Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].N[C@@H]1CCCC[C@H]1N.Br[C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH:39]=[CH:38][N:37]=[CH:36]2)=[CH:31][CH:30]=1>O1CCOCC1.[Cu]I>[N:35]1([C:32]2[CH:33]=[CH:34][C:29]([N:5]3[C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=4[C:3]([C:2]([F:1])([F:12])[F:13])=[N:4]3)=[CH:30][CH:31]=2)[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: Brc1ccc(-n2ccnc2)cc1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: FC(F)(F)c1nn(-c2ccc(-n3ccnc3)cc2)c2c1CCCC2
Temperature: 180 °C
Yield: 17.6 %

Procedure:
A mixture of 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (152 mg, 0.8 mmol), potassium carbonate (232 mg, 1.68 mmol) and copper (I) iodide (1 mg, 0.005 mmol) was treated with a solution of trans-1,2-diaminocyclohexane (9 mg, 0.08 mmol) in dioxane followed by a solution of 1-(4-bromophenyl)imidazole (161 mg, 0.72 mmol) in dioxane (4 ml total volume). This mixture was heated at 180° C. in a microwave reactor for 1 hour. Further copper (I) iodide (1 mg) and trans-1,2-diaminocyclohexane (9 mg) was added and the reaction heated at 180° C. in a microwave reactor for a further hour. Again further copper (I) iodide (1 mg) and trans-1,2-diaminocyclohexane (9 mg) was added and the reaction heated at 180° C. in a microwave reactor for a further hour. The reaction mixture was added to a 5 g sep-pack column and eluted with ethyl acetate. The solvent was removed by rotary evaporation and the crude product further purified by MDAP. Further purified using a 5 g SCX column, eluting from 1M ammonia in methanol which was then evaporated off using rotary evaporation to give the title compound (42 mg, 18%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:9]1([C:2]2[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH2:11][CH2:10]1
Reactant: Nc1ccc(Br)cn1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(C2CC2)cn1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 5-bromo-pyridin-2-ylamine (2 g, 11.55 mmol) and cyclopropyl boronic acid (2.98 g, 34.68 mmol) in toluene (40 mL) and water (2 mL) was added K3PO4 (8.59 g, 40.46 mmol) under an argon atmosphere. To this were added Pd(OAc)2 (259.52 mg, 1.16 mmol) and tricyclohexylphosphene (647.3 mg, 2.3 mmol) and stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature and water was added. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/hexane as eluent. The title compound was obtained as an off white solid (1.1 g, 71%).
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1Br.[Li]C(C)(C)C.[CH3:16][O:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.CON(C)[C:31](=[O:41])[CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37]>C1COCC1.ClCCl>[CH3:16][O:17][C:18]1[C:27]([C:31](=[O:41])[CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: COc1ccc2ccccc2n1
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1nc2ccccc2cc1C(=O)CNC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of mesityl bromide (4 eq.) in THF (1.7 M) cooled to −78° C. was added a solution of tBuLi in THF (8 eq., 1.7 M) dropwise. The mixture was left stirring at −78° C. for 1 h. Mixture was then allowed to reach 0° C. and a solution of 2-methoxyquinoline (3 eq.) in THF (0.32 M) was added dropwise over 10 min. The resulting mixture was aged at 0° C. for 1 h, then cooled to −78° C. and added dropwise with a solution of tert-butyl (2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (1 eq.) in THF (0.22 M). The reaction mixture was stirred at −78° C. for 30 min, then left at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with sat. aq. NaHCO3, dried over Na2SO4, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography (SiO2, Petroleum ether/EtOAc, from 5% to 40% EtOAc). Pooled fractions were concentrated under vacuum to give the title compound. MS (ES+) C17H20N2O4: 317 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[CH3:11][O:12][C:13]([C:15]1[NH:16][C:17]([CH:21]=O)=[C:18]([CH3:20])[CH:19]=1)=[O:14]>>[CH3:11][O:12][C:13]([C:15]1[NH:16][C:17]([CH:21]=[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]2=[O:1])=[C:18]([CH3:20])[CH:19]=1)=[O:14]
Reactant: O=C1C=c2ccccc2=N1
Reactant: COC(=O)c1cc(C)c(C=O)[nH]1
Product: COC(=O)c1cc(C)c(C=C2C(=O)Nc3ccccc32)[nH]1
Yield: 81 %

Procedure:
Oxoindole (105 mg, 0.79 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid methyl ester (110 mg, 0.67 mmol) using method E to give 153.2 mg (81%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([CH:9]=1)[NH2:8])#[N:2].[Cl:11][CH2:12][C:13](Cl)=[O:14]>>[Cl:11][CH2:12][C:13]([NH:8][C:7]1[CH:9]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=1[CH3:10])=[O:14]
Reactant: Cc1ccc(C#N)cc1N
Reactant: O=C(Cl)CCl
Product: Cc1ccc(C#N)cc1NC(=O)CCl

Procedure:
The subtitle compound was prepared from 5-cyano-2-methylaniline (1.6 g) and chloroacetyl chloride (1.1 ml) by the method of Example 33 step (iii) as a white solid. Yield: 1.85 g
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.[NH2:11]C(N)=O>C1(C)C=C(C)C=C(C)C=1.P(O)(O)O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:11])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(N)=O
Reactant: O=C(O)c1ccc(F)cc1
Agent: OP(O)O
Solvent: Cc1cc(C)cc(C)c1
Product: NC(=O)c1ccc(F)cc1
Temperature: 154 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
70.0 g (0.5 mol) of 4-fluorobenzoic acid, 30.0 g (0.50 mol) of urea and 0.5 g of phosphorous acid are heated in 100 ml of mesitylene with stirring at from 150 to 158° C. for 8 h. After cooling to 25° C. the solid is filtered off with suction and is washed with 50 ml of mesitylene. The filter cake is introduced into 250 ml of water, and the mixture is adjusted to a pH of 12 with aqueous sodium hydroxide solution and subjected to steam distillation. Subsequently the solid is filtered off with suction and dried at 100° C. 50.7 g of 4-fluorobenzamide are obtained having a melting point of from 147° to 150° C. This corresponds to a yield of 72.9% of theory. By acidification of the aqueous mother liquor to a pH of 2, 5.9 g of 4-fluorobenzoic acid (8.4% of theory) are obtained, which can be employed again in a subsequent batch.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([NH:14][NH2:15])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N+:16]([C:19]1[O:23][C:22](/[CH:24]=[CH:25]/[CH:26]=O)=[CH:21][CH:20]=1)([O-:18])=[O:17]>C(O)(=O)C>[OH:1][C:2]1[C:3]([C:12]([NH:14]/[N:15]=[CH:26]/[CH:25]=[CH:24]/[C:22]2[O:23][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C/C=C/c1ccc([N+](=O)[O-])o1
Reactant: NNC(=O)c1cc2ccccc2cc1O
Solvent: CC(=O)O
Product: O=C(N/N=C/C=C/c1ccc([N+](=O)[O-])o1)c1cc2ccccc2cc1O
Reaction time: 2 h
Yield: 97.9 %

Procedure:
Acetic acid (3 mL) is added to a mixture of 3-Hydroxy-2-naphthoic acid hydrazide (100 mg, 0.50 mmol) and (E)-3-(5-nitrofuran-2-yl)acrylaldehyde (99 mg, 0.59 mmol) and the resulting mixture is stirred for 2 h (Note: Immediate precipitation of the yellowish hydrazone product is observed after which the reaction mixture is stirred for another 2 h for completion). The reaction mixture is then diluted with 50% ether/hexanes. The yellowish solid is filtered with suction, washed with 50% ether/hexanes (100 mL) and dried to furnish 172 mg (99%) of the desired product as a yellowish solid. m. p. 259° C. 1H NMR (DMSO) δ 12.00 (br s, 1H), 11.3 (br s, 1H), 8.42 (s, 1H), 8.25 (d, 1H, J=8.1 Hz), 7.91 (d, 1H, J=8.4 Hz), 7.86-7.66 (m, 2H), 7.58-7.45 (m, 1H), 7.42-7.29 (m, 1H), 7.32 (s, 1H) and 7.25-7.06 (m, 3H); 13C NMR (DMSO) δ 163.7, 154.8, 153.8, 151.4, 148.5, 135.9, 130.5, 130.4, 128.7, 128.3, 126.8, 125.8, 124.3, 123.8, 120.5, 115.4, 113.6 and 110.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:30][C:31]([CH3:33])=[CH2:32]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([O:23][C:31]([CH3:33])([CH3:32])[CH3:30])=[O:22])[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: C=C(C)C
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1c(C(=O)OC(C)(C)C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: -10 °C

Procedure:
A solution of 5 g of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylic acid in 35 ml of dioxane is introduced into a 250 ml autoclave and then cooled to -10° C. 2 ml of concentrated H2SO4 and 70 ml of 2-methylpropene, cooled to -10° C., are then added and the autoclave is closed, allowed to warm up to RT and then heated at 40° C. for 18 hours, with vigorous stirring. After cooling to RT, the reaction mixture is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with water, with 5% Na2CO3 solution and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a toluene/AcOEt mixture (from 90/10 to 80/20; v/v) as the eluent to give 3.15 g of the expected product, m.p.=112° C.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:19])[O:6][C:7]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[C:8]=2[C:9]=1[CH3:10].[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:18][O:17][C:11]1[C:8]2[C:9]([CH3:10])=[C:4]([CH2:3][CH2:2][N:30]3[CH2:31][CH2:32][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[CH3:20])[CH2:28][CH2:29]3)[C:5](=[O:19])[O:6][C:7]=2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=1
Reactant: Cc1ccccc1N1CCNCC1
Reactant: COc1cc(OC)c2c(C)c(CCCl)c(=O)oc2c1
Product: COc1cc(OC)c2c(C)c(CCN3CCN(c4ccccc4C)CC3)c(=O)oc2c1
Yield: 14 %

Procedure:
Process A; starting materials: 3-(2-chloroethyl)-5,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 39) and 1-(2-methylphenyl)piperazine; yield 14% of oily crude product.
Reaction SMILES: [SH:1][CH2:2][C:3](OCC)=[O:4].[H-].[Na+].[NH2:10][C:11]1[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:12]=1Br>CN(C=O)C.CCOC(C)=O>[O:4]=[C:3]1[CH2:2][S:1][C:12]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[N:16][C:11]=2[NH:10]1
Reactant: CCOC(=O)CS
Reactant: COC(=O)c1ccc(Br)c(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(n1)NC(=O)CS2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ethyl 2-mercaptoacetate (1.473 mL) in DMF (48 mL) was ice-cooled and treated with sodium hydride (540 mg of a 60% dispersion in oil). After 1 h methyl 6-amino-5-bromopyridine-2-carboxylate (3 g) (T. R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623-4633) was added and the mixture stirred for 16 h at room temperature. The solution was diluted with EtOAc (1 L), washed with water (3×300 mL), dried and evaporated to about 10 mL. The white solid was filtered off and washed with a little EtOAc to give the ester (0.95 g); LC/MS (APCl−) m/z223 ([M-H]−, 100%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.[C:41]([O:45][C:46]([N:48]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[C:49]1[C:50]([C:56]([O:58][CH3:59])=[O:57])=[N:51][C:52](Br)=[CH:53][N:54]=1)=[O:47])([CH3:44])([CH3:43])[CH3:42].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl[Pd]Cl.O>[C:63]([O:62][C:60]([N:48]([C:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:47])[C:49]1[C:50]([C:56]([O:58][CH3:59])=[O:57])=[N:51][C:52]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=2)=[CH:53][N:54]=1)=[O:61])([CH3:66])([CH3:65])[CH3:64]
Reactant: COC(=O)c1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1nc(C2=CCN(C(=O)OC(C)(C)C)CC2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 97.6 %

Procedure:
A suspension of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (858 mg, 2.8 mmol), 4-ditert-butylphosphanyl-N,N-dimethyl-aniline; dichloropalladium (164 mg, 0.23 mmol), methyl 3-[bis(tert-butoxycarbonyl)amino]-6-bromo-pyrazine-2-carboxylate (1.0 g, 2.3 mmol), and Na2CO3 (490 mg, 4.6 mmol) under an atmosphere of nitrogen in toluene (15 mL) and water (2 mL) was heated to 95° C. for 2 h. The reaction mixture was diluted with ethyl acetate, washed with 1N HCl, 50% saturated sodium bicarbonate solution, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified via silica gel column chromatography using 10-50% ethyl acetate/hexane to provide methyl 3-[bis(tert-butoxycarbonyl)amino]-6-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)pyrazine-2-carboxylate (1.2 g, 97%) as a amber oil. 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 6.97 (s, 1H), 4.12 (s, 2H), 3.89 (s, 3H), 3.57 (t, J=5.2 Hz, 2H), 2.61 (s, 2H), 1.43 (s, 9H), 1.34 (s, 18H). LC/MS m/z 535.5 [M+H]+.
Reaction SMILES: ClC1C(NC2C=C(C)NN=2)=NC([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])=NC=1.C[Mg]Cl.C(O[C:32](=[O:34])[CH3:33])(=O)C.C(=O)([O-])O.[Na+]>C1COCC1.C(Cl)Cl>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]([NH:8][C:32](=[O:34])[CH3:33])=[CH2:10])=[N:12][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ncc2Cl)n[nH]1
Agent: C[Mg]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C(NC(C)=O)c1ccc(F)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-fluoropicolinonitrile (Method 35; 1875 g 1 equivalent) in THF (3.7 volumes) was added to methyl magnesium chloride (3N in THF, 1.2 equivalents) maintaining the temperature at 0° C. The reaction mixture was stirred for 30 minutes at 0° C. and then diluted with DCM (3.2 volumes) at 0° C. Acetic anhydride (2.0 equivalents) in DCM (1.6 volumes.) was added at a rate to maintain the temperature at 0° C. The batch was allowed to warm to room temperature and stirred overnight. Saturated, aqueous sodium hydrogen carbonate (13.9 volumes) was added and the product was extracted into EtOAc (1×0.53 volumes, 1×0.26 volumes). The combined extracts were dried, filtered and evaporated in vacuo and purification carried out by chromatography (5 w/w silica; 20-100% DCM in hexane). The mixture of N-mono and N,N-di-acetylated compounds was treated with potassium carbonate (0.1 w/w on mixture) in methanol (5 volumes) for 30 minutes. The inorganic solids were filtered and washed with methanol. Silica was added to the methanol solution to remove residual potassium carbonate prior to evaporation. The product, pre-adsorbed on silica, was eluted through a silica pad (2 w/w silica; 90-100% DCM in hexane) and evaporated to give an orange solid. Mp 61.0-62.2° C., 636 g, 23.0% theory.
Reaction SMILES: O[CH2:2][C@@H:3]1[O:8][C:7](=[O:9])[C@H:6]([NH:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:5]([CH3:20])([CH3:19])[CH2:4]1.C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)Cl>[CH3:19][C:5]1([CH3:20])[C@H:6]2[N:10]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[CH2:2][C@H:3]([O:8][C:7]2=[O:9])[CH2:4]1
Reactant: CC(N[C@H]1C(=O)O[C@@H](CO)CC1(C)C)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(c1ccccc1)N1C[C@H]2CC(C)(C)[C@@H]1C(=O)O2
Reaction time: 46 h
Yield: 30 %

Procedure:
To a solution of (3R,6R)-6-hydroxymethyl-4,4-dimethyl-3-(1-phenyl-ethylamino)-tetrahydro-pyran-2-one (compound of formula XXXIV, 1.42 g, 5.14 mmol) in 45 ml of methylene chloride was added triethylamine (1.1 ml, 7.9 mmol) and p-toluenesulfonyl chloride (1.2 g, 6.2 mmol) at about 0° C. The mixture was warmed to a temperature of about 20° C. to about 25° C. and was stirred for about 46 hours. The mixture was washed twice with water, and the aqueous layers were extracted with methylene chloride. The combined organic layers were dried over MgSO4, filtered and concentrated. Purification of the residue by filtration through a pad of silica gel eluting first with hexane followed by 20% ethyl acetate in hexane afforded 0.4 g of (1R,4R)-8,8-dimethyl-5-(1-phenyl-ethyl)-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (compound of formula XXXV) as a colorless solid after recrystallization from methanol-water.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH:7]1[C:8]2[C:3](=[C:2]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: C1COCCN1
Reactant: Brc1cccc2cnccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1cc(N2CCOCC2)c2ccncc2c1
Temperature: 110 °C
Yield: 99.3 %

Procedure:
A mixture of 5-bromoisoquinoline (4.07 g, 19.6 mmol), morpholine (3.41 mL, 39.1 mmol), Cs2CO3 (12.75 g, 39.1 mmol), Pd(OAc)2 (220 mg, 0.98 mmol) and BINAP (609 mg, 0.98 mmol) in toluene (160 mL) was heated at 110° C. for 6 h under N2. The mixture was then concentrated in vacuo and the black residue obtained was taken up in DCM and filtered over Celite. The filtrate was concentrated in vacuo and the brown oil obtained was purified by flash chromatography (SiO2, cHex to AcOEt) to give the title compound (4.17 g) as a brown oil. UPLC-MS: MS 215.1 (M+H+); UPLC rt 0.57 min.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[CH:27]=[C:26]([CH3:28])[NH:25][C:22]4=[N:23][CH:24]=3)[S:18][C:14]=2[C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:39](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[CH:27]=[C:26]([CH3:28])[N:25]([CH3:39])[C:22]4=[N:23][CH:24]=3)[S:18][C:14]=2[C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc4[nH]c(C)cc4c3)sc2c1-c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc4c(c3)cc(C)n4C)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]thiazol-6-yl)acetate (70 mg, 0.128 mmol) in DMF (5 mL) was added cesium carbonate (54 mg, 0.166 mmol). The reaction solution was stirred at room temperature for 5 minutes, then iodomethane (24 mg, 0.166 mmol) was added. The reaction solution was stirred for 30 minutes and quenched with water. Volatiles were removed and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4) and concentrated to give crude which was purified by chromatographic column to afford the desired product. LCMS-ESI+: calc'd for C31H32 ClN3O3S: 562.3 (M+H+); Found: 562.3 (M+H+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:28])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=3)=[CH:13][O:14]2)=[CH:9][CH:8]=1)(=O)=O.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[O:28]=[C:11]1[C:10]2[C:15](=[CH:16][C:7]([C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])=[CH:8][CH:9]=2)[O:14][CH:13]=[C:12]1[C:17]1[CH:18]=[CH:19][C:20]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)Nc1ccc(-c2coc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2=O)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2c(=O)c(-c3ccc(NS(C)(=O)=O)cc3)coc2c1
Temperature: 85 °C

Procedure:
3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yl trifluoromethanesulfonate (2.5 g, 5.39 mmol), trimethylsilylacetylene (0.92 ml, 1.2 eq), PdCl2(PPh3)2 (175 mg, 0.05 eq), copper iodide (28.8 mg 0.03 eq), triphenylphosphine (40 mg 0.03 eq) and triethylamine (3.12 ml, 4.0 eq) were combined in dry tetrahydrofuran (10 ml) and heated in microwave for 30 minutes at 85° C. The reaction mixture was partitioned between ethyl acetate and water, the organic phase dried with magnesium sulfate, and solvent removed under reduced pressure. The crude product was heated in acetonitrile, cooled down and the solids were filtered off. This procedure was repeated twice in order to afford N-(4-(4-oxo-7-((trimethylsilyl)ethynyl)-4H-chromen-3-yl)phenyl)methanesulfonamide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][NH:7]C(=O)OC(C)(C)C)#[N:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:17]=[CH:16][CH:15]=1)[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(CN)c1
Reaction time: 1 h

Procedure:
To tert-butyl 3-cyanobenzylcarbamate in CH2Cl2 (10 ml), TFA (3 ml) was added. After 1 h, volatiles were removed on a rotavap under reduced pressure. Crude residue 3-(aminomethyl)benzonitrile was dissolved in water, basified with 2N NaOH and extracted with CHCl3 (100 ml) and used without further purification.
Reaction SMILES: [Na].[CH3:2][C:3]1[N+:8]([O-:9])=[C:7]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:6]2=[C:5]([N+]([O-])=O)[C:4]=1[C:18]([O:20][CH2:21]C)=[O:19].[CH3:23][OH:24]>>[CH3:23][O:24][C:5]1[C:4]([C:18]([O:20][CH3:21])=[O:19])=[C:3]([CH3:2])[N+:8]([O-:9])=[C:7]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:6]=12
Reactant: CCOC(=O)c1c([N+](=O)[O-])c2c([n+]([O-])c1C)CCCCC2
Reactant: CO
Agent: [Na]
Product: COC(=O)c1c(OC)c2c([n+]([O-])c1C)CCCCC2
Temperature: 25 °C
Reaction time: 29 h
Yield: 86.3 %

Procedure:
In an atmosphere of argon and at room temperature, metallic sodium (86.0 mg, 0.005 g atom) was dissolved in anhydrous methanol (8.0 ml) to which was subsequently added dropwise methanol solution (20.0 ml) of ethyl 2-methyl-4-nitro-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate N-oxide (1.00 g, 3.40 mmol), and the resulting mixture was stirred at room temperature for 29 hours. After evaporation of the solvent under reduced pressure, the resulting residue was mixed with water and extracted with chloroform, and the thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, the resulting residue was purified by a silica gel column chromatography (ethyl acetate:hexane=5:1—ethyl acetate:methanol=15:1) to obtain the title compound (777.9 mg, 86.3%) as pale yellow powder.