Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[NH:13][C:12]2=[O:22])=[CH:5][CH:4]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>CN(C)C=O>[O:21]=[C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11](=[CH:10][NH:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][O:1][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:4][CH:5]=2)[C:12](=[O:22])[NH:13]1
Reactant: O=C1NC(=O)c2ccccc2C1=CNc1ccc(CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)OCc1ccc(NC=C2C(=O)NC(=O)c3ccccc32)cc1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 81.6 %

Procedure:
To a suspension of 4-[(4-Hydroxymethyl-phenylamino)-methylene]-4H-isoquinoline-1,3-dione (294 mg, 1 mmol) in N,N-dimethylformamide (10 mL) is added methanesulfonyl chloride (0.77 mL, 10 mmol) and triethylamine (2.79 mL, 20 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours. The crude product, methanesulfonic acid 4-[(1,3-dioxo-2,3-dihydro-1H-isoquinolin-4-ylidenemethyl)-amino]-benzyl ester (304 mg), thus obtained is used as such for the next reaction.
Reaction SMILES: CCCCCC.C([Li])CCC.CO[B:14]([O:17]C)[O:15]C.Cl.CCCCCC.Br[C:27]1[C:32]2[O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:31]=2[CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH:30]1[C:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[O:33][C:32]=2[C:27]([B:14]([OH:15])[OH:17])=[CH:28][CH:29]=1
Reactant: Brc1cccc2c1oc1ccccc12
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cccc2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
In a 300 ml three-necked flask, 7.2 g of 4-bromodibenzofuran was dissolved in −78° C. anhydrous tetrahydrofuran (THF) under an argon atmosphere. Then, 20 ml of an n-butyl lithium-n-hexane solution (1.6 M, 1.1 eq) was added and stirred for 1 hour. 4.23 ml (1.3 eq) of trimethoxyborane (B(OMe)3) was added and stirred for 2 hours, and the temperature of the reaction system was increased to room temperature. 200 ml of 1 N hydrochloric acid was added into the reactant and stirred for 3 hours. An organic layer was separated, and solvents were distilled off. In the crude product thus obtained, hexane was added. Precipitated product was filtered to obtain 4.94 g of dibenzofuran-4-boronic acid as a white solid (yield 80%). The product was measured by FAB-MS, and dibenzofuran-4-boronic acid having a molecular weight of 212 was detected.
Reaction SMILES: I[C:2]1[C:3](=[O:20])[N:4]([CH2:8][C:9]2[CH:19]=[CH:18][C:12]3[N:13]=[C:14]([S:16][CH3:17])[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:6][N:7]=1.[NH3:21]>CS(C)=O>[NH2:21][C:2]1[C:3](=[O:20])[N:4]([CH2:8][C:9]2[CH:19]=[CH:18][C:12]3[N:13]=[C:14]([S:16][CH3:17])[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: N
Reactant: CSc1nc2ccc(Cn3ccnc(I)c3=O)cc2s1
Solvent: CS(C)=O
Product: CSc1nc2ccc(Cn3ccnc(N)c3=O)cc2s1
Temperature: 150 °C
Yield: 27 %

Procedure:
A stirred mixture of 3-iodo-1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyrazin-2(1H)-one (750 mg, 1.81 mmol), ammonia (7 M solution in MeOH, 2 mL, 14 mmol), and DMSO (1.5 mL), was heated in a Biotage Microwave Synthesizer at 150° C. for 15 min. The mixture was cooled to and partitioned between EtOAc and a 1:1 mixture of water and brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% DCM to 2% MeOH in DCM to afford 3-amino-1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyrazin-2(1H)-one (149 mg) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.43 (dd, J=1.5, 8.4 Hz, 1H), 6.92 (d, J=4.7 Hz, 1H), 6.65-6.67 (br m, 3H), 5.11 (s, 2H), 2.78 (s, 3H); LCMS (ESI) m/z 305 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.Br[CH2:17][C:18]1[CH:48]=[CH:47][CH:46]=[CH:45][C:19]=1[CH2:20][O:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[O:6]=[C:5]([CH2:7][CH2:17][C:18]1[CH:48]=[CH:47][CH:46]=[CH:45][C:19]=1[CH2:20][O:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:4][C:3]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)CC(C)=O
Reactant: BrCc1ccccc1COCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CCc1ccccc1COCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a suspension of NaH (448 mg/l 1.2 mmol) in THF (22 ml) was added a solution of methyl acetoacetate (1.30 g/11.2 mmol) in THF (4.5 ml) dropwise at 0° C. over 15 minutes. After 20 minutes at 0° C., n-butyl lithium (7,3 ml/11.2 mmol) was added dropwise at 0° C. over 15 minutes. After 20 minutes at 0° C., a solution of 3-{[2-(bromomethyl)benzyl]oxy}-N-trityl-1-propanamine in THF (6.6 ml) was added dropwise at 0° C., and the solution was stirred at 0° C. for 3 hours. The mixture was quenched with water, and the whole was extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in diethylether (100 ml) and hexane (100 ml). The solution was washed with water (50 ml×5), brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, 200-350 mesh/hexane:ethyl acetate=10:0-3:1) to afford a colorless oil (3.70 g/74%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CCOC(C(C#N)=N[O:36][C:37]([N:41]([CH3:43])[CH3:42])=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:5][C:37]([N:41]1[CH2:42][CH2:13][N:12]([C:9](=[O:11])[C@@H:8]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:23])[CH2:8][CH2:43]1)=[O:36])[CH3:2]
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)CC1
Reaction time: 16 h

Procedure:
To a solution of 15.4 g (S)-2-Benzyloxycarbonylamino-succinic acid 4-tert-butyl ester, 24.4 ml NEM and 15.6 g TOTU in 80 ml DMF 7.5 g piperazine-1-carboxylic acid ethyl ester were added at RT and stirred for 16 h. The reaction mixture was then diluted with ethyl acetate and washed with aqueous LiCl (4 w/w) and saturated aqueous sodium hydrogen carbonate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was used in the subsequent reaction. Yield: 23.0 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]2[S:45][CH:46]=[CH:47][CH:48]=2)=[CH:34][CH:33]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[S:45][CH:46]=[CH:47][CH:48]=3)=[CH:36][CH:37]=2)[C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccc(-c2ccccc2-c2cccs2)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3cccs3)cc2)C1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 174 mg (0.465 mmol) of 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 1, Step I) in 3.0 mL of dry dimethylformamide was treated with 22.2 mg of 60% sodium hydride oil dispersion (13.3 mg NaH, 0.558 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 30 minutes. To the solution was added 153 mg (0.465 mmol) of a solution of 4-bromomethyl-2'-(2-thienyl)-1,1'-biphenyl dissolved in 3 mL of dry dimethylformamide. After stirring at room temperature for 3 hours, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water (4×), dried over magnesium sulfate, filtered and evaporated under vacuum. The residue was purified by chromatography on silica gel, eluting with hexane/ethyl acetate (1:1) to give 160 mg of the product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.N[C:37]1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.CC1C=CC(N=C=S)=CC=1>>[CH3:33][CH:32]([CH3:34])[C@H:27]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][CH:25]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:9]([NH:8][C:3]4[CH:4]=[CH:5][C:6]([CH3:37])=[CH:7][CH:2]=4)=[S:35])=[CH:12][CH:13]=3)[CH:18]=2)[C:22]1=[O:26])[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Agent: Cc1ccc(N=C=S)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccc(C)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 274 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 4-methyl phenyl isothiocyanate. The compound of example 274 was used directly without isolation, for the preparation of compound of example 275.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10](Cl)(=[O:12])[CH3:11].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([C:24]([NH:26][C@@H:27]1[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C@H:28]1[NH:36][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:25])=[CH:18]2>C1COCC1>[C:10]([N:36]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@@H:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:35][C@H:27]1[NH:26][C:24]([C:19]1[NH:20][C:21]2[C:17]([CH:18]=1)=[CH:16][C:15]([Cl:14])=[CH:23][CH:22]=2)=[O:25])(=[O:12])[CH3:11]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)CN[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(CC(=O)OC(C)(C)C)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
DIPEA (80 μL, 0.5 mmol) and acetyl chloride (30 μL, 0.5 mmol) were added to a solution of 1,1-dimethylethyl [((1R,2R)-2-{[(5-chloro-1H-indol-2-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)amino]acetate (Method 8, 200 mg, 0.5 mmol) in THF (10 mL). The reaction was stirred at ambient temperature for approximately 1 h. The volatiles were removed by evaporation under reduced pressure the residue dissolved in EtOAc (50 mL), washed with water (2×10 mL), brine (10 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure and the residue purified by column chromatography (EtOAc:isohexane 1:1) to afford the title compound (168 mg, 76%) as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.CC([O-])(C)C.[K+].[SiH:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18]>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18]
Reactant: CC[SiH](CC)CC
Reactant: c1ccc2occc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc2ccccc2o1
Yield: 37.9 %

Procedure:
The reaction was conducted according to the General Procedure by heating benzofuran (59 mg, 0.5 mmol, 1 equiv.), KOt-Bu (19.6 mg, 0.18 mmol, 0.35 equiv.) and Et3SiH (239 microliters, 1.5 mmol, 3 equiv.) in 1 mL of tetrahydrofuran for 45 hours at 60° C. After aqueous work up, the crude reaction mixture was purified by chromatography on silica eluting with hexanes (isochratic) to obtain 44 mg (38%) of the title compound as a colourless oil. 1H NMR (500 MHz, Acetone-d6) δ 7.64 (ddd, J=7.7, 1.3, 0.7 Hz, 1H), 7.53 (dd, J=8.2, 0.9 Hz, 1H), 7.30 (ddd, J=8.3, 7.2, 1.3 Hz, 1H), 7.22 (ddd, J=7.7, 7.2, 1.0 Hz, 1H), 7.16 (d, J=1.0 Hz, 1H), 1.09-0.98 (m, 9H), 0.92-0.84 (m, 6H). The HSQC spectrum of this reaction product as provided in FIG. 13.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[CH:32][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([N:26]3[CH2:31][CH2:30][S:29][CH2:28][CH2:27]3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:48])C=1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[CH:32][C:13]=2[C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([S:23]([N:26]3[CH2:27][CH2:28][S:29](=[O:48])[CH2:30][CH2:31]3)(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)Nc2ccc(S(=O)(=O)N3CCSCC3)cc2)cc1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Product: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)Nc2ccc(S(=O)(=O)N3CCS(=O)CC3)cc2)cc1OC
Temperature: 25 °C

Procedure:
500 mg (0.82 mmol) of 2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide in 50 ml of acetone were cooled to 0° C. A solution of 371 mg (1.23 mmol) of 57% m-chloroperbenzoic acid in 20 ml of acetone was added and the mixture was stirred at room temperature over night. For working up it was poured onto water/ice and the precipitate was filtered off with suction. The two products obtained as a mixture were separated by chromatography over silica with methylene chloride/methanol (97:3).
Reaction SMILES: [I:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7](S(C)(=O)=O)[S:8][C:4]=2[CH:3]=1.[NH:15]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[I:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([N:15]3[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16]3)[S:8][C:4]=2[CH:3]=1
Reactant: O[C@H]1CCNC1
Reactant: CS(=O)(=O)c1nc2ccc(I)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O[C@H]1CCN(c2nc3ccc(I)cc3s2)C1
Temperature: 150 °C

Procedure:
A stirred mixture of 6-iodo-2-(methylsulfonyl)benzo[d]thiazole (Reference Example 6c, 1.50 g, 4.42 mmol), (S)-pyrrolidin-3-ol (0.500 g, 5.74 mmol), and potassium carbonate (1.222 g, 8.84 mmol) in N,N-dimethylformamide (21.5 mL) was heated to 150° C. under microwave irradiation for 10 minutes. The reaction mixture was cooled to room temperature, then poured into water (350 mL) to give a precipitate. The precipitate was collected by filtration, rinsed with water, and then dissolved in ethyl acetate. The ethyl acetate solution was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a crude solid that was purified by silica gel chromatography (100% CHCl3 to 97:3 CHCl3/methanol). Fractions containing product were combined an concentrated under reduced pressure to provide (S)-1-(6-iodobenzo[d]thiazol-2-yl)pyrrolidin-3-ol. 1H NMR (300 MHz, CD3OD) δ ppm 2.03-2.14 (m, 1H), 2.15-2.29 (m, 1H), 3.47-3.55 (m, 1H), 3.58-3.75 (m, 3H), 4.53-4.59 (m, 1H), 7.23 (d, J=8 Hz, 1H), 7.53-7.59 (m, 1H), 7.95-7.98 (m, 1H); MS (DCI/NH3) m/z 347 (M+H)+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:11]1[CH2:17][S:14](=[O:16])(=[O:15])[O:13][CH2:12]1>C(#N)C>[S:14]([CH2:17][CH2:11][CH2:12][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)([OH:16])(=[O:15])=[O:13]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=S1(=O)CCCO1
Solvent: CC#N
Product: O=S(=O)(O)CCCN1CCCc2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 1,2,3,4-tetrahydroquinoline (4.76 g, 40 mmole) and 1,3-propane sultone (4.88 g, 40 mmole) in 50 mL reagent grade acetonitrile was heated under a nitrogen atmosphere and refluxed overnight. After cooling to room temperature, then to ice bath temperature, the resulting white solid was filtered and washed with cold acetonitrile. The yield was 8.1 g (84%), and the product had a melting point of greater than 200° C. Nuclear magnetic resonance (NMR) and elemental analysis showed the product to be consistent with the assigned structure. NMR (D2O): 7.45 (s, 4H), 2.8-4.0 (m, 8H), 2.2 (T, 2H).
Reaction SMILES: I[C:2]1[C:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:5]=2[N:4](C(OCC)=O)[N:3]=1.[N:23]1[CH:24]=[CH:25][N:26]2[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][C:27]=12.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[N:23]1[CH:24]=[CH:25][N:26]2[CH:31]=[C:30]([C:2]3[C:6]4[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:9][CH2:10][C:5]=4[NH:4][N:3]=3)[CH:29]=[CH:28][C:27]=12
Reactant: CCOC(=O)n1nc(I)c2c1CCN(C(=O)OC(C)(C)C)C2
Reactant: OB(O)c1ccc2nccn2c1
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: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc4nccn4c3)c2C1
Temperature: 160 °C

Procedure:
5-Tert-butyl 1-ethyl 3-iodo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-1,5(4H)-dicarboxylate (1 g, 0.002 mol), (synthesized from patent procedure: WO 2004014374 A1) was added to a vial containing imidazo[1,2-a]pyridin-6-ylboronic acid (0.577 g, 0.00356 mol) and tetrakis(triphenylphosphine)palladium (0.1372 g, 0.00011 mol). After purging the vial with nitrogen gas, dioxane: ethanol: water solution (7:3:2, 7.125 mL) and 2M sodium carbonate (0.007125 mol) was added to the vial respectively. The reaction mixture was stirred and was heated in the microwave at 160° C. for 20 min. Upon completion, the mixture was concentrated under vacuo. The residue was dissolved in ethyl acetate, and filtered through a fitted reservoir. The ethyl acetate layer was concentrated and columned using flash chromatography (0-100% ethyl acetate in hexane and 0-20% methanol in dichloromethane. The remaining residue that didn't dissolve in ethyl acetate was dissolved in methanol and filtered through a fritted reservoir. The methanol layer was concentrated and submitted for reverse phase prep. Pure product (quantitative yield) was recovered.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1.C1COCC1.[BH4-].[Na+]>CCO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)c1cc(Br)ccc1CO
Yield: 71.5 %

Procedure:
To a solution of 4-bromo-2-methansulfonyl-benzaldehyde (1.0 g, 3.88 mmol) in EtOH (11 mL)/THF (2.5 mL) was added NaBH4 (1.29 g, 34.2 mmol) in three portions. The reaction was carefully quenched with water and the product was extracted with EtOAc, dried (Na2SO4), and purified by silica gel chromatography to give 735 mg of (4-bromo-2-methansulfonyl-phenyl)-methanol.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH:7]=[N:6][C:5]=1[C:17]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:18].[H-].[Na+].[N+:30]([C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([N+:41]([O-:43])=[O:42])[CH:40]=1)[CH2:36]Cl)([O-:32])=[O:31]>CN(C=O)C>[N+:30]([C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([N+:41]([O-:43])=[O:42])[CH:40]=1)[CH2:36][N:9]1[C:8]2[CH:7]=[N:6][C:5]([C:17]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:18])=[C:4]([CH2:3][O:2][CH3:1])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)([O-:32])=[O:31]
Reactant: COCc1c(C(=O)OCCN2CCOCC2)ncc2[nH]c3ccccc3c12
Reactant: O=[N+]([O-])c1cc(CCl)cc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1c(C(=O)OCCN2CCOCC2)ncc2c1c1ccccc1n2Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Yield: 72.1 %

Procedure:
The title compound was prepared according to Method A, using 2-(4-morpholinyl)ethyl 4-(methoxymethyl)-9H-β-carboline-3-carboxylate (100 mg, 0.27 mmol), sodium hydride (0.30 mmol, 12 mg of 60% mineral oil suspension), and 3,5-dinitrobenzyl chloride (65 mg, 0.30 mmol) in DMF (2 mL). Purification of the crude material by preparative thin layer chromatography with ethyl acetate/hexane (7:3) afforded 2-(4-morpholinyl)ethyl 9-(3,5-dinitrobenzyl)-4-(methoxymethyl)-9H-β-carboline-3-carboxylate (107 mg, 72%). 1H NMR (CDCl3) δ8.98 (s, 1H), 8.81 (s, 1H), 8.44 (d, J=8.0 Hz, 1H), 8.31 (d,J=1.9 Hz, 2H), 7.68 (t,J=7.3 Hz, 1H), 7.49 (t,J=7.6 Hz, 1H), 7.42 (d, J=8.3 Hz, 2H), 5.83 (s, 2H), 5.44 (s, 2H), 4.59 (t,J=5.8 Hz, 2H), 3.76 (t, J=4.5Hz, 4H), 3.56 (s, 3H), 2.85 (t,J=5.8Hz, 2H), 2.63 (t,J=4.5 Hz, 4H); MS (APCI; (M+H)+) m/z 550.
Reaction SMILES: [OH-].[K+].[C:3]1(C)C=CC=CC=1.[O:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[C:23](=[N:27]\[O:28][CH3:29])/[C:24]([NH2:26])=[O:25])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(OC)(OC)(=O)=O>O>[O:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[C:23](=[N:27]\[O:28][CH3:29])/[C:24]([NH:26][CH3:3])=[O:25])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccccc1
Reactant: CO/N=C(/C(N)=O)c1ccccc1Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccccc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
85% Potassium hydroxide (0.79 g, 12.0 mmol) and toluene (20 ml) were added to (E)-2-(2-phenoxyphenyl)-2-methoxyiminoacetamide (2.70 g, 10.0 mmol) and dissolved by heating to 50° C. After 10 minutes, the solution was concentrated under reduced pressure. Toluene (20 ml) was added to the residue, and dimethyl sulfate (1.32 ml, 14.0 mmol) was added dropwise under ice-cooling and reacted at room temperature for 1 hour. After completion of the reaction, water (100 ml) was added. The mixture was extracted with ether (150 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give (E)-2-(2-phenoxyphenyl)-2-methoxyimino-N-methylacetamide (2.33 g, Yield: 82.1%).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[NH2:14][S:15]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2)(=[O:17])=[O:16].N1CCCCC1>C(O)C>[CH3:13][C:7]1[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:10][NH:9][C:8]=1[CH:11]=[C:21]1[C:20]2[C:24](=[CH:25][CH:26]=[C:18]([S:15](=[O:17])(=[O:16])[NH2:14])[CH:19]=2)[NH:23][C:22]1=[O:27]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(S(N)(=O)=O)cc21
Yield: 70.4 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90.6 mg), 106 mg 5-aminosulfonyl-2-oxindole, and 75 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 132 mg (70%) of the title compound as a yellow solid.