Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][N:10]=[C:9]2[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)=[C:4]([F:27])[CH:3]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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].ClCCl>[F:27][C:4]1[CH:3]=[C:2]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:35]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[CH2:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Reactant: COc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)OC(C)(C)C)C4)n[nH]c3=O)c(F)c2)c1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A solution of 1,1-dimethylethyl (3S)-3-{[4-(4-bromo-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]methyl}-1-pyrrolidinecarboxylate (0.499 mmol) in dioxane (3 mL) was treated with 3-methoxyphenylboronic acid pinacol ester (0.513 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (30 mg), and 2M aq potassium carbonate (1.5 mL). The reaction mixture was purged with nitrogen, sealed, and stirred at 110° C. for 2 h. The solution was cooled to room temperature and the dioxane layer separated from the aqueous layer. The dioxane layer was removed via pipette and was passed through a plug of celite and sodium sulfate. The plug was washed with dioxane (10 mL). All dioxane filtrates were combined and concentrated in vacuo. Silica gel chromatography (100% ethyl acetate) was utilized in purifying the title compound (212 mg, 88%). MS(ES)+ m/e 469.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]3[CH2:22][CH:21]=[C:20](B4OC(C)(C)C(C)(C)O4)[CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.Br[C:34]1[CH:35]=[C:36]([S:40][CH3:41])[CH:37]=[CH:38][CH:39]=1>>[CH3:32][N:2]([CH3:1])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]3[CH2:22][CH:21]=[C:20]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([S:40][CH3:41])[CH:35]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: CSc1cccc(Br)c1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)N3CC=C(B4OC(C)(C)C(C)(C)O4)CC3)cc2)C1
Product: CSc1cccc(C2=CCN(C(=O)Nc3ccc(N4CCC(N(C)C)C4)cc3)CC2)c1

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide was reacted with 3-bromothioanisole by method O-a. This resulted in the product with the molecular weight of 436.62 (C25H32N4OS); MS (ESI): 437 (M+H+)
Reaction SMILES: [H-].[Na+].C(O)C.[C:6]([O:14]CC)(=[O:13])[CH2:7][C:8](OCC)=O.[Br:17][C:18]1[CH:25]=[CH:24][C:21](CBr)=[CH:20][CH:19]=1>C1COCC1>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:8][CH2:7][C:6]([OH:14])=[O:13])=[CH:20][CH:19]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.9 %

Procedure:
Sodium hydride (60% dispersion in oil; 4 g) was added portionwise to an ethanol (100 ml) solution of diethyl malonate (16 g) under ice-cooling. The reaction mixture was stirred at room temperature for 10 minutes, to which was added dropwise a THF (50 ml) solution of p-bromobenzylbromide (12 g) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and concentrated. Acetic acid (200 ml) and6N hydrochloric acid (100 ml) were added to the residue. The reaction mixture was stirred under heating at 90° C. for 18 hours, and concentrated. Water was added to the residue, which was extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1), which was recrystallized from IPE to obtain the entitled compound (1.2 g).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C:11]1([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].CN1CCOCC1.[F:44][C:45]1[CH:53]=[CH:52][CH:51]=[CH:50][C:46]=1[C:47](Cl)=[O:48].C(O)C(N)(CO)CO>ClCCl>[OH:7][NH:8][C:9]([C:11]1([S:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:16][CH2:15][N:14]([C:47]([C:46]2[CH:50]=[CH:51][CH:52]=[CH:53][C:45]=2[F:44])=[O:48])[CH2:13][CH2:12]1)=[O:10]
Reactant: O=C(NOC1CCCCO1)C1(S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)CCNCC1
Reactant: O=C(Cl)c1ccccc1F
Agent: NC(CO)(CO)CO
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(c1ccccc1F)N1CCC(C(=O)NO)(S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)CC1
Reaction time: 2 h

Procedure:
To a solution of N-(2-tetrahydropyranoxy)-4[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide, the product of Example 94, (50 mg) dissolved in dichloromethane (2.5 mL) was added PS-NMM (135 mg, Argonaut) and 2-fluorobenzoyl chloride (12.1 [L) and stirred for 2 hours. To the reaction mixture was added PS-trisamine (50 mg, Argonaut) and the mixture was stirred 1 hour. The reaction mixture was filtered and washed with dichloromethane (2×2 mL) and methanol (1×2 mL). The combined organics were evaporated to afford N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl]-sulfonyl]-1-(2-fluorophenylcarbonyl)-4-piperidinecarboxamide (53.5 mg) as a white solid. MS (ES) m/z 583 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[H-].[Na+].[C:14]1([C:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([C:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1[nH]c2ccc(Br)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1oc2cc(Br)ccc2n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
6-Bromo-3H-benzooxazol-2-one (0.165 g, 0.77 mmol) was added portionwise into a 0° C. suspension of NaH (44.8 mg, 1mmol, 55%) in dry DMF (4 ml). After 1 hour stirring at room temperature, a solution of triphenylmethylchloride (0.24 g, 0.85 mmol) in DMF (0.5 ml) was added. The reaction mixture was stirred 1 hour at room temperature then quenched with H2O (15 ml). The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with H2O and brine, dried over Na2SO4 and concentrated to provide 6-bromo -3-trityl-3H-benzooxazol-2-one (0.27 g, 77 %) as a beige solid, MS: m/e=457.1 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[Cl:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30].C(N(CC)CC)C>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[Cl:27])=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1c(-c2ccc(Br)cc2)nc2cccnc21)Nc1ccccc1Cl
Temperature: 25 °C
Yield: 39.8 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (3.2 g, 0.025 mole) was added dropwise (slowly) to a stirred and chilled (5°-10° C.) solution of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (8.0 g, 0.024 mole) in anhydrous dimethylformamide (50 ml). The reaction mixture was heated at 55°-60° C. for 4 hrs, cooled to room temperature, and added dropwise to a stirred and chilled (10°-15° C.) solution of 2-chloroaniline (3.2 g, 0.25 mole) and triethylamin(2.5 g, 0.025 mole) in anhydrous dimethylformamide (100 ml). The reaction mixture was stirred at room temperature overnight, filtered, and poured into water (350 ml). The mixture was allowed to precipitate and filtered. The filter cake was twice suspended in water (250 ml) and filtered. The filter cake was air dried and twice recrystallized from tetrahydrofuran to give 4.22 g (40%) of a white solid, mp. 230.5°-232° C.
Reaction SMILES: [Li][CH3:2].[C:3]1([C:9]2[CH:10]=[CH:11][CH:12]=[N:13][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CCOCC>[CH3:2][C:12]1[CH:11]=[CH:10][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:14][N:13]=1
Reactant: c1ccc(-c2cccnc2)cc1
Reactant: [Li]C
Solvent: CCOCC
Product: Cc1ccc(-c2ccccc2)cn1

Procedure:
To a 0° C. solution of 1.4 M MeLi in Et2O (35 mm) was added 5-phenylpyridine (4.65 g). The Et2O was distilled off almost completely and replaced by THF (15 cc) and the solution was refluxed for 1 hour. 25% aqueous NH4OAc (25 cc) was added and the mixture extracted with ethyl acetate (2×50 cc). The organic layer was washed with brine and the solvents removed in vacuo. The residue was purified by chromatography to afford the title compound. p.m.r. (CD3COCD3) δ 8.7 (d, 1H), 7.2-7.9 (m, 7H), 2.5 (s, 3H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@@H:16]([CH2:24][CH3:25])[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].[CH:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]2[N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:35]=[C:36]([C:37]([O:39][CH3:40])=[O:38])[C:29]=12)=O>ClCCCl.C(O)(=O)C>[O:18]=[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[C@@H:16]([NH:15][CH2:26][C:28]1[CH:33]=[CH:32][N:31]=[C:30]2[N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:35]=[C:36]([C:37]([O:39][CH3:40])=[O:38])[C:29]=12)[CH2:24][CH3:25]
Reactant: CC[C@H](N)C(=O)N1CCCC1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC[C@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
A mixture of sodium triacetoxyborohydride (279 mg, 1.315 mmol) and (S)-2-amino-1-(pyrrolidin-1-yl)butan-1-one (123 mg, 0.789 mmol) in DCE (2 mL) was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C. A solution of 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (200 mg, 0.657 mmol) in DCE (2 mL) was added, followed by acetic acid (1 drop). The reaction was stirred at 0° C. for 30 min and then at room temperature for 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%) afforded the title compound as a yellow oil (83mg, 28.4%). [M+H] calc'd for C23H32N4O5, 445; found, 445.5.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.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>[CH3:26][N:24]1[CH:25]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]3[N:16]([C:12]([CH2:11][C:8]4[CH:9]=[CH:10][C:5]5[N:6]([C:2]([C:33]6[CH:34]=[C:29]([CH:30]=[CH:31][CH:32]=6)[C:27]#[N:28])=[CH:3][N:4]=5)[CH:7]=4)=[CH:13][N:14]=3)[N:17]=2)[CH:22]=[N:23]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(Br)n5c4)n3n2)cn1
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: CCOC(C)=O
Solvent: COCCOC
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(-c6cccc(C#N)c6)n5c4)n3n2)cn1
Temperature: 150 °C

Procedure:
3-(3-Bromo-imidazo[1,2-a]pyridin-6-ylmethyl)-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 296, 80 mg, 0.196 mmol) was dissolved in DME (0.653 mL) with 3-cyanophenylboronic acid (28.2 mg, 0.196 mmol), 2 M Na2CO3 solution (0.353 mL, 0.705 mmol) and tetrakis(triphenylphosphine)palladium (11.3 mg, 0.010 mmol). The RM was heated at 150° C. 5 min under microwave irradiations. It was taken up with EtOAc and washed with 10% Na2CO3 solution and brine. The precipitate from the aqueous layer was filtered off and dried to afford the title compound as a grey solid (tR 0.8 min (conditions 2), MH+=431).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][N:3]=1.C[Si](C)(C)[C:14]([F:17])([F:16])[F:15].Cl.C(OCC)(=O)C>COCCOC.O.C1C=CC=CC=1.[F-].[Cs+].O.C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6](=[O:8])[C:14]([F:17])([F:16])[F:15])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: c1ccccc1
Solvent: O
Product: O=C(c1ccc(Cl)nc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
To a solution of methyl 6-chloronicotinate (150.0 g, 874.2 mmol) and CsF (1.73 g, 11.36 mmol) in DME (480 mL) was added trimethyl(trifluoromethyl)silane (138.9 mL, 939.8 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 3 hours. 4 N HCl (655.7 mL, 2623 mmol) in water was added, and the mixture was stirred at ambient temperature for 18 hours. Ethyl acetate (500 mL) was added. The organic layer was separated, washed with saturated sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give brown oil. The oil was dissolved in benzene (200 mL) and then dehydrated by water/benzene in a Dean-Stark apparatus. After 18 hours, mixture was distilled under reduced pressure to give 1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethanone (171 g, 93.3%) as white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([CH3:21])[CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>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.CN(C)C=O>[N+:11]([C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([C:17]2[CH:18]=[C:19]([CH3:21])[CH:20]=[C:15]([CH3:14])[CH:16]=2)[CH:10]=1)([O-:13])=[O:12]
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(-c2cc([N+](=O)[O-])ccc2C(=O)O)c1
Temperature: 100 °C
Yield: 61.7 %

Procedure:
2-bromo-4-nitrobenzoic acid (0.50 g, 2.03 mmol) and 3,5-dimethylphenyl boronic acid (0.34 g, 2.23 mmol) were dissolved into anhydrous DMF (dimethylformamide) (25 ml) under nitrogen. To this mixture was added Cs2CO3 (1.66 g, 5.08 mmol) followed by Pd(Ph3P)4 (0.12 g, 5%). The mixture was heated at 100° C. overnight. The solution was poured onto 1N HCl and extracted into Et2O. It was dried over MgSO4 and the solvent was removed in vacuo. The crude material was chromatographed on silica gel using a 9:1 mixture of hexanes and ethyl acetate to yield 0.34 g (61.7%) of pure product. 1H NMR (CDCl3) 2.36 (6 H, s), 6.99 (2 H, s), 7.07 (1 H, s), 8.03 (1 H, d, J=9.0 Hz), 8.23-8.25 (2 H, m); 13C NMR (CDCl3) 21.28, 121.68, 123.68, 125.74, 126.07, 130.22, 131.19, 131.31, 135.04, 138.21, 144.74, 170.75.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][N:13]([CH2:24][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)[CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1
Reactant: O=Cc1ccccn1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Product: COc1ccc2c3c(c(=O)oc2c1)CN(Cc1ccccn1)CC3
Yield: 25 %

Procedure:
Prepared by the procedure of Example 3 from 8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one and 2-pyridinecarboxaldehyde. Yield 25%; mp 140°-142° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:6][CH2:5]2.C(=[NH:28])(C1C=CC=CC=1)C1C=CC=CC=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>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].O>[CH2:12]([O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][CH2:7]2)=[CH:3][C:2]=1[NH2:28])[CH2:13][CH3:14]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CCCOc1cc2c(cc1Br)CCC2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CCCOc1cc2c(cc1N)CCC2
Temperature: 100 °C
Reaction time: 47 h
Yield: 16.6 %

Procedure:
To a 5-bromo-6-propoxyindan (8.24 g, 32.2 mmol) toluene solution (80 ml) were added a benzophenone imine (6.40 g, 35.3 mmol) toluene solution (40 ml), tris(dibenzylideneacetone)dipalladium (742 mg, 0.8 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS, 936 mg, 1.6 mmol), and cesium carbonate (15.72 g, 48.3 mmol). The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 47 hours, and then cooled to room temperature. Water and saturated ammonium chloride solution were added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure. The generated residue was dissolved in diethyl ether (130 ml). Concentrated hydrochloric acid (25 ml) was added to the solution, followed by stirring for 2 hours. A 5N aqueous sodium hydroxide solution (72 ml) was added to the reaction mixture to adjust its pH to 11, followed by concentration under reduced pressure. The residue was dissolved in dichloromethane and washed with an aqueous saturated sodium chloride solution. The thus-obtained organic layer was concentrated to dryness under reduced pressure, and the generated residue was then purified using silica gel column chromatography (dichloromethane:ethyl acetate=90:1). The purified product was concentrated to dryness under reduced pressure, giving a pale brown oily substance of 6-propoxy-indan-5-ylamine (1.02 g, yield: 17%).
Reaction SMILES: C(O[C:4](=[O:19])[C@@H:5]([NH2:18])[C@@H:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[OH:7])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].N[C@H:27]([CH2:40]O)[C@@H:28](C1C=CC(S(C)(=O)=O)=CC=1)O.COC(C)=C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH3:28][C:27]1([CH3:40])[NH:18][C@H:5]([CH2:4][OH:19])[C@@H:6]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][CH:13]=2)[O:7]1
Reactant: CCOC(=O)[C@@H](N)[C@H](O)c1ccc(S(C)(=O)=O)cc1
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CO)cc1
Agent: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC1(C)N[C@H](CO)[C@@H](c2ccc(S(C)(=O)=O)cc2)O1

Procedure:
(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate (Compound IV) (100 g, 0.3480 moles) in tetrahydrofuran (500 mL) reacts with lithium aluminum hydride (16.0 g, 0.4224 moles) over 4-8 hours at 60-70° C. to quantitatively yield (1R,2R)-2-amino-1-[4-methylsulfonyl)phenyl]-1,3-propandiol (Compound VII: R1 is methylsulfonyl) (85.36 g, 0.3480 moles). Addition of ethyl acetate (75 mL) destroys any excess lithium aluminum hydride. Addition of xylene (600 mL), 2-methoxypropene (37.6 g, 0.5220 moles), and p-toluenesulfonic acid monohydrate (6.6 g, 0.0348 moles) with agitation at 20-30° C. for 10-16 hours produces (4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound VIII: R1 is methylsulfonyl and R2 and R3 are methyl). Addition of triethylamine (81.3 g, 0.8039 moles) and acetyl chloride (30.0 g, 0.3828 moles) at 20-25° C. for 2-4 hours then addition of water (650 mL) precipitates the crude product. Filtration, washing with water (300 mL) then drying yields (4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound II).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:19]([O:18][C:16]([N:10]1[CH2:15][CH2:14][N:13]([C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[CH3:9])[CH2:12][CH2:11]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(Cl)ccc1Br
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 20 %

Procedure:
2-Bromo-5-chlorotoluene (0.82 g, 4 mmol) and tert-Butyl 1-piperazine carboxylate (0.89 g, 2.32 mmol) were added to a solution of tri-t-butyl phosphine (0.033 g, 4 mmol %), tris(dibenzylideneacetone)dipalladium(0) (0.075 g, 2.0 mmol %) and cesium carbonate (1.95 g, 6.0 mmol) in toluene and heated to 80° C. overnight. The reaction mixture was filtered through celite and concentrated in vacuo. The crude product was purified on silica gel (gradient elution from 20% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound in 20% yield. ESI-MS m/z: 311 (M+1), UV retention time: 3.49 min.