Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]4[C:26]5[CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32][C:27]=5[N:28]([CH3:31])[C:29]=4[CH:30]=3)[C:18](=[O:43])[CH:17]=2)=[C:12]([CH3:44])[CH:11]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]4[C:26]5[CH2:35][NH:34][CH2:33][CH2:32][C:27]=5[N:28]([CH3:31])[C:29]=4[CH:30]=3)[C:18](=[O:43])[CH:17]=2)=[C:12]([CH3:44])[CH:11]=1
Reactant: COc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCN(C(=O)OC(C)(C)C)C5)c(=O)c2)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCNC5)c(=O)c2)c(C)c1
Reaction time: 1 h
Yield: 80.1 %

Procedure:
Trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl 7-(4-(4-methoxy-2-methylphenyl)-2-oxopyridin-1 (2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.25 g, 0.50 mmol) in CH2Cl2 (2.0 mL) under N2 and stirred for 1 h. The reaction mixture was made basic with saturated NaHCO3 solution and the resolution solution was extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. Flash column chromatography (12 g ISCO CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes to 0:100 over 20 column volumes and hold for 40 column volumes) yielded the title compound (0.16 g, 80%) as an off-white film: 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J=8.0 Hz, 1H), 7.42 (d, J=7.0 Hz, 1H), 7.38 (m, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.07 (dd, J=8.5, 2.0 Hz, 1H), 6.82-6.80 (m, 2H), 6.60 (d, J=1.5 Hz, 1H), 6.23 (dd, J=7.0, 1.5 Hz, 1H), 4.09 (s, 2H), 3.84 (s, 3H), 3.64 (s, 3H), 2.77 (t, J=5.5 Hz, 2H), 2.27 (t, J=6.0 Hz, 2H), 2.39 (s, 3H).
Reaction SMILES: Br[C:2]1[O:3][CH:4]=[CH:5][CH:6]=1.C([Li])CCC.[S:12](Cl)([Cl:15])(=[O:14])=[O:13]>O1CCCC1.C(OCC)C>[O:3]1[CH:4]=[CH:5][C:6]([S:12]([Cl:15])(=[O:14])=[O:13])=[CH:2]1
Reactant: Brc1ccco1
Reactant: O=S(=O)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=S(=O)(Cl)c1ccoc1
Reaction time: 1 h

Procedure:
In flame dried glassware under a nitrogen atmosphere to a solution of 428 mg (2.909 mmol) of 3 bromofuran in anhydrous tetrahydrofuran at -78° C. was added 2.0 mL n-butyl lithium (3.2 mmol at 1.6 molar in hexane). After 45 minutes the resultant solution was added via cannula to a 20° C. solution of sulfuryl chloride in diethyl ether (5 mL plus a 2 mL rinse). After 1 h, the reaction was quenched with 0.5N hydrochloric acid and extraced into diethyl ether. The ethereal extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 158 mg of the title product. (1H) NMR (CDCl3) consistent with structure.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.C(O[C:38](=[O:40])[CH3:39])(=O)C>ClCCl.C1COCC1>[OH:40][CH2:38][CH2:39][N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (30 mg, 0.07 mmol, Example 26a) was dissolved in dichloromethane (1 mL) and THF (1 mL). Acetic anhydride (6.61 μL, 0.07 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. The solvent was evaporated under reduced pressure, the crude was dissolved in dimethylformamide and acetonitrile, filtered and purified by preparative HPLC yielding 1-(4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (5.9 mg, 17.91%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([F:54])[C:40]=1[OH:55]>>[NH2:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:42]=[C:41]([F:54])[C:40]([OH:55])=[C:39]([Cl:38])[CH:44]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 36.5 %

Procedure:
Following general procedure D, (R)-tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.17 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (71 mg, 0.26 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (33 mg, 37% over 2 steps) as an orange-yellow solid 1H NMR (500 MHz, MeOD+TFA-d) δ 9.41 (s, 1H), 8.28-8.14 (m, 2H), 8.05 (br s, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.65 (dd, J=9.1, 2.8 Hz, 1H), 7.16-7.04 (m, 3H), 4.53 (d, J=11.6 Hz, 1H), 3.99 (dt, J=13.7, 4.0 Hz, 1H), 3.40-3.21 (m, 3H), 2.86 (br s, 3H), 2.23-2.15 (m, 1H), 1.98-1.89 (m, 1H), 1.79-1.65 (m, 2H), 1.27-1.16 (m, 4H). ESI MS m/z 532 [C29H27ClFN5O2+H]+; HPLC>99.0% (AUC), tR=10.77 min.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([C:10]2[CH:14]=[C:13]([O:15][CH:16]([F:18])[F:17])[N:12]([CH3:19])[N:11]=2)=[CH:5][C:3]=1[NH2:4].C([O-])(=O)C.[Na+].[Br:25]Br>C(O)(=O)C>[Br:25][C:5]1[C:6]([C:10]2[CH:14]=[C:13]([O:15][CH:16]([F:18])[F:17])[N:12]([CH3:19])[N:11]=2)=[C:7]([Cl:9])[CH:8]=[C:2]([Cl:1])[C:3]=1[NH2:4]
Reactant: BrBr
Reactant: Cn1nc(-c2cc(N)c(Cl)cc2Cl)cc1OC(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cn1nc(-c2c(Cl)cc(Cl)c(N)c2Br)cc1OC(F)F
Reaction time: 8 h

Procedure:
1 g (2.9 mmol) of 2,4-dichloro-5-(5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)aniline and 2.4 g (29 mmol) of sodium acetate were initially charged in 100 ml of glacial acetic acid, and 0.93 g (5.6 mmol) of bromine was added dropwise at room temperature. The reaction mixture was stirred overnight and then concentrated, and the residue was taken up in toluene and washed with 50 ml of 5% by weight strength aqueous sodium hydroxide solution until neutral. The organic phase was dried over magnesium sulfate and concentrated. This gave 1.3 g of the aniline IVa.4. The product that was obtained was identical to the compound obtained according to example 1.1.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH2:12]([O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:24][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:25][CH:26]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccccc1Cl
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Product: O=C(O)c1ccccc1Nc1ccc(OCc2ccccc2)cc1

Procedure:
2-(4-Benzyloxyphenylamino)benzoic acid [X; R=H, OR°=4-OCH2C6H5, R"=H] was prepared from 2-chlorobenzoic acid and 4-benzyloxyaniline hydrochloride according to the procedure of Example 1A, part (a), and the crude product was used directly in the following reaction.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:21]=4)[CH2:16][CH2:15][NH:14]3)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[N-:33]([C:36]#[N:37])[C:34]#[N:35].[Na+]>C(O)CCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[CH:21]=4)[CH2:16][CH2:15][N:14]3[C:36](=[NH:37])[NH:33][C:34]#[N:35])[CH2:10][CH2:11][CH2:12]2)=[CH:5][CH:4]=1
Reactant: N#C[N-]C#N
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)N(C(=N)NC#N)CC2
Reaction time: 4 h
Yield: 31.6 %

Procedure:
Propane-1-sulfonic acid (2-{1-[1-(4-chloro-phenyl)-cyclobutyl]-1,2,3,4-tetrahydro-isoquinolin-7-yloxy}-ethyl)-amide hydrochloride (example 4, 95.0 mg, 0.19 mmol) was dissolved in 1-butanol (10 ml) and sodium dicyanamide (42.3 mg, 0.48 mmol) was added. The reaction mixture was stirred under reflux. After 4 h, the solvent was removed and dichloromethane was added. The resulting precipitate was removed by filtration and purified by flash column chromatography on silica with dichloromethane/methanol 10:0→94:6. The product was obtained as a solid (30.0 mg, 0.06 mmol, 30.0%).
Reaction SMILES: [CH3:1][C:2]12[CH2:11][CH2:10][CH:5]([CH2:6][C:7]1=NO)[CH:4]([CH3:12])[O:3]2.N([O-])=[O:14].[Na+].O.S(=O)(=O)(O)O>C(OCC)C>[CH3:1][C:2]12[CH2:11][CH2:10][CH:5]([CH2:6][C:7]1=[O:14])[CH:4]([CH3:12])[O:3]2
Reactant: CC1OC2(C)CCC1CC2=NO
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC1OC2(C)CCC1CC2=O
Reaction time: 3 h

Procedure:
To a mixture of 20.5 g. 1,3-dimethyl-2-oxabicyclo[2,2,2]octan-6-one-oxime, 16 g. sodium nitrite, 350 ml. water and 100 ml. diethylether at 25° C. there is added dropwise 100 ml. of 2 N sulfuric acid and the mixture is allowed to stand with occasional stirring for 3 hours. The organic layer is washed with 10% aqueous sodium bicarbonate and evaporated. To the resulting residue at 0° C. there is added 70 ml. concentrated ammonium hydroxide. This mixture is then extracted several times with diethyl ether and the combined ether extracts are dried over magnesium sulfate and evaporated to give 1,3-dimethyl-2-oxabicyclo[2,2,2]octan-6-one.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][C@@H:7]([CH3:12])[CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([NH2:5])=[O:4].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])O.[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:1][C@H:2]([CH2:6][C@@H:7]([CH3:12])[CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([NH2:5])=[O:4]
Reactant: CCCC[C@H](C)C[C@@H](O)C(N)=O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCCC[C@H](C)C[C@@H](OC1CCCCO1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
In a flask were charged 3.5 g of (2R,4S)-2-hydroxy-4-methylcaprylic amide synthesized in Step 5, 2.21 g of 3,4-dihydropyran, 50 ml of diethyl ether, and 0.1 g of p-toluenesulfonic acid at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 100 ml of a 1% sodium hydrogencarbonate aqueous solution and extracted with diethyl ether. The extract was washed with water and concentrated to obtain 6.6 g of a crude product, which was then purified by silica gel column chromatography to obtain 3.5 g (67.4%) of the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9](Cl)(=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CO>N1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:6][CH:7]=1
Reactant: CCCCCC(=O)Cl
Reactant: Nc1ncc(O)cn1
Solvent: c1ccncc1
Solvent: CO
Product: CCCCCC(=O)Nc1ncc(O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
5-Hydroxypyrimidin-2-amine (40 g, 360 mmol) was dissolved in pyridine (200 mL), the solution was added with hexanoyl chloride (121 g, 899 mmol), and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was added with methanol (100 mL), the mixture was concentrated under reduced pressure, and the resulting residue was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was dissolved in methanol (200 mL). The solution was added with saturated ammonia solution in methanol (250 mL) under ice cooling and stirring, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:acetone=2:1) to obtain N-(5-hydroxypyrimidin-2-yl)hexanamide (39.5 g, 52%) as colorless solid.
Reaction SMILES: [CH2:1]([N:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([O:26]CC)=[O:25])[C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.C1C=CC=CC=1>[CH2:1]([N:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([OH:26])=[O:25])[C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccccc1N(Cc1ccccc1)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCO
Product: O=C(O)Cc1ccccc1N(Cc1ccccc1)c1c(Cl)cccc1Cl
Temperature: 80 °C
Reaction time: 9 h
Yield: 77.7 %

Procedure:
In a mixture of 50 ml of ethanol and 30 ml of benzene, 7.0 g (0.017 mole) of ethyl N-benzyl-o-(2,6-dichloroanilino)phenylacetate was dissolved and 31 ml of 2 N-NaOH aq. sol. was added and the mixture was stirred at about 80° C. for 9 hours. The reaction mixture was concentrated under reduced pressure and 70 ml of ether was added to the residue and the reaction product was extracted with 2 N-NaOH aq. sol. The pH of the water phase was adjusted with a dilute hydrochloric acid to 2.0 and the precipitate was extracted with ether and the ether phase was dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The reaction product was recrystallized and 5.1 g of N-benzyl-o-(2,6-dichloroanilino)phenyl acetic acid was obtained as colorless crystals. Yield: 78%
Reaction SMILES: [OH:1][S:2]([OH:5])(=[O:4])=[O:3].[Br:6][C:7]1[N:8]=[C:9]2[C:15]([CH2:16][OH:17])=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1.[CH3:18][C:19]([CH3:21])=[O:20].OS(O)(=O)=O.[O:27]=[Cr:28](=[O:30])=[O:29]>O.CC(C)=O>[CH3:18][C:19]([CH3:21])=[O:20].[OH:4][S:2]([OH:5])(=[O:3])=[O:1].[O:27]=[Cr:28](=[O:30])=[O:29].[Br:6][C:7]1[N:8]=[C:9]2[C:15]([CH:16]=[O:17])=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1
Reactant: OCc1c[nH]c2ncc(Br)nc12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: O=Cc1c[nH]c2ncc(Br)nc12
Reaction time: 0.25 h

Procedure:
A stock solution of Jones reagent (2.67 M) was prepared by carefully adding concentrated H2SO4 (2.3 mL) to CrO3 (2.67 g) then diluting to 10 mL with H2O. To a partial suspension of (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-methanol (4.6 g, 20.1 mmol) in acetone (300 mL) was slowly added Jones reagent (9 mL, 24.0 mmol). During the addition the starting material gradually dissolved and a thick green precipitate was formed. The reaction mixture was stirred for 15 min then quenched with i-PrOH (2 mL) and filtered over Celite, rinsing with acetone. The filtrate was concentrated to provide 4.76 g of 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a yellow-orange solid that was used without further purification. To a solution of this solid in DMF (50 mL) at 0° C. was added NaH (60% in mineral oil, 1.2 g, 30.1 mmol). The reaction mixture was stirred at room temperature for 30 min then cooled back to 0° C. and 2-(trimethylsilyl)ethoxymethyl chloride (4.3 mL, 24.1 mmol) was slowly added. The reaction mixture was warmed to room temperature and stirred for 1 h then quenched with H2O and extracted with EtOAc (3×). The combined organics were washed with H2O (3×) and brine then dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (20% to 30% EtOAc/hexanes) to isolate 3.82 g (53%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a yellow solid. 1H NMR (CDCl3, 300 MHz): 6 (ppm) 10.37 (s, 1H), 8.50 (s, 1H), 8.33 (s, 1H), 5.73 (s, 2H), 3.53-3.70 (m, 2H), 0.90-1.05 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:21]([O-])=O)=[C:4]2[C:9]3=[C:10]([O:13][CH2:14][C@H:15]([CH3:16])[N:8]3[CH:7]=[C:6]([C:17]([NH2:19])=[O:18])[C:5]2=[O:20])[C:11]=1[F:12].S(S([O-])=O)([O-])=O.[Na+].[Na+].O>O.CO>[NH2:21][C:3]1[C:2]([F:1])=[C:11]([F:12])[C:10]2[O:13][CH2:14][C@H:15]([CH3:16])[N:8]3[C:9]=2[C:4]=1[C:5](=[O:20])[C:6]([C:17]([NH2:19])=[O:18])=[CH:7]3
Reactant: C[C@H]1COc2c(F)c(F)c([N+](=O)[O-])c3c(=O)c(C(N)=O)cn1c23
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C(N)=O)cn1c23
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
To a suspension of 3 (1 g, 3.07 mmol) in a mixture of water/methanol (1:1 v/v, 30 mL) was added sodium hydrosulfite (Na2S2O4, 4.3 g, 24.6 mmol). The suspension was refluxed for 5 h until all starting material has disappeared. Upon completion, the reaction mixture was cooled to room temperature and 50 mL of water were added. After 20 minutes, a light yellow solid was collected by filtration and washed with water. The solid was dried under vacuo to give 4 (725 mg, 74% yield), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@H:19]([CH3:22])[CH2:20][OH:21])(=[O:17])=[O:16])=[CH:11][CH:10]=1.F[B-](F)(F)F.[H+].O>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH:18][C@H:19]([CH3:22])[CH2:20][O:21][CH3:1])(=[O:16])=[O:17])=[CH:13][CH:14]=1
Reactant: C[C@H](CO)NS(=O)(=O)c1ccc(Br)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Solvent: O
Product: COC[C@@H](C)NS(=O)(=O)c1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 14.8 %

Procedure:
(Trimethylsilyl)diazomethane (10 mL, 10 mmol) was added to a vigorously stirred mixture of 4-bromo-N-[(1R)-2-hydroxy-1-methylethyl]benzenesulfonamide (1.0 g, 3.4 mmol) and aqueous fluoroboric acid (conc. 42%, 6.8 mmol) in methylene chloride (25 mL), in 5 portions over 1 h at 0° C. The stirring was continued at 0° C. and another portion of trimethylsilyldiazomethane (5 mL, 5 mmol) was added over 30 min. The stirring was continued for 30 min, poured into water and extracted with methylene chloride. The organic phase was washed with water, dried over sodium sulfate and concentrated. Purification by column chromatography using gradient heptane to heptane/ethylacetate, (2:1), as the eluent gave 0.155 g (15% yield) of the title compound: MS (ESI) 309 m/z (M++1).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:19])[N:7]([CH2:9][CH2:10][C@H:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:8])([CH3:4])[CH3:3].[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([N+:28]([O-:30])=[O:29])=[C:25](O)[CH:26]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N+:28]([O-:30])=[O:29])=[C:23]([CH:22]=1)[O:18][C@@H:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:10][CH2:9][N:7]([CH3:8])[C:6](=[O:19])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4]
Reactant: CN(CC[C@H](O)c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(Cl)cc1O
Product: CN(CC[C@@H](Oc1cc(Cl)ccc1[N+](=O)[O-])c1ccccc1)C(=O)OC(C)(C)C

Procedure:
This was prepared by the method of Example 20(a) using [(3S)-3-hydroxy-3-phenylpropyl]methylcarbamic acid 1,1-dimethylethyl ester and 5-chloro-2-nitrophenol.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:26])[C:10]([CH3:25])=[C:11]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:24])[CH2:22][CH3:23])[CH2:17][CH2:16]3)[O:12]2)=[CH:7][CH:6]=1)C=C.Cl.CN(C)[C:30]1[CH:35]=CC=C[CH:31]=1>>[CH2:35]([C:14]1[C:5]([OH:4])=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:24])[CH2:22][CH3:23])[CH2:17][CH2:16]1)=[C:10]([CH3:25])[C:9]2=[O:26])[CH:30]=[CH2:31]
Reactant: C=CCOc1ccc2c(=O)c(C)c(C3CCN(C(=O)CC)CC3)oc2c1
Reactant: CN(C)c1ccccc1
Agent: Cl
Product: C=CCc1c(O)ccc2c(=O)c(C)c(C3CCN(C(=O)CC)CC3)oc12
Temperature: 200 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
A solution of 7-(allyloxy)-3-methyl-2-(1-propanoylpiperidin-4-yl)-4H-chromen-4-one (920 mg, 2.59 mmol) obtained in Example 31-3 in dimethylaniline (4 mL) was heated with stirring at 200° C. for 6 hours. A 1 N aqueous hydrochloric acid solution (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0→95/5) to obtain 798 mg of the title compound (yield: 87%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[CH:36]=1)[C:29]([C:42](O)=[O:43])=[CH:28]2.[NH2:45][CH2:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49]>C(Cl)Cl.O>[OH:49][CH2:48][C:47]([CH3:51])([CH3:50])[CH2:46][NH:45][C:42]([C:29]1[N:30]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[CH:36]=2)[C:31]2[C:27]([CH:28]=1)=[CH:26][C:25]([Cl:24])=[CH:33][CH:32]=2)=[O:43]
Reactant: Cc1cccc(Cn2c(C(=O)O)cc3cc(Cl)ccc32)c1
Reactant: CC(C)(CN)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(Cn2c(C(=O)NCC(C)(C)CO)cc3cc(Cl)ccc32)c1
Reaction time: 0.17 h
Yield: 38.8 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (0.14 g, 0.57 mmol) and 1-hydroxybenzotriazole hydrate (HOBT) (0.1 μg, 0.59 mmol) were added to a solution of 5-chloro-1-(3-methylbenzyl)-1H-indole-2-carboxylic acid (0.20 g, 0.67 mmol) in DCM (10 ml). After stirring for 10 min, 3-amino-2,2-dimethylpropan-1-ol (0.083 g, 0.80 mmol) was added. After stirring for 17.5 h, water (10 ml) was added, the layers separated, the organic phase washed with water (3×15 ml) and dried with magnesium sulfate. Purification was achieved by silica chromatography using DCM:methanol (3:1) as eluent. Crystallisation of the crude product afforded 5-chloro-1-(3-methylbenzyl)-1H-indole-2-carboxylic acid (3-hydroxy-2,2-dimethylpropyl)amide as a white solid (0.100 g, 43%).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[NH:12][C:13](=[O:36])[CH2:14][CH:15]([NH:22][S:23]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)(=[O:25])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[NH:37]([CH3:39])[CH3:38]>>[CH3:38][N:37]([CH2:1][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[NH:12][C:13](=[O:36])[CH2:14][CH:15]([NH:22][S:23]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)(=[O:25])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:39]
Reactant: O=Cc1cccc2c1CCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Reactant: CNC
Product: CN(C)Cc1cccc2c1CCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1

Procedure:
N-(4-Dimethylaminomethyl-indan-1-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide was prepared from N-(4-formyl-indan-1-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide (Step G) and Me2NH, using essentially the same procedure described in Example 1, Step H, yielding a White solid. MS (ESI) m/z 528 (M+H)+.