NMR (250 MHz, CDCl3) δ 7.62-7.43 (m, 1H), 7.29-7.12 (m, 1H), 6.91-6.67 (m, 2H), 4.10-3.94 (m, 2H), 3.90 and 3.84 (2 s, 3H),3.38-3.02 (m, 1H) 2.18-2.00 (m, 1H), 1.55-1.30 H (m, 5H), 1.43 (t, 3H), 0.92-0.80 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH:14]([CH2:15][OH:16])[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>ClCCl>[C:1]([O:5][C:6]([CH:8]1[CH:14]([CH2:15][O:16][C:44](=[O:46])[CH3:45])[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(CO)C2C(=O)OC(C)(C)C)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCCCC(COC(C)=O)C2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C

Procedure:
To a solution of 3-Hydroxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid tert-butyl ester (0.5 g, 1.25 mmoL) in 6.3 mL dichlormethane was added triethylamine (0.19 mL, 1.38 mmoL) and dimethylaminopyridine (15 mg, 0.125 mmoL). This solution was cooled to 0° C. and acetic anhydride (0.18 ml, 1.88 mmoL) was added in at once. After 5 minutes the reaction was diluted with dichloromethane and washed sequentially with 0.5N HCl, water, and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure to yield 3-Acetoxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid tert-butyl ester; MS: (M+H)+ =442, (M+NH4)+ =459.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].O.[C:10]1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[C:1]([O:8][CH3:10])(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: C=CCCCC(=O)O
Solvent: CO
Solvent: O
Product: C=CCCCC(=O)OC
Yield: 84 %

Procedure:
5-Hexenoic acid (4.9 g, 42.9 mmol) was refluxed in 80 ml of methanol with catalytic p toluene sulfonic acid monohydrate for 40 hours. The solution was cooled and concentrated then poured into ether/water. The ether layer was dried over sodium sulfate and concentrated to give 4.6 g (35.9 mmol), 84% of the title compound.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[O:19][C@H:18]2[C@H:14]([N:15]=[C:16]([N:20]([CH3:22])[CH3:21])[S:17]2)[C@@H:13]([OH:23])[C@@H:12]1[OH:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH3:26][C:27]1C=CC(S(O)(=O)=O)=C[CH:28]=1.COC(C)=C>CN(C=O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C@@H:12]2[C@H:13]([O:23][C:27]([CH3:28])([CH3:26])[O:24]2)[C@@H:14]2[C@@H:18]([S:17][C:16]([N:20]([CH3:21])[CH3:22])=[N:15]2)[O:19]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](COC(=O)c3ccccc3)O[C@@H]2S1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=C(C)OC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1=N[C@@H]2[C@H]3OC(C)(C)O[C@@H]3[C@@H](COC(=O)c3ccccc3)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To a solution of 154 (3.0 g, 8.5 mmol) in DMF (20 mL) was added 4-methylbenzenesulfonic acid hydrate (3.2 g, 17 mmol) and 2-methoxyprop-1-ene (6.1 g, 85 mmol) sequentially. The resulting solution was stirred for 15 minutes at room temperature, before the reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (20 mL), which was then extracted with dichloromethane (3×20 mL). The combined organic layer was washed with brine (2×10 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The crude residue was purified by flash column chromatography with 1%-10% ethyl acetate in petroleum ether to afford 155 as an off-white solid (1.6 g, 48%). (ES, m/z): [M+H]+ 393.0; 1H NMR (300 MHz, CDCl3) δ 8.08-8.05 (m, 2H), 7.63-7.45 (m, 3H), 6.32-6.30 (m, 1H), 4.60-4.52 (m, 2H), 4.41-4.31 (m, 2H), 3.97-3.91 (m, 1H), 3.70-3.63 (m, 1H), 3.55-3.50 (m, 1H), 3.39-3.30 (m, 1H), 3.10 (s, 6H), 1.50 (s, 6H).