Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH:8]([OH:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([OH:18])=O.[CH:19]([NH2:21])=O>O>[OH:15][CH:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:7][N:6]1[C:2]2[N:1]=[CH:19][NH:21][C:16](=[O:18])[C:3]=2[CH:4]=[N:5]1
Reactant: NC=O
Reactant: Nc1c(C(=O)O)cnn1CC(O)c1ccccc1
Solvent: O
Product: O=c1[nH]cnc2c1cnn2CC(O)c1ccccc1
Temperature: 190 °C
Yield: 69.9 %

Procedure:
A suspension of 5 (2.75 g, 10 mmol) in formamide (10 g, 333 mmol) was heated at 190° C. for 8 h and then poured in H2O (300 mL). The crude was filtered and purified by dissolving in 2M NaOH (100 mL), boiling with coal, followed by precipitation with glacial acetic acid. The solid was filtered and recrystallized from absolute ethanol to give 10 (1.79 g, 70%) as a white solid: mp 270-271° C. 1H NMR: δ 4.25-4.55 (m, 2H, CH2), 5.05-5.15 (m, 1H, CHO), 5.65 (d, 1H, OH, disappears with D2O), 7.25-7.45 (m, 5H Ar), 8.05 (s, 1H, H-3), 8.10 (s, 1H, H-6), 12.15 (br s, 1H, NH, disappears with D2O). IR cm−1: 3400 (NH), 3245-2500 (OH), 1740 (CO). Anal. (C13H12N4O2) C, H, N.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([OH:22])=[C:15]([O:23]C)[CH:14]=2)=[O:12])[CH:2]=1.[BrH:25]>>[BrH:25].[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([OH:22])=[C:15]([OH:23])[CH:14]=2)=[O:12])[CH:2]=1
Reactant: COc1cc(C(=O)c2cnc3ccccc3c2)cc([N+](=O)[O-])c1O
Agent: Br
Product: O=C(c1cc(O)c(O)c([N+](=O)[O-])c1)c1cnc2ccccc2c1
Reaction time: 3 h

Procedure:
820 mg of 4-hydroxy-3-methoxy-5-nitrophenyl (3-quinolinyl) ketone are treated with 50 ml of 48 percent hydrobromic acid and held at the reflux temperature for 3 hours. After distillation of the hydrobromic acid at 50°, the residue is treated with 70 ml of hot water and the insoluble constituent is filtered under suction. There is obtained 3,4-dihydroxy-5-nitrophenyl (3-quinolinyl) ketone hydrobromide in the form of yellow crystals of m.p. 270° (dec.).
Reaction SMILES: CS([C:5]1[N:6]=[CH:7][C:8]2[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:9]=2[N:10]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[F:27][C:28]([F:32])([F:31])[CH2:29][OH:30]>C(#N)C>[F:27][C:28]([F:32])([F:31])[CH2:29][O:30][C:5]1[N:6]=[CH:7][C:8]2[CH2:13][NH:12][CH2:11][C:9]=2[N:10]=1
Reactant: OCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1Cc2cnc(S(C)(=O)=O)nc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: FC(F)(F)COc1ncc2c(n1)CNC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the tert-butyl 2-(methylsulfonyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (300 mg) in dry acetonitrile (20 mL), 2,2,2-trifluoroethanol (1.8 mL) and cesium carbonate (815 mg) were added. The resulting mixture was stirred at room temperature for 1 h. The precipitate was removed by filtration. The solution was evaporated, and the resulting residue was purified on a Biotage Horizon® system (silica, gradient 35-65% ethyl acetate in hexanes). After concentration, tert-butyl 2-(2,2,2-trifluoroethoxy)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate was treated with HCl (4M in methanol) for 1 h. The residue was passed through an ion exchange resin (Strata-X-C™) and eluted with methanol containing 10% ammonium hydroxide to yield 2-(2,2,2-trifluoroethoxy)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine as the title compound. LC/MS 220.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(O)C.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>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH3:9]
Reactant: Brc1ccccc1I
Reactant: COc1ccccc1B(O)O
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: CCO
Solvent: COCCOC
Product: COc1ccccc1-c1ccccc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.6 %

Procedure:
2-Bromoiodobenzene (640 μL, 5.0 mmol) was added to a suspension of Pd(PPh3)4 (305 mg, 0.26 mmol) in DME (100 mL) at room temperature under argon. After 15 min at room temperature, a solution of 2-methoxyphenylboronic acid (760 mg, 5.0 mmol) in ethanol (2 mL) was added, followed by aqueous Na2CO3 (2.0 M, 5 mL, 10 mmol). The reaction vessel was fitted with a reflux condenser and heated to reflux under argon for 22.5 h. The reaction mixture was then cooled to room temperature and filtered through Celite. The filter cake was washed with ether and water, and the filtrate was concentrated in vacuo. The resulting aqueous residue was diluted with brine and extracted with ether. The ethereal layer was dried (MgSO4), filtered and concentrated. The crude residue was purified by flash chromatography on silica gel to afford 823 mg (63%) of a colorless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Br:16])[CH:11]=[C:12](I)[CH:13]=2)[C:8]([OH:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:7]1=[O:25])[CH3:2].[O:28]=[C:29]1[N:33]([CH2:34][C:35]#[CH:36])[CH:32]=[CH:31][O:30]1.CCN(CC)CC.C1(C)C=CC=CC=1>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.C1COCC1>[CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Br:16])[CH:11]=[C:12]([C:36]#[C:35][CH2:34][N:33]3[CH:32]=[CH:31][O:30][C:29]3=[O:28])[CH:13]=2)[C:8]([OH:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:7]1=[O:25])[CH3:2]
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Br)cc(I)cc21
Reactant: C#CCn1ccoc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Br)cc(C#CCn3ccoc3=O)cc21
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 76.3 %

Procedure:
To 1-(2-diethylaminoethyl)-3-hydroxy-3-(2-chlorophenyl)-4-bromo-6-iodooxindole (31.5 mg, 5.84×10−5 mol), 3-(2-Oxo-1,3-oxazolin-3-yl)-1-propyne (10.95 mg, 1.5 eq.), Pd(PPh3)2Cl2 (6.15 mg, 15 mol %) and CuI (1.7 mg, 15 mol %) under a nitrogen atmosphere was added anhydrous Et3N (0.5 mL), anhydrous toluene (0.5 mL) and anhydrous THF (0.5 mL). The resulting yellow mixture was heated to 50° C. (bath temperature) and stirred at that temperature for 1 hour and 20 minutes. The solvent was then removed in vacuo to give a yellow solid. Purification was carried out by column chromatography (silica gel, 3% MeOH in CHCl3) to yield the title compound (24.9 mg, 76%) as a white solid. The hydrochloride of the title compound was obtained by treating with 4 N HCl in dioxane followed by concentration to dryness.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13]C(=O)C.CCO.[OH-].[K+]>O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH2:13]
Reactant: COc1cc(OC)c(Cl)c(NC(C)=O)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)c(Cl)c(N)c1Cl
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a suspension of N-(2,6-Dichloro-3,5-dimethoxy-phenyl)-acetamide 15 (6.50 g, 24.61 mmol) in mixture of EtOH (80 mL) and water (30 mL), is added KOH (20 g) and stirred 2 days at 80° C. After the solvent (EtOH) is removed on vacuum, water (˜15 mL) is added, a white solid is collected by filtration and washed with water, dried to give final product 16: 1H NMR 600 MHz (CDCl3) δ 6.03 (s, 1H), 4.55 (s, 2H), 3.88 (s, 6H); MS m/z 222.00 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH2:12])=[N:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH2:12])=[N:8][N:9]([CH2:20][C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:22])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: CCOC(=O)c1c(N)n[nH]c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(N)nn(CC(=O)N2CCN(c3ccc(F)cc3)CC2)c1C

Procedure:
Protocol T was followed using 3-Amino-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4) afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): 6.94-7.1 (m, 2H), 6.84-6.88 (m, 2H), 5.52 (s, 2H), 4.78 (s, 2H), 4.24-4.32 (q, 2H), 3.74-3.82 (m, 4H), 3.0-3.1 (m, 4H), 2.3 (s, 3H), 1.31-1.38 (t, 3H). MS (ES) M+H expected 389.43, found 390.1.
Reaction SMILES: C([N:4]([C:31]1[S:32][CH:33]=[CH:34][N:35]=1)[S:5]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:18][CH2:17][C@H:16]([N:19]3[C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[CH2:22][CH2:21][CH2:20]3)[C:15]2=[O:30])=[CH:12][CH:13]=1)(=[O:7])=[O:6])C=C.CN1C(=O)CC(=O)N(C)C1=O>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].C(#N)C>[Cl:29][C:25]1[CH:24]=[C:23]2[C:28](=[CH:27][CH:26]=1)[N:19]([C@H:16]1[CH2:17][CH2:18][N:14]([C:11]3[N:10]=[CH:9][C:8]([S:5]([NH:4][C:31]4[S:32][CH:33]=[CH:34][N:35]=4)(=[O:6])=[O:7])=[CH:13][CH:12]=3)[C:15]1=[O:30])[CH2:20][CH2:21][CH2:22]2
Reactant: C=CCN(c1nccs1)S(=O)(=O)c1ccc(N2CC[C@H](N3CCCc4cc(Cl)ccc43)C2=O)nc1
Agent: [Pd]
Agent: CN1C(=O)CC(=O)N(C)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C1[C@@H](N2CCCc3cc(Cl)ccc32)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cn1
Temperature: 60 °C

Procedure:
Prepared using General Procedure 5. The (S)-N-allyl-6-(3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)pyridine-3-sulfonamide (94 mg, 0.18 mmol), 1,3-dimethylbarbituric acid (166 mg, 1.06 mmol), and palladium-tetrakis(triphenylphosphine) (42 mg, 0.036 mmol) were combined in a flask and the flask placed under N2. Acetonitrile (1.2 mL) was then added and the suspension was heated to 60° C. After 1.5 hours the suspension was filtered and concentrated. The residue was purified by mass-trigger LC/MS (10%-99% CH3CN/H2O (0.05% TFA)) over 15 minutes to yield (S)-6-(3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)pyridine-3-sulfonamide. LC/MS (10%-99% CH3CN/H2O (0.05% TFA)), m/z: M+1 obs=490.3, tR=1.81 min.
Reaction SMILES: Cl.[OH:2][C:3]1[C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[N:7]([CH2:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.[CH3:16][N:17]([CH3:22])[CH2:18]N(C)C>C(O)C>[CH3:16][N:17]([CH2:22][C:8]1[N:7]([CH2:9][C:10]([F:11])([F:12])[F:13])[C:6]([CH3:14])=[CH:5][C:4](=[O:15])[C:3]=1[OH:2])[CH3:18]
Reactant: Cc1cc(=O)c(O)cn1CC(F)(F)F
Reactant: CN(C)CN(C)C
Agent: Cl
Solvent: CCO
Product: Cc1cc(=O)c(O)c(CN(C)C)n1CC(F)(F)F
Temperature: 80 °C
Yield: 70 %

Procedure:
5-Hydroxy-2-methyl-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one hydrochloride (415 mg, 1.7 mmol) was mixed with N,N,N′,N′-tetramethylmethanediamine (4 mL) in ethanol (10 mL) and heated at 80° C. for 21 hours. The reaction mixture was concentrated by rotary evaporator and the residue was triturated with water to give 2-[(dimethylamino)methyl]-3-hydroxy-6-methyl-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (315 mg) as white solid. Yield=70%; 1H NMR (DMSO-D6+D2O, 90 MHz) δ (ppm): 6.20 (s, 1H), 5.15 (q, J=8.8 Hz, 2H), 4.69 (br. s, 2H) and 2.37 (s, 3H); MS m/z 265 [M+1]+.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:34])([CH3:33])[C:8]12[O:15][C:12]([C:16]([CH3:24])([CH3:23])[O:17][SiH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH:13]=[CH:14]1)[CH2:11][C:10](OS(C(F)(F)F)(=O)=O)=[CH:9]2)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[C:1]([SiH2:5][O:6][C:7]([CH3:34])([CH3:33])[C:8]12[O:15][C:12]([C:16]([CH3:23])([CH3:24])[O:17][SiH2:18][C:19]([CH3:21])([CH3:22])[CH3:20])([CH:13]=[CH:14]1)[CH2:11][C:10]([C:43]1[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=1)=[CH:9]2)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CC(C)(C)[SiH2]OC(C)(C)C12C=CC(C(C)(C)O[SiH2]C(C)(C)C)(CC(OS(=O)(=O)C(F)(F)F)=C1)O2
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: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)[SiH2]OC(C)(C)C12C=CC(C(C)(C)O[SiH2]C(C)(C)C)(CC(c3ccc(N)cc3)=C1)O2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a mixture of trifluoromethanesulfonic acid 1,5-bis-(tert-butyl-dimethyl-silanyloxymethyl)-8-oxa-bicyclo[3.2.1]octa-2,6-dien-3-yl ester (as prepared in the previous step, 1.22 g, 2.24 mmol), Pd(PPh3)4 (259 mg, 0.224 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (540 mg, 2.46 mmol) in 20 mL of 1,4-dioxane was added 2.0 M aqueous Na2CO3 solution (9.0 mL, 18 mmol). The resulting mixture was stirred at 80° C. for 2 h and then cooled to RT. Treated with 100 mL of EtOAc, the mixture was washed with H2O (3×20 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1:1 hexane/DCM-DCM) gave 802 mg (73% for two steps) of the title compound as a light brown oil. Mass spectrum (ESI, m/z): Calcd. for C27H45NO3Si2, 488.3 (M+H), found 488.4.
Reaction SMILES: C(OC([NH:11][C:12]1[C:13]([C:29]([NH:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][C:37]=2[N:38]2[CH2:43][C@H:42]([CH3:44])[C@H:41]([NH:45][C:46](=[O:49])[O:47][CH3:48])[C@H:40]([NH:50]C(=O)OC(C)(C)C)[CH2:39]2)=[O:30])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH:16]=2)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:50][C@H:40]1[C@@H:41]([NH:45][C:46](=[O:49])[O:47][CH3:48])[C@@H:42]([CH3:44])[CH2:43][N:38]([C:37]2[CH:36]=[CH:35][N:34]=[CH:33][C:32]=2[NH:31][C:29]([C:13]2[C:12]([NH2:11])=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:30])[CH2:39]1
Reactant: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)CC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)N[C@@H]1[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)CC4)ccc3cc2N)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
To a solution of tert-butyl methyl {(3R,4S,5S)-1-[3-({[3-{[(benzyloxy)carbonyl]amino}-7-(4-methylpiperazin-1-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-5-methylpiperidine-3,4-diyl}biscarbamate (62 mg, 0.080 mmol) in MeOH (3.0 mL), 10% Pd on carbon (15 mg) was added. The reaction mixture was deoxygenated under reduced pressure and hydrogen was introduced via a balloon. The reaction mixture was stirred at room temperature under the hydrogen balloon for 1 h. The mixture was filtered and concentrated under reduced pressure. The resulting residue was dissolved in DCM (2 mL), and TFA (2 mL) was added. The resulting mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure. The residue was purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the title compound as a yellow powder (29 mg, 65%). LCMS calc. for C28H38N9O3 (M+H)+: m/z=548.3. Found: 548.4.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([CH3:31])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]1[CH2:62][CH2:61][CH:60]([NH2:63])[CH2:59][CH2:58]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:63][CH:60]5[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]5)=[O:27])=[C:24]([CH3:31])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: Cc1cc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)ccc1C(=O)NC1CCN(C)CC1

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-methylbenzoic acid as described in the general procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36-1.77 (m, 11H) 1.98 (m, 4H) 2.16 (s, 3H) 2.31 (s, 3H) 2.75 (d, J=11 Hz, 2H) 3.17 (br. s., 2H) 3.67 (d, J=7 Hz, 1H) 4.03 (t, J=14 Hz, 3H) 4.81 (m, 1H) 7.22 (d, J=8 Hz, 1H) 7.46 (d, J=8 Hz, 1H) 7.68 (br. s., 1H) 7.99 (d, J=8 Hz, 1H) 8.25 (s, 1H) 9.51 (br. s., 1H). [M+H] calc'd for C27H35F2N7O2, 528. found 528.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:43])([CH3:42])[CH2:6][N:7]([S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][CH3:41])[CH:35]=1)(=[O:33])=[O:32])[CH2:8][C@@H:9]([OH:30])[C@@H:10]([NH:18][C:19](=[O:29])[O:20][C@@H:21]1[C@H:28]2[C@H:24]([O:25][CH2:26][CH2:27]2)[O:23][CH2:22]1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C.[CH3:53][N:54]([CH3:58])[C:55](Cl)=[O:56]>C1COCC1>[CH2:11]([C@H:10]([NH:18][C:19](=[O:29])[O:20][C@@H:21]1[C@H:28]2[C@H:24]([O:25][CH2:26][CH2:27]2)[O:23][CH2:22]1)[C@H:9]([OH:30])[CH2:8][N:7]([CH2:6][C:5]([CH3:43])([CH3:42])[CH2:4][CH2:3][CH2:2][NH:1][C:55]([N:54]([CH3:58])[CH3:53])=[O:56])[S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][CH3:41])[CH:35]=1)(=[O:33])=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCN)c1
Reactant: CN(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCNC(=O)N(C)C)c1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A solution of 50 mg (0.081 mmol) of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-3-((5-amino-2,2-dimethylpentyl)[3-(methylamino)phenyl]sulfonylamino)-1-benzyl-2-hydroxypropyl]carbamate and 17 μL (0.097 mmol) of N,N-diisopropylethylamine in 5 mL of anhydrous THF at 0° C. was treated with 8.2 μL (0.089 mmol) of N,N-dimethylcarbamyl chloride. The solution was allowed to warm to RT with stirring. After 18 hours the solution was concentrated in vacuo and the residue was subjected to flash chromatography (SiO2, 95:5 CH2Cl2/2M NH3 in MeOH) to afford 44 mg (79%) of the desired compound as a white foam. H1-NMR (CDCl3): δ 7.31-7.11 (m, 6H), 7.03 (d, 1H), 6.95 (s, 1H), 6.73 (d, 1H), 5.92 (d, 1H), 5.60 (d, 1H), 4.94 (q, 1H), 4.63 (t, 1H), 4.19 (m, 2H), 3.94-3.73 (m, 4H), 3.63 (m, 2H), 3.30-3.00 (m, 6H), 2.91-2.78 (m, 11H), 2.69 (dd, 1H), 1.59-1.19 (m, 6H), 0.94 (s, 3H), 0.86 (s, 3H). MS(ESI): 690(M+H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]=[C:17]([C:24]3[CH:28]=[CH:27][S:26][CH:25]=3)[C:16]=2[CH:29]=1.CC(C1C=C(C(C)C)C(S([N:45]=[N+:46]=[N-:47])(=O)=O)=C(C(C)C)C=1)C.C(O)(=O)C>>[N:45]([CH:19]1[N:18]=[C:17]([C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)[C:16]2[CH:29]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[N:21]([CH3:22])[C:20]1=[O:23])=[N+:46]=[N-:47]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: CN1C(=O)CN=C(c2ccsc2)c2cc(Cl)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Product: CN1C(=O)C(N=[N+]=[N-])N=C(c2ccsc2)c2cc(Cl)ccc21
Yield: 97.4 %

Procedure:
As illustrated in the scheme above and following General Procedure 6, KHMDS (10.4 mL of 0.5 M in toluene, 5.20 mmol), 7-chloro-1,3-dihydro-1-methyl-5-(3-thienyl)-2H-1,4-benzodiazepin-2-one (1.44 g, 4.95 mmol), trisyl azide (3.83 g, 12.4 mmol) and acetic acid (1.25 mL, 21.8 mmol) were combined. After workup, purification of the crude product by silica gel column chromatography (7:3 hexanes:EtOAc) provided the title compound as a pale yellow solid (1.60 g, 98%). 1H-NMR (CDCl3): δ 7.61-7.55 (m, 4H), 7.40 (dd, J=2.9 Hz, J=5.1 Hz, 1H), 7.33 (dd, J=1.0 Hz, J=8.2 Hz, 1H), 4.54 (s, 1H), 3.44 (s, 3H). MS (ESI) (M+H)+=332.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C.CCOC(C)=O>[C:14]1([S:20]([N:1]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=3[CH:3]=[CH:2]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1

Procedure:
1H-Indole-4-carbaldehyde (24.8 g, 0.17 mol) was dissolved in dry DMF (500 ml), cooled in ice-bath and NaH (7.5 g (60% suspension in oil), 0.19 mol, 1.1 eq.) was added. After stirring for a few minutes, the cold bath was removed and the r×n mixture was stirred at room temperature for 40 min. under Ar. The insoluble NaH clumps were brought in solution by means of sonication for a few minutes. The mixture was cooled in ice-bath and benzenesulfonyl chloride (23.9 ml, 0.188 mol, 1.1 e.q.) was added dropwise over 3 min. The reaction mixture was stirred at room temperature for 1 hour, then poured slowly into a mixture of water (1 L) and EtOAc (200 ml). The aqueous phase was extracted with EtOAc (5×100 ml), the organic phase was washed with brine (200 ml), dried over Na2SO4 and evaporated. The residue was purified on silica flash column using petroleum ether/EtOAc (1:1) giving the product as a colorless crystalline solid. Yield: 45.5 g. MS m/z 286 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[CH3:9][O:10][P:11]([O-:14])[O:12][CH3:13].Cl[Si](Cl)(C)C>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH2:2][P:11](=[O:14])([O:12][CH3:13])[O:10][CH3:9]
Reactant: C=Cc1ccccn1
Reactant: COP([O-])OC
Agent: C[Si](C)(Cl)Cl
Product: COP(=O)(CCc1ccccn1)OC
Yield: 46.5 %

Procedure:
A dry r. b. flask was loaded with 108 ml of 20 vinylpyridine (1 mole) and 92 ml of dimethylphosphite (1 mole) under nitrogen. Dropwise addition of 25 ml of dichlorodimethylsilane (0.21 mole) gave exothermic reaction to 86° C. even with ice bath cooling. Once the exotherm subsided the reaction mixture was fitted for vacuum distillation. A possible exotherm was noted around 98° C. The distillation was shut down, the traps cleaned, and distillation recommenced giving 100 g dimethyl 2-(2-pyridyl)ethylphosphonate b0.2 =131-146° C. as a yellow fluid. Proton NMR in CDC13 /TMS showed a 2H 1:1 doublet at 3.7 ppm, and 4.5 aromatic H as multiplets between 7.1 and 9.6 ppm.