Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:11]1[CH:12]=[C:13]([C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[C:14](=[O:28])[N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:16]=1[CH3:17].C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(O)C>[CH3:17][C:16]1[N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=2)[C:14](=[O:28])[C:13]([C:29]([NH:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])=[CH:12][C:11]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
A mixture of phenylboronic acid (25 mg, 0.20 mmol), 1,1′bis(diphenylphosphino)ferrocenedichloropalladium(II) (4 mg, 0.005 mmol), 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (100 mg 0.17 mmol), toluene (1 ml), ethanol (99%, 0.25 ml) and Na2CO3 (2M, 0.25 ml) was stirred at 80° C. overnight, concentrated and the residue was purified by flash chromatography to give the title compound (70 mg, 76%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[CH3:12][C:13]([CH3:16])([CH3:15])[CH2:14][S:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: CC(C)(C)CI
Reactant: Cc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(SCC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.9 %

Procedure:
Dissolve 4-methyl-benzenethiol (1.5 g, 12.08 mmol) in anhydrous DMF (6 mL). Cool the solution to 0° C., add sodium hydride (435 mg, 17.21 mmol, 95%) and stir the mixture under nitrogen atmosphere for 15 min. Add 1-iodo-2,2-dimethylpropane (1.93 mL, 14.5 mmol), stir the mixture for 1 h at 0° C., warm to room temperature and stir overnight. Add water and extract the aqueous phase twice with EtOAc. Wash the combined organic extracts twice with iced-water, dry over Na2SO4, filter and concentrate in vacuo to give the desired intermediate (1.476 g, 63% yield).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.Br[C:24]1[CH:36]=[CH:35][C:34]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[C:26]=2[CH:25]=1.CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.CC([O-])(C)C.[Na+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[N:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[N:27]1[C:26]2[CH:25]=[C:24]([N:12]3[C:13]4[CH:1]=[C:2]([C:14]5[O:15][C:16]6[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=6[N:18]=5)[CH:3]=[CH:4][C:5]=4[C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2
Reactant: Brc1ccc2c3ccccc3n(-c3ccccn3)c2c1
Reactant: c1ccc2oc(-c3ccc4c(c3)[nH]c3ccccc34)nc2c1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: c1ccc(-n2c3ccccc3c3ccc(-n4c5ccccc5c5ccc(-c6nc7ccccc7o6)cc54)cc32)nc1
Temperature: 102.5 °C

Procedure:
To a dry Schlenk tube equipped with a magnetic stir bar was added 2-(9H-carbazol-2-yl)benzo[d]oxazole (569 mg, 2.0 mmol, 1.0 eq), 2-bromo-9-(pyridin-2-yl)-9H-carbazole (711 mg, 2.2 mmol, 1.1 eq), Pd2(dba)3 (37 mg, 0.04 mmol, 0.02 eq), JohnPhos (24 mg, 0.04 mmol, 0.04 eq) and tBuONa (308 mg, 3.2 mmol, 1.6 eq). The tube was evacuated and back-filled with nitrogen, and this evacuation/back-fill procedure was repeated twice. Then dry toluene (16 mL) was added under the atmosphere of nitrogen, the tube was then sealed quickly. The mixture was stirred in an oil bath at a temperature of 100-105° C. The reaction was monitored by TLC. 24 hours later, some starting material was not consumed. So more Pd2(dba)3 (37 mg, 0.04 mmol, 0.02 eq), SPhos (33 mg, 0.08 mmol, 0.04 eq) and tBuONa (96 mg, 1.0 mmol, 0.5 eq) and dioxane (3 mL) were added. The mixture was stirred in an oil bath at a temperature of 105-105° C. for another 24 hours and cooled to ambient temperature. The mixture was concentrated and the residue was purified through column chromatography on silica gel using dichloromethane/methanol (10:1) as an eluent to obtain the desired product, 2-(9-(pyridin-2-yl)-9H-2,9′-bicarbazol-2′-yl)benzo[d]oxazole Ligand N13N, as a brown solid (1056 mg in 99% yield). 1H NMR (DMSO-d6, 400 MHz): δ 7.37-7.50 (m, 6H), 7.52-7.61 (m, 2H), 7.66 (dd, J=8.0, 1.6 Hz, 1H), 7.75-7.78 (m, 2H), 7.91 (d, J=8.4 Hz, 2H), 8.06-8.11 (m, 2H), 8.17-8.19 (m, 2H), 8.40 (d, J=7.6 Hz, 1H), 8.45 (d, J=7.6 Hz, 1H), 8.52 (d, J=7.2 Hz, 1H), 8.64 (d, J=8.4 Hz, 1H), 8.67-8.68 (m, 1H).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:14][P:15]([CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:34][CH:33]=2)[CH:25]=1)O)(=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:13])([CH3:12])[CH3:11].[OH-].[K+]>ClCCl>[C:10]([O:14][P:15]([CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:34][CH:33]=2)[CH:25]=1)[F:7])(=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(O)c1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)c1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Temperature: -70 °C
Reaction time: 20 h
Yield: 36 %

Procedure:
Diethylaminosulfur trifluoride (2.2 ml, 8.2 mmol) was dissolved in dichloromethane (25 ml) and the solution was cooled to -70° C. and added dropwise to a solution of the above hydroxymethylphosphonic acid di-tert-butyl ester (4.0 g, 8.3 mmol) in dichloromethane (15 ml) at -70° C. The mixture was stirred at -70° C. for 3 h and at room temperature for 20 h. With stirring the mixture was poured into 1 N aqueous potassium hydroxide (200 ml) and the mixture was extracted with dichloromethane (1×300 ml) and (1×100 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (100 ml), dried (MgSO4), filtered and evaporated in vacuo affording 1.43 g (36%) of ((3-(biphenyl-4-ylmethoxy)-phenyl)fluoromethyl)phosphonic acid di-tert-butyl ester as a solid.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(OC(=O)C)=O.[CH3:14][NH:15][C@@H:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1.[OH-].[Na+]>C(O)=O>[C@@H:16]1([N:15]([CH3:14])[CH:5]=[O:7])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: CN[C@H]1CCCc2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)OC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN(C=O)[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Acetic anhydride (73.5 g) was chilled and stirred as 98% formic acid (44.2 g) was added over 30 minutes keeping the temperature below 10° C. The resulting solution of acetic-formic anhydride was stirred for a further 15 minutes at 5° C. and added over 5 minutes to a stirred, chilled solution of (S)(+)-N-methyl-1,2,3,4-tetrahydro-1-naphthylamine (26 g) in 98% formic acid (26 ml). The reaction solution was stirred at ambient temperature for 1 hour, poured into an ice-water mixture (200 g) and basified with 10N aqueous sodium hydroxide solution (about 250 ml) to pH 10; the mixture was then extracted with dichloromethane (3×200 ml). The combined extracts were back-washed with 1N aqueous hydrochloric acid (100 ml ), then water (100 ml), and evaporated under vacuum to give the title compound (28.69 g, 94%) as a solid, m.p. 52°-54° C.; Rf 0.80 (silica; chloroform, methanol; 95:5). A chiral HPLC assay on an acetylated β-cyclodextrin column showed this material to be a 94:6 mixture of the (S)- and (R)-enantiomers, respectively.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].CCN(CC)CC.[C:27](Cl)(=[O:29])[CH3:28]>C1COCC1>[NH2:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:5]([O:6][CH2:7][C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:27](=[O:29])[CH3:28])[C:4]=1[C:2]#[N:3]
Reactant: CC(=O)Cl
Reactant: N#Cc1c(OC[C@@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC[C@H]1COc1cccc(N)c1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
To a suspension of (S)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (130 mg, 0.46 mmol) (Example 209b) in THF (5 mL) were added Et3N (135 μL, 0.97 mmol) and acetyl chloride (36 μL, 0.50 mmol). The reaction was stirred at rt for 18 h, filtered and diluted with EtOH (20 mL). The resulting solution was hydrogenated (20 Bar) using 10% Pd/C as the catalyst. Upon completion, the reaction mixture was concentrated to provide the title compound (61 mg, 51%) as a clear syrup. MS 260 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:22]#[N:23])=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:5]([CH2:11][O:12][CH2:13][CH3:14])[C:6]=1[C:7]([F:10])([F:9])[F:8].[OH-:24].[Na+].OO>CO.O>[Br:1][C:2]1[C:3]([C:22]([NH2:23])=[O:24])=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[N:5]([CH2:11][O:12][CH2:13][CH3:14])[C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: [OH-]
Reactant: CCOCn1c(-c2ccc(Cl)cc2)c(C#N)c(Br)c1C(F)(F)F
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOCn1c(-c2ccc(Cl)cc2)c(C(N)=O)c(Br)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 86.9 %

Procedure:
A mixture of 4-bromo-2-(p-chlorophenyl)-1-(ethoxymethyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (4.07 g, 10 mmol), sodium hydroxide (0.8 g, 20 mmol) and 30 wt/wt % hydrogen peroxide solution (7.2 mL, 70 mmol) in methanol is stirred at room temperature for 7 hours, treated with sodium hydroxide solution (0.8 g NaOH in 5 mL of H2O) and 30 wt/wt % hydrogen peroxide solution (7 mL), stirred at room temperature overnight, heated at 40° C. for 8 hours and diluted with water. The aqueous mixture is filtered and the filter cake is washed with water and heptane and dried to give the title product as a white solid (3.7 g) which is identified by 1H and 13C NMR spectral analyses.
Reaction SMILES: [CH:1]1([CH:4]([O:16][CH3:17])[C:5]2[O:6][C:7]3[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:8]=3[CH:9]=2)[CH2:3][CH2:2]1.[Br:18]N1C(=O)CCC1=O>C(#N)C>[Br:18][C:10]1[C:8]2[CH:9]=[C:5]([CH:4]([CH:1]3[CH2:2][CH2:3]3)[O:16][CH3:17])[O:6][C:7]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc2cc(C(OC)C3CC3)oc12
Solvent: CC#N
Product: COc1ccc(Br)c2cc(C(OC)C3CC3)oc12

Procedure:
Prepared from 2-(cyclopropyl-methoxy-methyl)-7-methoxybenzofuran (3.12 g) and N-bromosuccinimide (2.4 g) in acetonitrile (45 ml). The title compound was obtained as an orange gum (3.49 g).
Reaction SMILES: FC1C=CC(C(Cl)=O)=CC=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1)[NH2:15].[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.C(O)C>[F:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:39][CH:40]=1.[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:44]([NH:43][C:41](=[O:42])[C:38]2[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=2)=[S:45])[CH:16]=[CH:17][C:18]=1[O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1
Agent: O=C(N=C=S)c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
4-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (67 mg, yield 87%).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH:25]([OH:27])[CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13](B1OC(C)(C)C(C)(C)O1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:36]2[NH:44][C:43]3[CH2:42][CH2:41][NH:40][C:39](=[O:45])[C:38]=3[CH:37]=2)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([NH:5][C:6]1[C:7]([CH:25]([OH:27])[CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:36]1[NH:44][C:43]3[CH2:42][CH2:41][NH:40][C:39](=[O:45])[C:38]=3[CH:37]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(O)c1nc2cccc(B3OC(C)(C)C(C)(C)O3)c2nc1NC(C)(C)C
Reactant: CC1(C)OB(c2cc3c([nH]2)CCNC3=O)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(O)c1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Temperature: 105 °C
Yield: 26 %

Procedure:
A mixture of 1-(3-(tert-butylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-2-yl)ethanol (310b; 960 mg, 1.732 mmol), 2-bromo-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (608) (596 mg, 2.77 mmol), K2PO4 (1177 mg, 5.54 mmol), X-Phos (Strem Chemicals, Inc., 83 mg, 0.173 mmol), and Pd2dba3 (Aldrich) (79 mg, 0.087 mmol) in a mixture of 1,4-dioxane (15 mL) and water (3.00 mL) was heated under argon at 105° C. for 1.5 h. The reaction mixture was then cooled to RT, diluted with water (100 mL), and extracted with 5% MeOH/DCM (3×100 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) followed by trituration of the collected solid with Et2O (10 mL) furnished 2-(3-(tert-butylamino)-2-(1-hydroxyethyl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (310) (172 mg, 0.45 mmol, 26% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.99 (1H, br. s.), 7.85 (1H, dd, J=7.5, 1.3 Hz), 7.58 (1H, dd, J=8.0, 1.2 Hz), 7.47 (1H, s), 7.34 (1H, t, J=7.8 Hz), 7.04 (1H, d, J=2.2 Hz), 6.93 (1H, s), 6.43 (1H, br. s.), 4.96 (1H, q, J=6.8 Hz), 3.43 (2H, td, J=6.8, 2.5 Hz), 2.86 (2H, t, J=6.8 Hz), 1.54 (9H, s), 1.50 (3H, d, J=6.7 Hz). m/z (ESI, +ve) 380.1 (M+H)+. Separation of this material (310c) by supercritical-fluid chromatography (Chiralpak IC (150×30 mm, 10 μm), 70% liquid CO2/30% MeOH (+20 mM NH4OH), 70 mL/min) separately afforded: first-eluting peak, (S)-2-(3-(tert-butylamino)-2-(1-hydroxyethyl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one, (310; 35.0 mg, 0.092 mmol, m/z (ESI, +ve) 380.1 (M+H)+); and second-eluting peak, (R)-2-(3-(tert-butylamino)-2-(1-hydroxyethyl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (311; 39.0 mg, 0.103 mmol, m/z (ESI, +ve) 380.1 (M+H)+).
Reaction SMILES: CO[C:3](=[O:42])[C@@H:4]([NH:32][S:33]([C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34])[CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)=[O:15])[CH:9]=1.O[Li].O.[CH2:46]([O:53][C:54](=[O:57])[CH2:55][NH2:56])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.Cl.CN1CCOCC1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C.C1COCC1.CO.O>[CH2:46]([O:53][C:54](=[O:57])[CH2:55][NH:56][C:3](=[O:42])[C@@H:4]([NH:32][S:33]([C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)(=[O:34])=[O:35])[CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:19]2)=[O:15])[CH:9]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: COC(=O)[C@H](CNC(=O)c1cccc(C(=O)NCC2CCN(C(=O)OC(C)(C)C)CC2)c1)NS(=O)(=O)c1cccnc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2cccc(C(=O)NC[C@H](NS(=O)(=O)c3cccnc3)C(=O)NCC(=O)OCc3ccccc3)c2)CC1

Procedure:
A solution of 31-1 (0.75 g, 1.5 mmol) in 1:1:1 THF/MeOH/H2O (15 mL) was treated with LiOH·H2O (0.37 g, 8.8 mmol). After 45 min. the solution was concentrated, diluted with water, washed with EtOAc. The aqueous layer was acidified to pH 2-3 with 10% KHSO4 and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and evaporated to give an acid which was dissolved in acetonitrile (3 mL) and treated with glycine benzyl ester·HCl (0.1 g, 0.5 mmol), N-methylmorpholine (0.11 mL, 0.98 mmol), and BOP reagent (0.26 g, 0.58 mmol) for 24 h. The solution was concentrated, dissolved in water and EtOAc and the layers separated. The organic layer was dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 70% acetone/hexanes) gave 31-2 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].Br[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Oc1cc([N+](=O)[O-])ccc1Cl
Reaction time: 3.5 h

Procedure:
A mixture of 17.4 g. of 2-chloro-5-nitrophenol, 19.0 g. of ethyl α-bromopropionate, 15.2 g. of potassium carbonate and 85 ml. of acetone was refluxed with stirring for 3.5 hours and the solvent was distilled off. 2N-HCl was added to the residue to obtain a crude crystal. The product was separated by a filtration and washed with water and dried and recrystallized from n-hexane to obtain 27.4 g. of the object compound (melting point of 46° to 46.5° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][C:5]([OH:15])=[C:4](I)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][N:25]=[N:24][CH:23]=1)CCC.[F-].[Cs+]>C(#N)C.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][C:5]([OH:15])=[C:4]([C:22]2[CH:27]=[CH:26][N:25]=[N:24][CH:23]=2)[CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: Oc1cc(-c2ccc(F)cc2)c(Cl)cc1I
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Product: Oc1cc(-c2ccc(F)cc2)c(Cl)cc1-c1ccnnc1
Temperature: 45 °C
Yield: 58 %

Procedure:
A suspension of 6-chloro-4′-fluoro-4-iodobiphenyl-3-ol (Preparation 103, 300 mg, 0.86 mmol), 4-(tributylstannyl)-pyridazine (413 mg, 1.12 mmol), caesium fluoride (261 mg, 1.72 mmol), and copper (I) iodide (33 mg, 0.17 mmol) in acetonitrile (5 mL) was degassed for 20 minutes under nitrogen. Tetrakistriphenylphosphinepalladium (0) (100 mg, 0.09 mmol) was added and the reaction mixture was heated for 18 hours at 45° C. under nitrogen. The cooled reaction mixture was filtered through Arbocel and the Arbocel pad was washed with ethyl acetate (100 mL). The organic layer was washed with brine (2×15 mL), dried over MgSO4, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 20% heptane in ethyl acetate to afford the title compound (150 mg, 58%) as an oil.
Reaction SMILES: [H-].[Na+].C1(C)C=CC(S([N:12]2[C:28]3[C:15]4=[C:16]([CH:25]=[CH:26][CH:27]=3)[C@H:17]3[O:22][CH2:21][C:20](=O)[NH:19][C@@H:18]3[CH2:24][C:14]4=[CH:13]2)(=O)=O)=CC=1.[CH3:30]I.O>CN(C=O)C>[CH3:30][N:19]1[C@@H:18]2[CH2:24][C:14]3[C:15]4[C:28]([NH:12][CH:13]=3)=[CH:27][CH:26]=[CH:25][C:16]=4[C@H:17]2[O:22][CH2:21][CH2:20]1
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(cccc42)[C@H]2OCC(=O)N[C@@H]2C3)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCO[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
Sodium hydride (50% in mineral oil, 1.1 gms, 0.045 m) is added in portions to a stirred solution of trans 4-(p-tolylsulphonyl)-4,6,6a,8,9,10a hexahydro-7H-indolo-[3,4 gh]-[1,4] benzoxazin-8-one (7.0 gm, 0.018 m) in DMF (14 ml). The resulting mixture is stirred at room temperature for 1/2 hour. Methyl iodide (5.0 gm, 0.035 m) is added dropwise to the reaction mixture. After stirring an additional 1/2 hour, the reaction solution is poured into water, and the solid is removed by filtration. The tan solid is chromatographed (silica, chloroform) to give 3 gms of trans-4,6,6a,8,9,10a-Hexahydro-7-methyl-7H-indolo-[3,4 gh]-[1.4]-benzoxazine.
Reaction SMILES: [CH2:1]([C:5]1(O)[CH2:30][N:9]2[C@H:10]([C:26](C)(C)C)[CH2:11][C:12]3[C:17]([CH:8]2[CH:7](CO[SiH3])[C:6]1=[O:34])=[C:16](OC)[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[C:13]=3OC)[CH2:2][CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH2:54]>C1COCC1>[CH2:1]([CH:5]1[CH2:30][N:9]2[C@H:10]([CH2:26][OH:54])[CH2:11][C:12]3[C:17]([CH:8]2[CH2:7][C:6]1=[O:34])=[CH:16][C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[CH2:2][CH2:3][CH3:4]
Reactant: O
Reactant: CCCCC1(O)CN2C(c3c(c(OC)c(OC)c(OC)c3OC)C[C@H]2C(C)(C)C)C(CO[SiH3])C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCC1CN2C(CC1=O)c1cc(OC)c(OC)cc1C[C@H]2CO
Reaction time: 2 h

Procedure:
To a solution of 0.40 g of (6S)-3-Butyl-3-hydroxy-6-tert-butyldimethoxy-siloxymethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one in 13 ml of THF at 0° C. was slowly added a solution of 1.78 ml of tetrabutylammonium fluoride (1M in THF). The reaction mixture was stirred for 2 hours keeping the temperature between 0-5° C. The reaction mixture was poured into ice cooled water (49 ml) and then extracted two times with 30 ml of ethyl acetate. The organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was then purified by chromatography (silica gel, hexane/ethyl acetate 0-70%) to give 0.30 g of (6S)-3-Butyl-6-hydroxymethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one, MS (ISP) 348.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=O)=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O=S(Cl)Cl.[NH3:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH2:28])=[O:23])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: N
Solvent: O=S(Cl)Cl
Product: NC(=O)Cc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
from 4-[2-(4-chlorophenylsulphonylamino)-ethyl]-phenylacetic acid, SOCl2 and ammonia.