Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1.Cl[P:32](Cl)[C-:33]1[CH:37]=[CH:36][CH:35]=[CH:34]1.[C-:39]1([P:44](Cl)Cl)[CH:43]=[CH:42][CH:41]=[CH:40]1.[Fe+2:47]>C(OCC)C.C1COCC1>[C:11]1([C@@H:9]2[C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][P:32]([C-:33]3[CH:37]=[CH:36][CH:35]=[CH:34]3)[O:10]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C-:39]1([P:44]2[O:8][C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C@@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10]2)[CH:43]=[CH:42][CH:41]=[CH:40]1.[Fe+2:47]
Reactant: O[C@H](c1ccccc1)[C@H](O)c1ccccc1
Reactant: ClP(Cl)[c-]1cccc1
Agent: [Fe+2]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: c1ccc([C@H]2OP([c-]3cccc3)O[C@@H]2c2ccccc2)cc1

Procedure:
At −78° C., 651 mg (3.04 mmol) of (R,R)-hydrobenzoin is charged in a vessel together with 1.0 ml of abs. triethylamine (6.63 mmol) in 150 ml of abs. toluene. A solution of 425 mg (0.80 mmol) of 1,1′-bis(dichlorophosphino)ferrocene (X) in 25 ml of abs. THF is added dropwise within 2 h. Then, thawing is allowed slowly in a cooling bath over night with stirring. The solution obtained is completely freed from solvent, and the orange solid is taken up in 200 ml of abs. diethyl ether. Insolubles are separated off by filtration through a P4 frit with Celite 545® as a filtering aid. The clear orange filtrate is completely freed from solvent to obtain an orange solid. Analytical results: 1H NMR (d8-THF, 300 MHz): 7.40 (s) [8H], 7.36-7.30 (m) [6H], 7.29-7.23 (m) [4H], 7.22-7.11 (m) [6H], 5.05 (d) JH-P=8.1 Hz [2H], 4.95 (d) JH-P=9 Hz [2H], 4.82-4.60 (m) [8H]; 31P NMR (d8-THF, 121 MHz): 181.7 (s).
Reaction SMILES: C([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[C:31]([Br:39])=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:40])(=[O:15])=[O:14])=[CH:9][C:8]=1[OH:41])(C)(C)C.[C:43](O)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[N:46][CH:45]=1.[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[C:31]([Br:39])=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:40])(=[O:15])=[O:14])=[CH:9][C:8]=1[O:41][C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[N:46][CH:45]=1)([OH:5])=[O:42]
Reactant: O=C(O)c1cccnc1
Reactant: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Product: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)O)c(OC(=O)c2cccnc2)c1
Yield: 80 %

Procedure:
The title compound was prepared according to the procedure in Example 25, step 1, using 4-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.500 g, 0.749 mmol), nicotinic acid (0.092 g, 0.749 mmol), 2-chloro-1-methylpyridinium iodide (0.230 g, 0.899 mmol) and triethylamine (0.251 mL, 1.80 mmol). Purification on Biotage KP-Sil eluting with 20% EtOAc/hexane gave 0.460 g, (80%) of the title compound. 1H NMR (DMSO-d6) 6 1.34 (s, 9 H), 1.55 (s, 3 H), 2.16 (s, 6 H), 2.36 (s, 3 H), 7.19 (s, 2 H), 7.45-7.46 (m, 2 H), 7.61-7.71 (m, 2 H), 8.12-8.25 (m, 4 H), 8.50 (ddd, 1 H), 8.94 (d, 1 H), 9.29 (s, 1 H).
Reaction SMILES: Cl.[C:2]([O:5][C@H:6]1[C@H:11]([NH2:12])[C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[C@H:9]([O:17][C:18](=[O:20])[CH3:19])[C@@H:8]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:7]1)(=[O:4])[CH3:3].C(N(CC)CC)C.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl>[C:2]([O:5][C@H:6]1[C@H:11]([NH:12][C:36](=[O:37])[CH2:35][O:34][CH3:33])[C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[C@H:9]([O:17][C:18](=[O:20])[CH3:19])[C@@H:8]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:7]1)(=[O:4])[CH3:3]
Reactant: COCC(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
To a suspension of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-amino-tetrahydro-2H-pyran-2,4,5-triyl triacetate hydrochloride (0.500 g, 1.31 mmol) in CH2Cl2 (20 mL) was added triethylamine (0.544 mL, 3.915 mmol), followed by 2-methoxyacetyl chloride (0.13 mL, 1.44 mmol). The reaction was stirred at room temperature for 18 h. The reaction mixture was washed once with saturated aqueous NaHCO3 (3 mL) and once with brine (3 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification of the crude material by flash chromatography on silica gel (5:1 EtOAc:hexanes) afforded (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(2-methoxyacetamido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white solid (0.380 g, 70% yield).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[CH3:9][O:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]2[S:23][C:22]([SH:24])=[N:21][N:20]=2)=[C:13]([N+:25]([O-:27])=[O:26])[CH:12]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:9][O:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]2[S:23][C:22]([S:24][CH3:1])=[N:21][N:20]=2)=[C:13]([N+:25]([O-:27])=[O:26])[CH:12]=1
Reactant: COc1cc(-c2nnc(S)s2)c([N+](=O)[O-])cc1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc(SC)s2)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.6 %

Procedure:
Potassium carbonate (13.8 mg, 1.0 mmol) and 0.0624 ml (1.0 mmol) of methyl iodide were added to a solution of 150 mg (0.510 mmol) of 5-(4,5-dimethoxy-2-nitrophenyl)-1,3,4-thiadiazole-2-thiol produced in Reference Example 2 in N,N-dimethylformamide (2 ml), and the mixture was stirred at room temperature for 10 min. The mixture was diluted with 30 ml of ethyl acetate, and the diluted solution was washed with 30 ml of a 10% aqueous ammonium chloride solution and 30 ml of saturated brine. The organic layer was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure, and the resultant crystal was washed with diisopropyl ether to give 140 mg (yield 89%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](F)=[O:7].[CH3:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([NH2:24])[C:20]=1[C:21]([OH:23])=[O:22].C(N(CCCC)CCCC)CCC.ClCC(Cl)C>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:24][C:19]1[C:20](=[C:15]([CH3:14])[CH:16]=[CH:17][CH:18]=1)[C:21]([OH:23])=[O:22])=[O:7]
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: O=C(F)c1cccc(C(F)(F)F)c1
Solvent: CC(Cl)CCl
Solvent: CCCCN(CCCC)CCCC
Product: Cc1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1C(=O)O
Reaction time: 0.33 h

Procedure:
15.4 parts of 3-trifluoromethylbenzoyl fluoride are added to a stirred mixture of 13.3 parts of 6-methylanthranilic acid and 16.3 parts of tri-n-butylamine in 250 parts of 1,2-dichloropropane at 20°-25° C., and stirring is continued for 20 minutes. The precipitate formed is filtered off and washed with 1 N hydrochloric acid and then with water; the organic filtrate is washed similarly, dried and evaporated down. 27 parts of N-(3'-trifluoromethylbenzoyl)-6-methylanthranilic acid, of melting point 198°-204° C., are obtained.
Reaction SMILES: C([O:8][CH2:9][CH:10]([CH2:30][O:31]CC1C=CC=CC=1)[O:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1)C1C=CC=CC=1>CO>[C:26]([O:25][C:23]([NH:22][C@H:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH:10]([CH2:9][OH:8])[CH2:30][OH:31])=[CH:13][CH:14]=1)[C:19]([OH:21])=[O:20])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC(COCc2ccccc2)COCc2ccccc2)cc1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC(CO)CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A hydrogenation vessel containing a solution of (R)-[4-(2-benzyloxy-1-benzyloxymethyl-ethoxy)-phenyl]-tert-butoxycarbonylamino-acetic acid (3.86 g, 7.4 mmol) in methanol (30 mL) was purged with nitrogen and 10% palladium on carbon (300 mg) added. The atmosphere above the methanol solution was exchanged for hydrogen and the reaction mixture stirred vigorously for 30 minutes at ambient temperature. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to give (R)-tert-butoxycarbonylamino-[4-(2-hydroxy-1-hydroxymethyl-ethoxy)-phenyl]-acetic acid which was used without additional purification (2.43 g, 96%). HR-MS: calcd for C30H28FlN4O5 [M+H+] 671.1161. Found 671.1158.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[CH:30]=[CH:31][C:32]([O:34][Si](C(C)(C)C)(C)C)=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:42])[CH2:15][N:14]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[CH:30]=[CH:31][C:32]([OH:34])=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:42])[CH2:15][N:14]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])[CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CN(OC(C)(C)C)C1)C2c1ccc(Sc2nc3cc(O[Si](C)(C)C(C)(C)C)ccc3[nH]2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CN(OC(C)(C)C)C1)C2c1ccc(Sc2nc3cc(O)ccc3[nH]2)o1
Yield: 67.5 %

Procedure:
6-tert-Butyloxy-9-{5-[5-(tert-butyl-dimethyl-silanyloxy)-1H-benzimidazol-2-ylsulfanyl]-furan-2-yl}-8-oxo-2,4,5,7,8,9-hexahydro-pyrrolo[3,4-b]-1,7-naphthyridine-3-carboxylic acid ethyl ester (0.5 g, 0.71 mmol) is treated with tetra-N-butylammonium fluoride (0.185 g, 0.71 mmol) in tetrahydrofuran (5 ml) for 4 hours at room temperature. The reaction mixture is concentrated under reduced pressure and the residue is purified on a silica gel column (40 g) eluted with a mixture of dichloromethane and methanol (9/1, v/v). The fractions containing the expected product are concentrated under reduced pressure and the solid obtained is washed with actonitrile (30 ml), pentane (30 ml) and dried under vacuum to yield 270 mg of 6-tert-butyloxy-9-[5-(5-Hydroxy-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-2,4,5,7,8,9-hexahydro-pyrrolo[3,4-b]-1,7-naphthyridine-3-carboxylic acid ethyl ester. Yield=64%. Analytical LC/MS (method B): retention time=3.34 min., m/z=592.31 (positive ion mode).
Reaction SMILES: [CH2:1]1[C:15](=O)[C:14]2[C:5](=[C:6]([OH:18])[C:7]3[C:12]([C:13]=2[OH:17])=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3](=O)[CH2:2]1.[NH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH:24]([CH2:28][OH:29])[CH2:23]1>C(O)C>[OH:29][CH2:28][CH:24]1[CH2:25][CH2:26][CH2:27][N:22]([CH2:21][CH2:20][NH:19][C:15]2[C:14]3[C:13](=[O:17])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6](=[O:18])[C:5]=3[C:3]([NH:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH:24]([CH2:28][OH:29])[CH2:23]3)=[CH:2][CH:1]=2)[CH2:23]1
Reactant: NCCN1CCCC(CO)C1
Reactant: O=C1CCC(=O)c2c1c(O)c1ccccc1c2O
Solvent: CCO
Product: O=C1c2ccccc2C(=O)c2c(NCCN3CCCC(CO)C3)ccc(NCCN3CCCC(CO)C3)c21

Procedure:
Although not shown in scheme 3, the method follows that of HAQ70 using leucoquinizarin (0.23 g, 0.95 mmol), [1-(2-aminoethyl)-piperidin-3-yl-]methanol (0.06 g, 3.8 mmol) and ethanol (25 mL). The title compound was yielded as a dark-blue solid (0.15 g, 29%). M.p. 112-114° C.; δH(250 MHz; CDCl3); 1.15 (m, 2H, 2×CH2CHCH2OH), 1.5-1.75 (m, 6H, 2×CH2CH2CH and 2×CH2CH2CH2), 1.85 (m, 2H, 2×CH2CH2CH), 2.3 (m, 4H, 4×ring-H), 2.5 (s (broad), 4H, 2×ring-H, 2×OH), 2.65 (t, 4H, J=5 Hz, 2×HNCH2CH2N), 2.75 (2×d, 2H, J=3 Hz and 12 Hz, 2×ring-H), 3.42 (q, 4H, J=5 Hz, 2×HNCH2CH2N), 3.55 (2×d, 2H, J=5 Hz and 12 Hz, 2×CHCH2OH), 3.7 (2×d, 2H, J=9 Hz and 12 Hz, 2×CHCH2OH), 7.1 (s, 2H, C(2)H and C(3)H), 7.6 (m, 2H, C(6)H and C(7)H), 8.3 (m, 2H, C(5)H, C(8)H) and 10.75 (t, 2H, C(1)NH and C(4)NH); δC(62.9 MHz; CDCl3); 24.08, 26.92, 37.90, 40.52, 54.43, 56.95, 57.75, 65.70, 109.89, 123.87, 126.13, 132.09, 134.46, 146.6 and 182.36; FAB MS, m/z(M+H)+ 521; IR υmax/cm−1; 3400 (OH), 3090 (Ar—CH), 2960-2800 (CH2, CH3), 1650, 1585, 1550, 1520, 1265, 1175 and 1125; Anal. calcd for C30H40N4O4: C, 69.21; H, 7.74; N, 10.76. Found: C, 69.22; H, 7.88; N, 10.69.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].Cl.[N:20]1([C:26]([CH2:28][CH2:29][NH2:30])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C.O>C(#N)C>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:30][CH2:29][CH2:28][C:26]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:27])[N:6]=1)[CH:2]=[CH2:3]
Reactant: NCCC(=O)N1CCCCC1
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: C=CCNc1nc(NCCC(=O)N2CCCCC2)nc2ccc([N+](=O)[O-])cc12
Yield: 87.2 %

Procedure:
150 mg (0.57 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline was dissolved in 10 ml of acetonitrile, and then 220 mg (1.14 mmol) of 2-piperidinocarbonylethylamine hydrochloride and 0.40 ml (2.85 mmol) of triethylamine were added thereto, followed by heating under reflux overnight. To the reaction solution was added water, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 191 mg (87.7%) of the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[O:29][CH3:30])[C:15]3[S:19][N:18]=[CH:17][N:16]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[C:34]([C:41]2[N:45]([CH3:46])[N:44]=[CH:43][CH:42]=2)[CH:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[C:10]3[C:5](=[CH:6][C:7]([S:11]([N:14]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH3:30])[C:15]4[S:19][N:18]=[CH:17][N:16]=4)(=[O:13])=[O:12])=[CH:8][CH:9]=3)[NH:4][CH:3]=2)=[C:34]([C:41]2[N:45]([CH3:46])[N:44]=[CH:43][CH:42]=2)[CH:33]=1
Reactant: Cn1nccc1-c1cc(Cl)ccc1B(O)O
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)c[nH]c3c2)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4-c4ccnn4C)c[nH]c3c2)c(OC)c1
Temperature: 90 °C
Yield: 72.6 %

Procedure:
A microwave vial was charged with 3-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (83.6 mg, 0.164 mmol), (4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenyl)boronic acid (Intermediate F) (50.4 mg, 0.213 mmol), potassium phosphate (105 mg, 0.492 mmol), and Pd(AmPhos)2Cl2 (5.81 mg, 8.21 μmol). The vial was flushed with Ar, then dioxane (0.6 mL) and water (0.2 mL) were added. The vial was sealed and heated in a microwave reactor for 20 min at 90° C. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The crude product was purified by chromatography on silica gel (0 to 100% EtOAc/Heptane) to give 3-(4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (74 mg, 0.119 mmol, 72.6% yield) as an off-white foam. 1H NMR (400 MHz, DMSO-d6) δ=11.81 (s, 1 H), 8.34 (s, 1 H), 8.01-7.94 (m, 1 H), 7.70-7.58 (m, 3 H), 7.55-7.51 (m, 1 H), 7.45 (dd, J=1.9, 8.6 Hz, 1 H), 7.36 (d, J=1.9 Hz, 1 H), 7.16 (s, 1 H), 6.91 (d, J=8.4 Hz, 1 H), 6.45 (d, J=2.4 Hz, 1 H), 6.37 (dd, J=2.4, 8.5 Hz, 1 H), 6.28 (d, J=1.9 Hz, 1 H), 5.08 (s, 2 H), 3.72 (s, 3 H), 3.68 (s, 3 H), 3.21 (s, 3 H). m/z (ESI) 621.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:10]=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=[CH:13][C:14]=2[OH:15])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].C1(=O)O[CH2:31][CH2:30][O:29]1.Cl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:10]=[C:11]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:12]=[CH:13][C:14]=2[O:15][CH2:31][CH2:30][OH:29])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCCO1
Reactant: Oc1ccc(-c2ccccc2)cc1Sc1cccc(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccc(-c2ccccc2)cc1Sc1cccc(F)c1
Temperature: 100 °C

Procedure:
3-(3-Fluoro-phenylsulfanyl)-biphenyl-4-ol (2.65 g, 8.94 mmol) and potassium carbonate (2.113 g, 15.3 mmol) was dissolved in DMF (30 mL). Ethylene carbonate (1.601 g, 18.2 mmol) was added and the reaction was heated at 100° C. for 150 minutes. The solution was allowed to cool before the solution was carefully poured into 2M HCl (50 mL). The product was extracted with diethyl ether (50 mL). The separated organic phase was washed with water (4×50 mL), 4% aq. MgSO4, brine and then the separated organic phase was dried (MgSO4). The title product was isolated after concentration in vacuo. Yield: 2.96 g, 97%
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:3][C@H:2]([C@H:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Reactant: O=Cc1ccccc1
Product: C[C@@H](C(=O)n1c(=O)oc2ccccc21)[C@H](O)c1ccccc1

Procedure:
Prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolinone with benzaldehyde; mp 155-158° C. 1H NMR (CDCl3) δ 8.10 (m, 1H), 7.45 (m, 2H), 7.35 (m, 2H), 7.26 (m, 4H), 5.30 (d, 1H), 4.26 (dq, J=3,6 Hz, 1H), 1.26 (d, 3H). 13C NMR (CDCl3) δ 175.6, 151.0, 142.2, 141.0, 128.4, 127.7, 126.0, 125.5, 124.9, 116.3, 110.0, 73.2, 46.0, 10.3.
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18](=[N:22][O:23][CH3:24])[CH2:17][CH2:16]3)[CH:12]=1)=[O:7])(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH3:24][O:23][N:22]=[C:18]1[C:19]2[C:15](=[CH:14][C:13]([C:11]3[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[O:9][C:10]=3[C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:16][CH2:17]1
Reactant: CON=C1CCc2cc(-c3cc(C(=O)OC(C)(C)C)oc3-c3ccncc3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CON=C1CCc2cc(-c3cc(C(=O)O)oc3-c3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from Step 2 (4.74 g, 11.7 mmol) was dissolved in trifluoroacetic acid (50 ml) and dichloromethane (50 ml). The solution was stirred at room temperature for 3 hours and then evaporated in vacuo, azeotroping three times with dichloromethane. The resulting solid was triturated with diethyl ether, filtered and dried to afford the title product (5.46 g), which was used without further purification; MS (AP−) m/e 347 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C-:19]#[N:20].C([Al+]CC)C.C1(C)C=CC=CC=1>C1COCC1>[C:19]([CH:7]([C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:20]
Reactant: [C-]#N
Reactant: CCOC(=O)C(=Cc1ccc(C)s1)C(=O)OCC
Agent: CC[Al+]CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(C#N)c1ccc(C)s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 50.60 g (0.189 moles) sample of diethyl 2-[(5-methyl-2-thienyl)methylene]propanedioate, the product of Example 1a., was taken up in 560 ml dry THF. The solution was cooled in an ice bath. 560 ml of 1N diethyl aluminum cyanide in toluene (0.57 moles) was added dropwise over one hr. The ice bath was then removed and the reaction was stirred at room temperature for 1.5 hr. After this time the reaction was cooled again in an ice bath and 168 ml of 3N sodium hydroxide was added slowly. This was stirred for one hr. The reaction was partitioned between methylene chloride and water, the organics were washed with water, brine, and dried (MgSO4). The solvents were evaporated in vacuo. The residue was distilled in a Kugelrohr at 140° C. and 0.005 mm Hg. 117.17 g of diethyl 2-[cyano(5-methyl-2-thienyl)methyl]-propanedioate was collected as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:11]=[C:5]2[NH:4][C:3]1=[O:29].Br[CH2:31][C:32]1[C:33]([CH3:38])=[N:34][O:35][C:36]=1[CH3:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:38][C:33]1[C:32]([CH2:31][N:4]2[C:5]3=[N:11][N:10]([CH2:12][C:13]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH:16]=[CH:15][CH:14]=4)[C:9]([C:23]4[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=4)=[C:6]3[C:7](=[O:8])[N:2]([CH3:1])[C:3]2=[O:29])=[C:36]([CH3:37])[O:35][N:34]=1
Reactant: Cc1noc(C)c1CBr
Reactant: Cn1c(=O)[nH]c2nn(Cc3cccc4ccccc34)c(-c3ccncc3)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1c(=O)n(C)c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-methyl-2-(1-naphthylmethyl)-3-pyridin-4-yl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 4-(bromomethyl)-3,5-dimethylisoxazole using potassium carbonate as abase in DMF at 80° C. Mass: 492.94 (M+H).
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[Br:15][C:16]1[C:17]2[CH:43]=[CH:42][CH:41]=[CH:40][C:18]=2[O:19][C:20]=1[C:21]1[C:22]([CH3:39])=[N:23][N:24]2[C:29]3[N:30]([CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH2:31][CH2:32][C:28]=3[C:27]([CH3:38])=[N:26][C:25]=12>C(Cl)Cl>[Br:15][C:16]1[C:17]2[CH:43]=[CH:42][CH:41]=[CH:40][C:18]=2[O:19][C:20]=1[C:21]1[C:22]([CH3:39])=[N:23][N:24]2[C:29]3[N:30]([CH:33]([CH2:34][CH3:35])[CH2:36][CH3:37])[CH:31]=[CH:32][C:28]=3[C:27]([CH3:38])=[N:26][C:25]=12
Reactant: CCC(CC)N1CCc2c(C)nc3c(-c4oc5ccccc5c4Br)c(C)nn3c21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: CCC(CC)n1ccc2c(C)nc3c(-c4oc5ccccc5c4Br)c(C)nn3c21
Reaction time: 1 h
Yield: 68.2 %

Procedure:
DDQ (33 mg, 0.15 mmol) was added to a solution of 3-(3-bromobenzo[b]furan-2-yl)-8-(1-ethylpropyl)-2,5-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (60 mg, 0.13 mmol) in methylene chloride (10 mL) at room temperature, followed by stirring for one hour. After overnight, the residue was purified by silica gel column chromatography (10% ethyl acetate/hexane), to give the title compound (40 mg) as a reddish brown oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Si]([O:15][CH2:16][CH2:17][N:18]1[C:24]2[N:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]2[CH:29]=[CH:30][CH:31]=[CH:32][C:21]=2[CH:20]([NH:33][C:34](=[O:45])[C@@H:35]([NH:37]C(=O)OC(C)(C)C)[CH3:36])[C:19]1=[O:46])(C(C)(C)C)(C)C.ClCCl>CO>[NH2:37][C@@H:35]([CH3:36])[C:34]([NH:33][CH:20]1[C:21]2[CH:32]=[CH:31][CH:30]=[CH:29][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[N:25][C:24]=2[N:18]([CH2:17][CH2:16][OH:15])[C:19]1=[O:46])=[O:45]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1C(=O)N(CCO[Si](C)(C)C(C)(C)C)c2ncccc2-c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C[C@H](N)C(=O)NC1C(=O)N(CCO)c2ncccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 102 %

Procedure:
Add trifluoroacetic acid (30 mL, 396.76 mmol) over 5 minutes to a 0° C. solution of tert-butyl N-[(1S)-2-[[5-[2-(tert-butyl(dimethyl)silyl)oxyethyl]-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]carbamate (5.56 g, 10.0 mmol) and dichloromethane (30 mL) and allow to warm and stir at ambient temperature for 5 hours. Purify the residue by flash chromatography via SCX® columns (Isolute SCX-2×6) eluting with methanol followed by ethyl acetate: methanol (2N ammonia) (1:1) to obtain the title compound as a white solid (3.48 g, 10.2 mmol) in quantitative yield. MS (m/z): 341 (M+1).