Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][O:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.C([O:35][CH:36](OCC)/[CH:37]=[CH:38]/B1OC(C)(C)C(C)(C)O1)C.C(=O)([O-])[O-].[Na+].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>COCCOC.O.CC(C)=O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][O:10][C:6]=2[C:5](/[CH:38]=[CH:37]/[CH:36]=[O:35])=[CH:4][N:3]=1
Reactant: CCOC(/C=C/B1OC(C)(C)C(C)(C)O1)OCC
Reactant: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(-c2coc3c(/C=C/C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Yield: 61.8 %

Procedure:
A mixture of N-[4-(4-amino-7-iodofuro[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide (3.16 g, 5.86 mmol) in 1,2-dimethoxyethane (40 mL) and water (20 mL) was reacted 2-[(E)-3,3-diethoxy-1-propenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.87 g, 7.03 mmol,), sodium carbonate (1.55 g, 14.66 mmol) and tetrakis triphenylphosphine palladium (0) (0.68 g, 0.59 mmol) at 80° C. for eighteen hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (15 mL) and water (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×15 mL). The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel using 10% methanol in dichloromethane as an eluent to give a mixture of diethyl acetal, methyl ethyl acetal, and aldehyde. This mixture was reacted with p-toluenesulfonic acid monohydrate (0.10 g, 0.53 mmol) in acetone (100 mL) and water (10 mL) at ambient temperature for eighteen hours. The acetone was removed in vacuo and the precipitate was filtered, washing with water. The precipitate was triturated with 2-propanol (30 mL) for 1 hour. The solid was filtered and dried in vacuo to give the title compound (1.690 g, 62%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) 9.64 (d, 1H), 9.49 (s, 1H), 8.26 (s, 1H), 8.22 (s, 1H), 8.06 (t, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.59 (d, 1H), 7.30-7.38 (m, 2H), 7.27 (d, 1H), 7.12-7.20 (m, 2H), 6.94 (dd, 1H), 6.33-6.59 (b, 2H), 4.04 (s, 3H), 3.94 (s, 3H); RP-HPLC (Conditions d) Rt 7.36 min.; MS: MH30 467.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]2[O:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:27]=2)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])C(=O)OC(C)(C)C)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH2:43][CH2:44][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:46][CH:47]=2)O1.C(P(CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(Cl)Cl.O.Cl[Pd]Cl>[C:19]([O:18][C:16]([NH:8][C:5]1[N:6]=[CH:7][C:2]([C:42]2[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH:43]=2)=[CH:3][C:4]=1[C:23]1[O:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:26][N:27]=1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)cc1-c1nnc(-c2ccccc2)o1
Agent: Cl[Pd]Cl
Agent: CCP(CC)CC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ncc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1-c1nnc(-c2ccccc2)o1
Temperature: 140 °C
Yield: 47 %

Procedure:
A mixture of tert-butyl N-[5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (300 mg, 0.5799 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (215.2 mg, 0.6959 mmol), dichloropalladium; triethylphosphane (12.00 mg, 0.02900 mmol) and Na2CO3 (184.4 mg, 1.740 mmol) in DMF (3.000 mL) was heated to 60° C. for 16 hours. Analysis indicated that there was starting material remaining so the reaction was heated to 140° C. in the microwave for a further 2 hours. The reaction mixture was allowed to cool to ambient temperature, diluted with DCM and water and the two layers separated. The organics were washed with 1M NaOH solution, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was purified by column chromatography (EtOAc/Petroleum ether) to give the desired product that was used directly in the next step without further purification (142 mg, 47% Yield). MS (ES+) 302.31.
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH:4]3[OH:11])[CH2:2]1)[CH2:8]2.[Cl:13][C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>N1C=CC=CC=1.C(Cl)Cl>[Cl:13][C:14]([O:11][CH:4]1[CH:5]2[CH2:10][C:1]3([OH:12])[CH2:8][CH:7]([CH2:9][CH:3]1[CH2:2]3)[CH2:6]2)=[O:16]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1C2CC3CC1CC(O)(C3)C2
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)OC1C2CC3CC1CC(O)(C3)C2
Temperature: 0 °C

Procedure:
A solution of 1,4-adamantanediol (210 mg, 1.25 mmol) in dry pyridine (3 mL) and dry CH2Cl2 (6 mL) was cooled in an ice bath and a solution of triphosgene (122 mg, 0.41 mmol) in dry Ch2Cl2 (3 mL) was added dropwise over 5 min. The mixture was stirred in the ice bath for 3 h to afford a 0.1 M solution of 1-hydroxy-4-adamantyl chloroformate.
Reaction SMILES: [OH:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([NH2:20])=[O:19])=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1.Cl.[CH:28](Cl)(Cl)Cl>>[CH3:28][O:1][CH:2]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([NH2:20])=[O:19])=[CH:17][C:11]=3[N:10]=2)=[CH:7][CH:8]=1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(C(O)c4ccccc4)cc3)nc2c1
Reactant: ClC(Cl)Cl
Agent: Cl
Product: COC(c1ccccc1)c1ccc(-c2nc3cc(C(N)=O)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of 2-[4-(hydroxy-phenyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide (Example 19, 8.7 mg, 0.02 mmol) in chloroform (1.0 mL) was added concentrated HCl (0.1 mL). The reaction mixture was stirred at RT for 2 h. Organics were removed under reduced pressure, and purification using preparative TLC (silica, 1% methanol saturated with ammonia/9% methanol/CH2Cl2) afforded 4.2 mg (47%) of the title compound. HPLC (Method A): Rt=6.97. MS (ESI+): mass calculated for C22H19N3O2, 357.1; m/z found, 358.2 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.18 (br s, 1H), 8.08 (d, J=8.2 Hz, 2H), 7.82 (br d, J=8.0 Hz, 1H), 7.64 (br s, 1H), 7.56 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 7.35 (t, J=7.5 Hz, 2H), 7.28–7.25 (m, 1H), 5.39 (s, 1H), 3.40 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][O:9][CH2:8][C:7]2=O.FC1C=CC=C2C=1OCCC2[NH2:24]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][O:9][CH2:8][CH:7]2[NH2:24]
Reactant: O=C1COCc2c(F)cccc21
Reactant: NC1CCOc2c(F)cccc21
Product: NC1COCc2c(F)cccc21

Procedure:
The title compound was prepared from 8-fluoro-1H-isochromen-4(3H)-one via the procedure described above for the synthesis of 8-fluorochroman-4-amine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1C(C1C=CC(Cl)=CC=1)O)=[O:5])[CH3:2].[F:24][C:25]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:21])[CH3:22])[C:10]=1[N:27]([C:26]1[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:25]=1[F:24])[C:28]1[CH:26]=[CH:25][C:31]([Cl:32])=[CH:30][CH:29]=1)=[O:5])[CH3:2]
Reactant: Nc1cccc(Cl)c1F
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1N(c1ccc(Cl)cc1)c1cccc(Cl)c1F

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 using 2-bromo-5-[(4-chlorophenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (intermediate B) and 2-fluoro-3-chloro-aniline as starting materials; 1H-NMR (DMSO-d6, 400 MHz) δ ppm 7.46 (d, 2H), 7.30 (d, 2H), 6.98 (dd, 1H), 6.82 (d, 1H), 6.73-6.69 (m, 2H), 4.82 (sep (1H), 4.26 (q, 2H), 1.45 (d, 3H), 1.24 (t, 3H), 1.17 (d, 3H).
Reaction SMILES: C[O:2][C:3]([CH2:5][C@H:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:9][CH2:8][CH2:7]1)=[O:4].[OH-].[Na+].Cl>CO>[C:3]([CH2:5][C@H:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:18])=[O:19])[CH2:9][CH2:8][CH2:7]1)([OH:4])=[O:2]
Reactant: COC(=O)C[C@@H]1CCCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CCC[C@@H](CC(=O)O)c3ccccc32)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
A mixture of (5S)-5-methoxycarbonylmethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.20 g), a 5% aqueous sodium hydroxide solution (10 ml) and methanol (10 ml) is heated with stirring at 80° C. for three hours. To the reaction solution is added ice, and the mixture is acidified with conc. hydrochloric acid, and extracted with dichloromethane. The extract is dried over sodium sulfate, and concentrated under reduced pressure to remove the solvent to give (5S)-5-carboxymethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.19 g).
Reaction SMILES: C(OC(=O)C[O:8][C:9]1[C:14]2[N:15]([CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)C(=O)[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)(C)(C)C.BrCC(OC(C)(C)C)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CN(C=O)C>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[CH2:19][NH:15][C:14]1[C:9]([OH:8])=[CH:10][CH:11]=[CH:12][C:13]=1[OH:17]
Reactant: CC(C)(C)OC(=O)COc1cccc2oc(=O)n(Cc3ccc4ccccc4c3)c12
Agent: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Oc1cccc(O)c1NCc1ccc2ccccc2c1

Procedure:
Synthesis of (3-Naphthalen-2-ylmethyl-2-oxo-2,3-dihydro-benzooxazol-4-yloxy)-acetic acid tert-butyl ester, I-88. A mixture of compound I-87 (140 mg, 0.48 mmol), tert-butyl bromoacetate (136 mg, 0.7 mmol) and K2CO3 (95 mg, 0.7 mmol) in acetone (10 ml) and DMF (5 ml) was stirred at rt over night and then partitioned between EtOAc and water. Water layer was extracted with EtOAc. The combined organic phase was washed with water, brine and dried over sodium sulfate. After removal of solvent, 160 mg of compound I-88 was obtained. 1H-NMR (500 MHz, CDCl3).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.Cl>O1CCCC1.CCCCCC>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8])=[CH:21][CH:20]=1
Reactant: COc1ccc(CBr)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCc1ccc(OC)cc1
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
Into a 3 l. 3-necked r.b. flask equipped with a mechanical stirrer, thermometer, dropping funnel, and nitrogen gas inlet was placed 24 g. (0.5 mole) of 50% NaH prewashed with hexane, and 1000 ml. of dry tetrahydrofuran. 65 g. (0.5 mole) of ethyl acetoacetate was then added dropwise at -10° to 0° C. using a dry ice-acetone bath. After addition of ethyl acetoacetate was finished, the mixture was gradually warmed up to 10° C. in the course of 15 minutes and then 240 ml. (0.528 mole) of 2.2M n-butyllithium was added dropwise maintaining temperature below -40° to -20° C. After the mixture was stirred at -10° for 15 minutes, 100.5 g. (0.5 mole) of 4-methoxybenzyl bromide was added dropwise over a period of 45 minutes at -10° C. The reaction mixture was gradually warmed up to room temperature and stirred for an additional hour, and then cooled to -20° C. 5N HCl was then carefully added until the solution was slightly acidic.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[C:22]([CH3:34])[N:23]2[CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:19][CH:18]=1.[Cl-].[Cl-].C([Al+2])C>C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:12]([C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2]([CH3:1])=[CH:3][CH:4]=3)=[O:13])=[C:22]([CH3:34])[N:23]2[CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2cc(C)n(CCN3CCOCC3)c2c1
Reactant: Cc1ccc(C(=O)Cl)c2ccccc12
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc2c(C(=O)c3ccc(C)c4ccccc34)c(C)n(CCN3CCOCC3)c2c1
Temperature: 25 °C

Procedure:
To a solution of 4-methyl-1-naphthoyl chloride (11 mg, 0.055 mmol) and 4-(2-(6-methoxy-2-methyl-1H-indol-1-yl)ethyl)morpholine (15 mg, 0.055 mmol) in 1 mL CH2Cl2 at −70° C. was added dropwise ethyl aluminum dichloride (70 μL, 0.12 mmol, 1.8 M in toluene). The reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and cold H2O, and the aqueous layer extracted twice with ethyl acetate. The combined organic extract was washed successively with H2O, 10% K2CO3, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 10% MeOH in CH2Cl2 to give CBX006 (4 mg, 0.009 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.46 (s, 3H), 2.50-2.63 (m, 4H), 2.72 (t, J=7.1 Hz, 2H), 2.81 (s, 3H), 3.73 (t, J=4.5 Hz, 4H), 3.87 (s, 3H), 4.23 (t, J=7.1 Hz, 2H), 6.72 (dd, J=8.7 Hz, 2.2 Hz, 1H), 6.83 (d, J=2.2 Hz, 1H), 7.23 (d, J=8.7 Hz, 1H), 7.38 (d, J=7.1 Hz, 1H), 7.44-7.54 (m, 2H), 7.58 (t, J=7.6 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 8.19 (d, J=8.4 Hz, 1H). MS m/z 443.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:24])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]3=2)[CH:13]=[CH:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+]>C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:24])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]3=2)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](Cn1ccc2ccc3ccccc3c21)NC(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@@H](CN1CCc2ccc3ccccc3c21)NC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a stirred solution of (S)-1-[2-(tert-butoxycarbonylamino)propyl]-benz[g]indole (0.49 g, 1.5 mmol) in acetic acid (10 mL) was added portionwise sodium cyanoborohydride (95%, 0.30 g, 4.5 mmol). The mixture was stirred for 16 h and partitioned between ether (40 mL) and saturated aqueous sodium bicarbonate solution (3×50 mL). The organic layer was washed with brine (2×), dried (magnesium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; heptane-ethyl acetate (6:1)] to give the product (0.24 g, 49%) as a pale yellow solid: IR νmax (Nujol)/cm−1 1689, 1528, 1362, 1298, 1051 and 790; NMR δH (400 MHz, CDCl3) 1.39 (3H, d, J 6.5 Hz), 1.45 (9H, s), 3.11–3.28 (2H, m), 3.32–3.42 (2H, m), 3.62–3.69 (2H, m), 3.98–4.08 (1H, m), 4.78 (1H, brs), 7.30–7.38 (1H, m), 7.33–7.41 (3H, m), 7.72–7.81 (1H, m) and 7.98–8.01 (1H, m).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:14]=[O:15])C1C=CC=CC=1.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=2)[C:28]([O:30][CH3:31])=[O:29])=[CH:17]1.C([O-])(=O)C.[Na+]>CNC=O>[CH:14]([C:17]1[O:16][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]=1[C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29])=[O:15]
Reactant: CN(C=O)c1ccccc1
Reactant: COC(=O)c1cccc(-c2coc3ccccc23)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CNC=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc(-c2c(C=O)oc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a mixture of phosphorus oxychloride (3 g) and N-methylformanilide (3 g) was added a solution of methyl 3-(benzofuran-3-yl)benzoate (3 g) in N-methylformamide (1.5 g) at room temperature. The mixture was stirred overnight at room temperature and was poured onto aqueous sodium acetate solution. The product was extracted with ethyl acetate and the organic layer was washed with hydrochloric acid solution, water and brine. The layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (5:1) to afford methyl 3-(2-formylbenzofuran-3-yl)benzoate (2.39 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[CH:20][C:19]2[N:18]3[CH2:22][CH2:23][CH2:24][C:17]3=[CH:16][C:15]=2[C:14]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:11])=[O:10].[CH2:29]([N:31]([CH2:48][CH3:49])[CH2:32]/[CH:33]=[CH:34]\[Sn](CCCC)(CCCC)CCCC)[CH3:30]>O1CCOCC1.CS(C)=O>[CH2:29]([N:31]([CH2:48][CH3:49])[CH2:32]/[CH:33]=[CH:34]\[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[CH:20][C:19]2[N:18]3[CH2:22][CH2:23][CH2:24][C:17]3=[CH:16][C:15]=2[C:14]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:11])=[O:10])[CH3:30]
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1cc1n2CCC1
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(cc3n2CCC3)c1C(=O)OC
Temperature: 95 °C
Yield: 90.7 %

Procedure:
A mixture of methyl 7-(2-bromo-4-fluorobenzenesulfonylamino]-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (Intermediate 17, 0.100 g) and N,N-diethyl-N—((Z)- 1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3, 0.172 g) in dioxane (2 mL) and DMSO (0.2 mL) was de-gassed and purged with nitrogen. Tris-(dibenzylideneacetone)-dipalladium (0.009 g) and tri-tert-butylphosphonium tetrafluoroborate (0.006 g) were added and the reaction mixture was heated at 95° C., under an atmosphere of nitrogen for 45 minutes. After cooling, the mixture was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-7.5% to give methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (0.097 g) as a yellow oil.
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C:23]1[N:28]=[N:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=1)=[O:21].C1C2C(=CC=CC=2)CN1C([NH:43][C:44]1C=C[C:47]([C:48]([OH:50])=O)=[CH:46][CH:45]=1)=O>>[O:50]1[CH2:48][CH2:47][CH2:46][C@@H:45]1[CH2:44][NH:43][C:29]([C:26]1[N:27]=[N:28][C:23]([NH:22][C:20]([N:12]2[CH2:11][C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH2:13]2)=[O:21])=[CH:24][CH:25]=1)=[O:31]
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccncc3C2)nn1
Agent: NCCCc1ccccc1
Product: O=C(NC[C@H]1CCCO1)c1ccc(NC(=O)N2Cc3ccncc3C2)nn1

Procedure:
The title compound was prepared as described in Example 1C, substituting (2R)-tetrahydrofuran-2-ylmethamine for 3-phenylpropan-1-amine and 6-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)pyridazine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ 10.09 (bs, 1H), 8.81 (t, J=6.1 Hz, 1H), 8.61 (s, 1H), 8.51 (d, J=5.0 Hz, 1H), 8.31 (d, J=9.3 Hz, 1H), 8.12 (d, J=9.3 Hz, 1H), 7.44 (d, J=5.1 Hz, 1H), 5.05-4.76 (m, 4H), 4.04 (p, J=6.2 Hz, 1H), 3.85-3.74 (m, 1H), 3.70-3.59 (m, 1H), 3.35 (d, J=25.7 Hz, 2H), 1.99-1.72 (m, 3H), 1.69-1.54 (m, 1H); MS (ESI(+)) m/e 369 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10].C(O)(=O)C.[OH-].[Na+]>C(O)C.[Fe]>[NH2:15][C:13]1[CH:12]=[CH:11][C:3]([CH2:4][N:5]2[CH2:9][CH2:8][O:7][C:6]2=[O:10])=[C:2]([F:1])[CH:14]=1
Reactant: O=C1OCCN1Cc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(CN2CCOC2=O)c(F)c1
Reaction time: 0.17 h

Procedure:
To a solution of the compound obtained in Step B (10.37 mmoles) in ethanol (25 ml) there are added 122 microliters of acetic acid. The solution is heated at reflux and stirred for 10 minutes. Powdered iron (2.08 g) and 75 mg of FeCl3.6H2O are added. After stirring for 2 hours at reflux, the mixture is brought to ambient temperature and then concentrated to dryness. 50 ml of water are added to the residue obtained, and the pH is made alkaline using sodium hydroxide. The solution is extracted 4 times with AcOEt. The organic phases are combined and washed with saturated aqueous NaCl solution and then dried with MgSO4. After filtration, the organic phase is evaporated to dryness to yield the title product, which is used directly in the next Step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:24])[NH:18][NH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:11]([O:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:38][C@@H:39]1[C@@H:44]([O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[C@H:43]([O:52][C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[C@@H:42]([CH2:59][O:60][C:61](=[O:66])[C:62]([CH3:65])([CH3:64])[CH3:63])[O:41][C@@H:40]1Br)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([O:24][C@@H:40]3[O:41][C@H:42]([CH2:59][O:60][C:61](=[O:66])[C:62]([CH3:65])([CH3:64])[CH3:63])[C@@H:43]([O:52][C:53](=[O:58])[C:54]([CH3:55])([CH3:56])[CH3:57])[C@H:44]([O:45][C:46](=[O:51])[C:47]([CH3:48])([CH3:49])[CH3:50])[C@H:39]3[O:38][C:32](=[O:37])[C:33]([CH3:36])([CH3:34])[CH3:35])=[N:18][NH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:11]([O:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccc(OCc2ccccc2)cc1OC1CCOCC1
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c1Cc1ccc(OCc2ccccc2)cc1OC1CCOCC1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 17 using 4-{[4-benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide instead of 4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-glucose, respectively.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH2:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]1=[O:19].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH2:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]1=[O:19])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1Nc2ccccc2C1CCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCC1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Methanesulfonyl chloride (0.42 mL, 5.39 mmol) was added dropwise at 0° C. to 3-(3-hydroxypropyl)indolin-2-one (1.03 g, 5.39 mmol) and triethylamine (1.13 mL, 8.09 mmol) in dichloromethane (20 mL). The mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was washed with 2M aqueous hydrochloric acid and brine, dried (MgSO4), and evaporated. The residue was purified by Biotage flash column chromatography (30% ethyl acetate/hexanes) to give product as an oil (1.45 g, quant.); 1H NMR (DMSO-d6); δ1.66-1.70 (m, 2H); 1.85-1.94 (m, 2H); 3.15 (s, 3H); 3.48 (t, J=6.4 Hz, 1H); 4.19 (t, J=6.4 Hz, 2H); 6.82 (d, J=8 Hz, 1H); 6.96 (m, 1H); 7.18 (m, 1H); 7.25 (d, J=7.6 Hz, 1H); 10.4 (s, 1H); MS for C12H15NO4S m/z 270 (M+H)+.