Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1)([O-:12])=[O:11]>CC(C)=O>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:21])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: CCCCC(=N)N
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1ccc([N+](=O)[O-])cc1

Procedure:
Following a procedure similar to that described in Example 1 but using 3.39 g. sodium in 200 ml. dry acetone, 20 g. valeramidine hydrochloride, and 21.9 g. 4-nitrophenyl isocyanate in 100 ml. dry acetone, there was obtained after recrystallization from methyl alcohol 10.8 g. of the hydrochloride of 1-(4-nitrophenyl)-3(-pentanimidoyl)urea; m.p. 187°-191°C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](C1NC=CN=1)=[O:29])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl-].[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42][S:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][NH3+:64].CCN(CC)CC>CN(C=O)C>[N+:13]([C:10]1[CH:9]=[CH:8][C:7]([O:6][P:4]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:29])[NH:64][CH2:63][CH2:62][O:61][CH2:60][CH2:59][O:58][CH2:57][CH2:56][O:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][S:43][S:42][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=2)(=[O:5])[O:3][CH2:1][CH3:2])=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: CCOP(=O)(CCCCCCCCCCCOC(=O)c1ncc[nH]1)Oc1ccc([N+](=O)[O-])cc1
Reactant: [NH3+]CCOCCOCCOCCCCCCCCCCCSSc1ccccn1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCCCCCCCCCCOC(=O)NCCOCCOCCOCCCCCCCCCCCSSc1ccccn1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 66 h

Procedure:
A solution of phosphonate 17 (68 mg, 0.14 mmol), amino disulfide 18 (60 mg, 0.13 mmol), and Et3N (35 mL, 0.25 mmol) dissolved in DMF was stirred at 60° C. for 66 h. After concentration of the reaction mixture, the crude residue was purified by column chromatography (hexane/EA=1:1) to afford the disulfide, which contained approximately 20% starting materials. ′H NMR (CDCl3, 500 MHz) δ 8.44 (s, 1H), 8.32 (s, 1H), 8.21 (d, J=9 Hz, 2H), 7.78 (br s, 1H), 7.70 (br s, 1H), 7.32 (d, J=9.0 Hz, 2H), 7.07 (br s, 1H), 4.15 (m, 2H), 3.98 (m, 2H), 3.62-3.49 (br m, 10H), 3.45 (m, 2H), 3.32 (m, 2H), 2.78 (t, J=7.5 Hz, 2H), 1.90 (m, 2H), 1.79 (m, 2H), 1.71-1.44 (br m, 4H), 1.40-1.07 (br, 33H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([CH2:19][CH2:20][CH2:21][N:15]4[C:14](=[O:22])[CH2:13][CH2:12]3)[CH:18]=2)O1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.Br[C:43]1[CH:44]=[C:45]([CH2:49][NH:50][S:51]([CH2:54][CH3:55])(=[O:53])=[O:52])[CH:46]=[N:47][CH:48]=1>>[O:22]=[C:14]1[CH2:13][CH2:12][C:11]2[C:16]3=[C:17]([CH2:19][CH2:20][CH2:21][N:15]13)[CH:18]=[C:9]([C:43]1[CH:44]=[C:45]([CH2:49][NH:50][S:51]([CH2:54][CH3:55])(=[O:52])=[O:53])[CH:46]=[N:47][CH:48]=1)[CH:10]=2
Reactant: CC1(C)OB(c2cc3c4c(c2)CCC(=O)N4CCC3)OC1(C)C
Reactant: CCS(=O)(=O)NCc1cncc(Br)c1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CCS(=O)(=O)NCc1cncc(-c2cc3c4c(c2)CCC(=O)N4CCC3)c1

Procedure:
In analogy to the procedure described for the preparation of example 45, 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,6,7-tetrahydropyrido[3,2,1-ij]quinolin-3(5H)-one (prepared from 9-bromo-1,2,6,7-tetrahydropyrido[3,2,1-ij]quinolin-3(51H)-one and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) in analogy to the procedure described for the preparation of intermediate A-1 [B]) has been coupled to ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide (intermediate A-11) to give the title compound as an off-white amorphous solid. MS: 386.2 (M+H+).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:16][CH:17]=2)=[CH2:11])=[CH:2]1>O1CCCC1.CO>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:25]=3)=[N:16][CH:17]=2)[CH3:11])=[CH:2]1
Reactant: C=C(c1ccc(NCc2ccc(C(F)(F)F)cc2)nc1)c1c[nH]c2ncccc12
Solvent: CO
Solvent: C1CCOC1
Product: CC(c1ccc(NCc2ccc(C(F)(F)F)cc2)nc1)c1c[nH]c2ncccc12
Reaction time: 8 h
Yield: 4.8 %

Procedure:
5-[1-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-vinyl]-pyridin-2-yl-(4-trifluoromethyl-benzyl)-amine (623, 0.043 g, 0.00011 mol) was dissolved in tetrahydrofuran (10 mL) and methanol (10 mL). The reaction was shaken under an atmosphere of hydrogen (30 psi) overnight. The reaction was filtered through Celite and the filtrate adsorbed onto silica and purified by silica gel column chromatography (ethyl acetate:hexanes) to provide the desired compound as a white solid (P-0388, 2.1 mg, 5%), consistent with compound structure by 1H-NMR and MS (ESI): [M+H+]+=397.6.
Reaction SMILES: [C:1]([NH:20][C@@H:21]1[C@@H:25]([CH:26](C(=O)C2C=CC(OC)=CC=2)[OH:27])[O:24][C@@H:23]([N:38]2[CH:46]=[C:44]([CH3:45])[C:42](=[O:43])[NH:41][C:39]2=[O:40])[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.CO>[C:1]([NH:20][C@@H:21]1[C@@H:25]([CH2:26][OH:27])[O:24][C@@H:23]([N:38]2[CH:46]=[C:44]([CH3:45])[C:42](=[O:43])[NH:41][C:39]2=[O:40])[CH2:22]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc(C(=O)C(O)[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2NC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cn([C@H]2C[C@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
The 5'-O-anisoyl protecting group was removed by dissolving 2t (30.1 g, 48.7 mmol) in 57:43 1,4-dioxane/MeOH (150 mL), followed by the addition of 2M aq. NaOH (73.1 mL, 146.2 mmol). After stirring for 1.5 h at ambient temperature, the reaction mixture was neutralized with Dowex 50W-X8 cation exchange resin (ca. 150 g of dry pyridinium H+ -form, 1.6 meq/g). Once the pH was neutral (ca. 10 min), the resin was filtered, washed extensively with CH2Cl2 and MeOH, and the crude product was concentrated in vacuo. The residue was redissolved in EtOAc (500 mL) and extracted with saturated. aq. NaHCO3 (2×250 mL), H2O (250 mL), and saturated. aq. NaCl (250 mL). After drying over Na2SO4 and filtration, the solvents were removed in vacuo, and the resulting foam was redissolved in 95:5 CH2Cl2 /MeOH (300 mL). This solution was added slowly to a rapidly stirring mixture of 1:1 Et2O/hexane (1250 mL) to precipitate the pure 3'-(Trityl)amino-3'-deoxythymidine, 3t, in 90% yield (21.2 g, 43.8 mmol). Conversion to phosphoramidite monomers and/or succinylated nucleoside is described in Examples 5-7 below.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4]1.[Cl:9][C:10]1[C:19]2[C:14](=[CH:15][C:16](F)=[C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])[CH:18]=2)[CH:13]=[C:12]([NH:26][C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][N:28]=2)[N:11]=1.O>CN(C=O)C>[Cl:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:8][CH:5]3[CH2:6][CH2:7][O:3][CH2:4]3)=[C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])[CH:18]=2)[CH:13]=[C:12]([NH:26][C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][N:28]=2)[N:11]=1
Reactant: OC1CCOC1
Reactant: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1OC1CCOC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
NaH (70 mg) was carefully added to a solution of tetrahydro-furan-3-ol (0.2 ml) in DMF (3 ml) and the mixture was stirred for 1 hour. [1-Chloro-6-fluoro-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (100 mg) was added under N2, and the mixture was heated at 90° C. overnight. The mixture was poured to 50 ml of water. The mixture was extracted by ethyl acetate (50 ml×3). The organic layer was evaporated to give [1-Chloro-7-(2-methoxy-ethoxy)-6-(tetrahydro-furan-3-yloxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine as oil (100 mg). LC-MS: m/e 419(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][C:7]=1[F:8].C=O.[C:20](O)(=O)C>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[F:8])[CH2:20][N:11]([C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9]2
Reactant: CC(=O)O
Reactant: O=C(NCCc1ccc(F)c(Cl)c1)C(F)(F)F
Agent: C=O
Agent: O=S(=O)(O)O
Product: O=C(N1CCc2cc(Cl)c(F)cc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-[2-(3-Chloro-4-fluoro-phenyl)-ethyl]-2,2,2-trifluoro-acetamide (400 mg, 1.48 mmol) and paraformaldehyde (89 mg, 2.96 mmol) were added sequentially at 0° C. to a solution of acetic acid (3 mL) in sulfuric acid (2 mL). After stirring of the reaction mixture at room temperature for 16 hours, the clear colorless solution was poured into ice-water (20 mL). The mixture was extracted with EtOAc (2×30 mL) and the organic layer was washed with satd. aq. NaHCO3 (20 mL), H2O (2×25 mL), dried over anhy. Na2SO4, filtered and concentrated in vacuo to give the crude title product together with a regioisomer (400 mg) as white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].CC(C)([O-])C.[K+].Cl[C:13]1[C:22]2[C:17](=[C:18]([NH:23][C:24](=[O:33])[C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>CN1CCCC1=O.C(OCC)(=O)C>[Cl:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([Cl:31])[C:25]=1[C:24]([NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[N:16]=[CH:15][CH:14]=[C:13]2[O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:33]
Reactant: COCCO
Reactant: O=C(Nc1cccc2c(Cl)ccnc12)c1c(Cl)cccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COCCOc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
To a stirred solution of 2-methoxyethanol (130 mg) in N-methylpyrrolidone (2 ml) was added potassium tert-butoxide (172 mg) under ice-cooling, and the mixture was stirred for 30 minutes at ambient temperature. To the mixture was added 4-chloro-8-(2,6-dichlorobenzoylamino)quinoline (200 mg), and the mixture was stirred for 5 hours at 80° C. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-4-(2-methoxyethoxy)quinoline (175 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[CH2:14]([O:21][C:22]([C:24]1([C:27](=[O:53])[NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:41]=[CH:40][N:39]=[C:38]([NH:42][C:43](OC4C=CC=CC=4)=[O:44])[CH:37]=3)=[CH:31][C:30]=2[F:52])[CH2:26][CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN1CCCC1=O>[CH2:14]([O:21][C:22]([C:24]1([C:27](=[O:53])[NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH:36]3[CH2:41][CH2:40][NH:39][CH:38]([NH:42][C:43]([N:11]4[CH2:12][CH2:13][CH:8]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)[CH2:9][CH2:10]4)=[O:44])[CH2:37]3)=[CH:31][C:30]=2[F:52])[CH2:25][CH2:26]1)=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)OCc4ccccc4)CC3)c(F)c2)ccn1)Oc1ccccc1
Solvent: CN1CCCC1=O
Product: CN1CCN(C2CCN(C(=O)NC3CC(Oc4ccc(NC(=O)C5(C(=O)OCc6ccccc6)CC5)c(F)c4)CCN3)CC2)CC1
Temperature: 40 °C
Yield: 60.7 %

Procedure:
1-Methyl-4-(piperidin-4-yl)piperazine (1.46 g) was added to a mixture of 1-[2-fluoro-4-(2-phenoxycarbonylaminopyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester (3.60 g) and N-methyl-2-pyrrolidone (25 ml), followed by stirring with heating at 40° C. for 1 hour and 51 minutes. The reaction mixture was partitioned after the addition of ethyl acetate (180 mL) and water (90 mL). The resultant organic layer was washed with water (36 ml, twice) and a 10% aqueous solution of sodium chloride (36 ml), dried over anhydrous magnesium sulfate (10 g), and filtered, and the filtrate was concentrated. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:1, ethyl acetate, ethyl acetate:isopropyl alcohol=9:1). The eluate was concentrated under reduced pressure, and the precipitate appeared after the addition of tert-butyl methyl ether (60 ml) and seed crystals obtained in (Method 1). The resultant precipitate was collected by filtration, washed with tert-butyl methyl ether (10 ml), and dried under reduced pressure at 40° C. for 2 hours to give the target title compound (2.57 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][CH:11]=[C:10]3[N:14]([CH3:18])[N:15]=[C:16]([NH2:17])[C:9]=23)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]=[C:27]=[O:28])[CH:21]=1.FC1C=CC(C)=CC=1N=C=O>>[NH2:17][C:16]1[C:9]2[C:10](=[CH:11][N:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[O:28])=[CH:7][CH:6]=2)[N:14]([CH3:18])[N:15]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: Cn1nc(N)c2c(-c3ccc(N)cc3)cncc21
Agent: Cc1ccc(F)c(N=C=O)c1
Product: Cn1nc(N)c2c(-c3ccc(NC(=O)Nc4cccc(Cl)c4)cc3)cncc21

Procedure:
The title compound was prepared using the procedure described in Example 1E using the product from Example 6A and 1-chloro-3-isocyanato-benzene instead of the product from Example 1D and 1-fluoro-2-isocyanato-4-methyl-benzene. MS (ESI(+)) m/e 393 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 3.92 (s, 3H) 4.67 (s, 2H) 7.01-7.06 (m, 1H) 7.29-7.34 (m, 2H) 7.48 (d, J=8.48 Hz, 2H) 7.63 (d, J=8.48 Hz, 2H) 7.73 (s, 1H) 7.95 (s, 1H) 8.87 (s, 1 H) 8.97 (br.s, 2H).
Reaction SMILES: [Br:1][C:2]1[C:15]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10](NC(=O)C(C)(C)C)[NH:9][C:8](=[O:23])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CCOCC>[CH2:24]([NH:31][C:10]1[NH:9][C:8](=[O:23])[C:7]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[C:15]=3[CH:14]=[CH:13][C:12]=2[N:11]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)C(=O)Nc1nc2ccc3c(Br)cccc3c2c(=O)[nH]1
Reactant: NCc1ccccc1
Solvent: CCOCC
Product: O=c1[nH]c(NCc2ccccc2)nc2ccc3c(Br)cccc3c12

Procedure:
A mixture of N-(7-bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.3 g, 0.8 mmole) and benzylamine (10 ml) was stirred and heated at reflux under a nitrogen atmosphere for 18 hours. The cooled reaction mixture was then mixed with 4 volumes of ether to cause precipitation of the product. The precipitate was filtered and recrystallized from methanol to give 3-(benzylamino)-7-bromobenzo-[f]quinazolin-1(2H)-one as an off-white solid. (0.11 g, 37%) 1H NMR(DMSO-d6, 200 MHz) δ: 4.62(d, J=5.7 Hz, 2H, CH2); 7.02(m, 1H, benzyl-NH); 7.20-7.55(m, 7H, Ar); 7.79(dd, J=7.5, 1.1 Hz, 1H, Ar); 8.30(d, J=9.2 Hz, 1H, Ar); 9.74(d, J=8.6 Hz, 1H, Ar); 11.2(br s, 1H, pyr-NH).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:15][C:16]1[S:20][C:19]([C:21]2[S:22][CH:23]=[CH:24][C:25]=2[NH2:26])=[N:18][CH:17]=1>>[CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([NH:26][C:25]3[CH:24]=[CH:23][S:22][C:21]=3[C:19]3[S:20][C:16]([CH3:15])=[CH:17][N:18]=3)=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C(O)Cc1cccc2cnccc12
Reactant: Cc1cnc(-c2sccc2N)s1
Product: Cc1cnc(-c2sccc2NC(=O)Cc2cccc3cnccc23)s1

Procedure:
The title compound was prepared from 2-(isoquinolin-5-yl)acetic acid and 2-(5-methylthiazol-2-yl)thiophen-3-amine using Protocol A. Method[7], MS(ESI) 366.0 [M+H], Retention time=3.157 min; 1H-NMR (300 MHz, CDCl3) δ 11.24 (s, 1H), 9.67 (s, 1H), 8.57 (d, J=6.6 Hz, 1H), 8.30 (d, J=6.6 Hz, 1H), 8.26 (d, J=8.24 Hz, 1H), 8.08-8.04 (m, 2H), 7.96-7.91 (m, 1H), 7.20 (d, J=5.5 Hz, 1H), 6.97 (d, J=1.1 Hz, 1H), 4.31 (s, 2H), 2.43 (d, J=1.1 Hz, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:5][N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O>[OH:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C@H:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:26][CH:25]=2)(=[O:28])=[O:29])[CH2:3][N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCCO)[C@H](N)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](CCCO)[C@H](NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (3S*,4R*)-tert-butyl 3-amino-4-(3-hydroxypropyl)pyrrolidine-1-carboxylate (0.55 g, 2.25 mmol) and p-nitrophenylsulfonyl chloride (0.50 g, 2.25 mmol) and Na2CO3 (0.29 g, 2.70 mmol) in 8 mL THF-water, 3:1, was stirred overnight at room temperature. THF was evaporated, the mixture was diluted with H2O, extracted with CH2Cl2, the combined organic extracts were dried with Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 1→5% MeOH in CH2Cl2 giving the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[C:16]([OH:25])[C:15]=2[C:14]2[C:13]([C:26]([NH2:28])=[O:27])=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[C:16]([O:25][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[C:26](=[O:27])[NH2:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cccc2c1c1c(O)c3c(cc1n2Cc1ccccc1)CCCC3
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1c2c(cc3c1c1c(C(N)=O)cccc1n3Cc1ccccc1)CCCC2
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 31.2 %

Procedure:
40% Methanolic Triton B (0.148 mL, 0.325 mM) was added to a solution of 5-benzyl-11-hydroxy-7,8,9,10-tetrahydro-5H-benzo[b]carbazole-1-carboxylic acid amide, (0.094 g, 0.25 mM) in 5 mL DMF at room temperature. After 2 minutes, methyl bromoacetate (0.049 mL, 0.076 g, 0.5 mM) was added and the resultant mixture stirred at room temperature for 2 h. Cesium carbonate (0.041 g, 0.125 mM) was then added as a solid, and the mixture allowed to stir at room temperature for an additional 2 h. The mixture was diluted with ethyl acetate, washed with H2O, 1N HCl, saturated aqueous NaHCO3 solution, and saturated brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting tan foam was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 0.035 g (31%) of the title compound (5-benzyl-1-carbamoyl-7,8,9,10-tetrahydro-5H-benzo[b]carbazol-11-yloxy)-acetic acid, methyl ester as a white solid (MP 174–177° C., MW 442.52).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH2:13](Cl)[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:13]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccco1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCc1ccco1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
43.5 g of N-hydroxyphthalimide were added to a solution of 31.1 g of furfuryl chloride in 80 ml of dimethylformamide, and the mixture was cooled to 0° C. 40.6 ml of triethylamine were then added dropwise to the mixture, after which the reaction mixture was stirred at 0° C. for 2 hours and then at room temperature for 24 hours. At the end of this time, the reaction mixture was poured into ice-water. The resulting colorless crystals were collected by filtration, to afford 53.1 g of N-furfuryloxyphthalimide, melting at 145-147° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][NH2:20])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1
Reactant: NCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(NCCN2CCOCC2)c(Br)c1
Yield: 74 %

Procedure:
2-Bromo-1-fluoro-4-nitrobenzene (1.0 g, 4.5 mmol), 2-morpholinoethanamine (0.77 g, 5.9 mmol) and potassium carbonate (1.571 g, 11.4 mmol) in DMSO (5 mL) were stirred at room temperature for 1.5 hours. The mixture was triturated with water, and 2-bromo-N-(2-morpholinoethyl)-4-nitroaniline (1.1 g, 72.8% yield) was collected via filtration. HPLC: Rt=0.61 min. (PHENOMENEX® Luna 5 micron C18 4.6×30 mm, 10-90% aqueous methanol containing 0.1% TFA, 2 min. gradient, flow rate=5 mL/min., detection at 254 nm). MS (ES): m/z=332.06 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH:5]=[O:6].[N+:14]([CH:16](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:17])#[C-:15].C([O-])([O-])=O.[K+].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH:15]=[N:14][C:16]=2[CH3:17])[CH:7]=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13]
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(C(F)(F)F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ncoc1-c1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A mixture of Example 45A (2.84 g, 13.6 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (2.85 g, 13.6 mmol), and K2CO3 (2.26 g, 16.3 mmol) in MeOH (70 mL) was heated to reflux. After 2 hr the reaction mixture was cooled to ambient temperature, and the volatiles were evaporated at reduced pressure. The residue was partitioned between Et2O and H2O. The separated aqueous layer was extracted with Et2O, and the combined organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Flash chromatography (Analogix® Intelliflash 280; 10% to 30% EtOAc/hexanes eluant; SF40-150 g column) yielded 3.04 g (85%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.96 (d, J=8.4, 1H), 7.87 (s, 1H), 7.78 (dd, J=8.3, 0.8, 1H), 2.43 (s, 3H). MS (DCI+) m/z 262 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:38]3[CH:39]=[CH:40][C:35]([C:34]([F:45])([F:44])[F:33])=[CH:36][CH:37]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:20][CH:21]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(F)(F)F)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(OC(F)(F)F)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-trifluoromethoxyphenyl)indole-3-carboxylic acid ethyl ester (158 mg, 0.35 mmol, see step (b) Example 9) and 4-trifluoromethylphenylboronic acid. Yield 135 mg (65%).