Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][C:21]([NH2:23])=[O:22])=[CH:12]1.C[O:25][C:26](=O)[C:27]([C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[CH:31]=[CH:32][N:33]2[CH3:38])=O>CN(C)C=O>[CH3:38][N:33]1[C:34]2[C:30](=[C:29]([C:27]3[C:26](=[O:25])[NH:23][C:21](=[O:22])[C:20]=3[C:13]3[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:11]([CH2:10][CH2:9][CH2:8][OH:7])[CH:12]=3)[CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:32]1
Reactant: COC(=O)C(=O)c1cccc2c1ccn2C
Reactant: NC(=O)Cc1cn(CCCO)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ccc2c(C3=C(c4cn(CCCO)c5ccccc45)C(=O)NC3=O)cccc21
Yield: 54.4 %

Procedure:
Add potassium tert-butoxide (4.1 ml, 4.1 mmol, 1M in tetrahydrofuran) to a suspension of 2-[1-(3-hydroxypropyl)-1H-indol-3-yl]acetamide (0.32 g, 1.38 mmol) and (1-methyl-1H-indol-4-yl)oxoacetic acid methyl ester (0.30 g, 1.38 mmol) in dimethylformamide (10 ml). Stir the reaction at room temperature for 12 hours, quench with 1N HCl, and extract into ethyl acetate. Wash the organic extract with 5% aqueous lithium chloride and saturated aqueous sodium chloride, dry over magnesium sulfate, filter, and concentrate under reduced pressure. Chromatograph on flash silica using a gradient from neat hexanes to 100% ethyl acetate:hexane to obtain the title compound (0.3 g, 54%) as a red solid. ES(M++1)400.2 ES(M−−1)398.6.
Reaction SMILES: [O:1]=[C:2]([CH2:20][CH3:21])[C:3](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)[C:4]([O:6][CH3:7])=[O:5].[CH3:22]OC(OC)N(C)C>>[CH3:21][C:20]1[C:2](=[O:1])[C:3]([C:4]([O:6][CH3:7])=[O:5])=[N:8][N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH:22]=1
Reactant: CCC(=O)C(=NNc1cccc(C(F)(F)F)c1)C(=O)OC
Reactant: COC(OC)N(C)C
Product: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(C)c1=O
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution of methyl 3-oxo-2-{[3-(trifluoromethyl)phenyl]hydrazono}pentanoate (4.00 g, 13.2 mmol) in N,N-dimethylformamide dimethylacetal (33 mL) was heated at reflux for 2.5 hours. After that time, the reaction was cooled to room temperature and the resulting solid was collected by filtration and washed with a small amount of hexanes to give methyl 5-methyl-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylate (3.55 g, 87%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cu][C:16]#[N:17].C(Cl)Cl>CN(C)C=O>[C:16]([C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)#[N:17]
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1ccc(Br)c2ncccc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccc([N+](=O)[O-])c2cccnc12

Procedure:
5.80 g of 8-bromo-5-nitroquinoline and 2.00 g of copper(I) cyanide in 15 ml of dimethylformamide were heated to 150° C. for 5 hours. After cooling, methylene chloride was added, insoluble particles were filtered off and the filtrate was concentrated.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[CH2:18][N:19]2[C@@H:23]([CH3:24])[C@@H:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:21][C:20]2=[O:31])=[CH:6][C:5]([CH2:32][C:33]([OH:35])=[O:34])=[CH:4][CH:3]=1.Cl.[CH3:37]O>>[CH3:37][O:34][C:33](=[O:35])[CH2:32][C:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:9]=2[CH2:18][N:19]2[C@@H:23]([CH3:24])[C@@H:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:21][C:20]2=[O:31])[C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1O
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccc(O)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Temperature: 80 °C

Procedure:
To [6-hydroxy-2′-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid (0.5 g, 1.0 mmol) in MeOH (20 mL) was added hydrogen chloride (4N in 1,4-dioxane; 2 mL), and the reaction was heated to 80° C. for 2 hours. The mixture was then concentrated and worked-up with EtOAc and saturated aqueous NaHCO3 to give the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=1)(=[O:3])[CH3:2].NC(C(O)=O)CCSC.CS(O)(=O)=O.C(OCC)C>O>[C:1]([O:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1)(=[O:3])[CH3:2]
Reactant: COc1cccc(CC2CCCCC2COC(C)=O)c1
Agent: CS(=O)(=O)O
Agent: CSCCC(N)C(=O)O
Solvent: CCOCC
Solvent: O
Product: CC(=O)OCC1CCCCC1Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
The reaction mixture of [2-(3-methoxybenzyl)cyclohexyl]methyl acetate (66 mg), DL-methionine (357 mg), and methanesulfonic acid (1.55 mL) was stirred at ambient temperature for 18 hours. To the reaction mixture was added diethylether and water. The reaction mixture was stirred. The organic layer was washed with water, brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The mixture was purified by silica gel column chromatography (n-hexane:EtOAc=5:1) to afford [2-(3-hydroxybenzyl)cyclohexyl]methyl acetate (42 mg) as colorless oil.
Reaction SMILES: C([O:4][C:5]([C:7]1[CH:8]=[C:9]([CH:35]=[CH:36][CH:37]=1)[CH2:10][O:11][CH2:12][C@@H:13]([NH:16][C:17](=[O:34])[C@H:18]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]#[N:15])=[O:6])C=C.N1CCOCC1>C1COCC1>[C:5]([C:7]1[CH:8]=[C:9]([CH:35]=[CH:36][CH:37]=1)[CH2:10][O:11][CH2:12][C@@H:13]([NH:16][C:17](=[O:34])[C@H:18]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]#[N:15])([OH:6])=[O:4]
Reactant: C=CCOC(=O)c1cccc(COC[C@H](C#N)NC(=O)[C@H](Cc2cccc(C)c2)Nc2ccccc2)c1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: Cc1cccc(C[C@H](Nc2ccccc2)C(=O)N[C@@H](C#N)COCc2cccc(C(=O)O)c2)c1
Reaction time: 0.17 h

Procedure:
To a solution of N-[2-[3-(allyloxycarbonyl)-benzyloxy]-1(S)-cyanoethyl]-3-methyl-Nα-phenyl-L-phenylalaninamide (12.48 g, 25.11 mmol) in THF (500 mL), is added morpholine (21.9 mL, 251 mmol), and the solution is deoxygenated with bubbling N2 for 5 min. Pd(PPh3)4 is then added in one portion, and the solution is stirred at room temp. for 10 min. Solvent is evaporated, and the residue is dissolved in EtOAc (500 mL), and washed with 1 N HCl (500 mL), brine (200 mL), dried (MgSO4), evaporated and chromatographed (2%-10% MeOH/CH2Cl2) to yield N-[2-(3-carboxy-benzyloxy)-1(S)-cyanoethyl]-3-methyl-Nα-phenyl-L-phenylalaninamide, as a white solid; m.p. 135-137°.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:19])(=O)=O>C(Cl)(Cl)Cl>[Cl:19][C:4]1[CH:3]=[C:2]([F:1])[CH:15]=[CH:14][C:5]=1[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7]
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(=O)c1ccc(F)cc1Cl
Yield: 88.3 %

Procedure:
A mixture of 10.5 g (0.05 mole) of ethyl p-fluorobenzoylacetate, 6.7 g (0.05 mole) of sulfuryl chloride and 30 ml. of chloroform was held at reflux for 18 hours and cooled. The chloroform solution was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 10.8 g (88%) of ethyl 2-chloro-(p-fluoro)-benzoylacetate as an oil. A mixture of 10.8 g (0.441 mole) of ethyl 2-chloro-(p-fluoro)-benzoylacetate, 3.36 g (0.0441 mole) of thiourea, 20 ml. of water and 10 ml. of ethanol was held at reflux for 3 hours. Ethanol was removed under reduced pressure. The residue was made basic with saturated sodium bicarbonate. The solid was filtered, washed with water and recrystallized from ethanol to give 8.9 g (76%) of ethyl 2-amino-4-(p-fluorophenyl)-5-thiazolecarboxylate as white prisms, m.p. 205°-208° C.
Reaction SMILES: C1(CC(NC2C(=O)N3C2CCOC3(C)C)=O)C=CC=CC=1.[N:22]([CH:25]1[C:32](=[O:33])[N:31]2[CH:26]1[CH2:27][CH2:28][O:29]C2(C)C)=[N+:23]=[N-:24]>>[N:22]([CH:25]1[CH:26]([CH2:27][CH2:28][OH:29])[NH:31][C:32]1=[O:33])=[N+:23]=[N-:24]
Reactant: CC1(C)OCCC2C(N=[N+]=[N-])C(=O)N21
Agent: CC1(C)OCCC2C(NC(=O)Cc3ccccc3)C(=O)N21
Product: [N-]=[N+]=NC1C(=O)NC1CCO

Procedure:
Following the procedure of Example 7 except substituting for the indicated 7-phenylacetamido-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane the 7-azido-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane, the title compound is obtained.
Reaction SMILES: [K+].[C:2]([C:4]1[N:5]=[C:6]([C:17]([O-:19])=O)[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)#[N:3].N1C=CC=CC=1.O=S(Cl)Cl.[C:30]1([C:36]2[CH:41]=[C:40]([S:42]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)(=[O:44])=[O:43])[CH:39]=[CH:38][C:37]=2[NH2:51])[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl>[C:30]1([C:36]2[CH:41]=[C:40]([S:42]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)(=[O:44])=[O:43])[CH:39]=[CH:38][C:37]=2[NH:51][C:17]([C:6]2[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[CH:8]=[C:4]([C:2]#[N:3])[N:5]=2)=[O:19])[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: Nc1ccc(S(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(S(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
A suspension of 24.0 mg (0.0785 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 11, step (d)) in CH2Cl2 (5 mL) was treated with 6.40 μL (0.0785 mmol) of pyridine for 5 min. The mixture was cooled to 0° C., and 5.70 μL (0.0785 mmol) of SOCl2 was added, allowed to warm to RT, and stirred for 30 min. A solution of 20.0 mg (0.0620 mmol) of 2-cyclohex-1-enyl-4-(morpholine-4-sulfonyl)-phenylamine (as prepared in the previous step) and triethylamine (12.0 μL, 0.0854 mmol) in CH2Cl2 (1 mL) was treated with the acid chloride solution and stirred at RT for 7 h. The mixture was diluted with CH2Cl2 (10 mL) and washed with water (1×10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 15.0 mg (37%) of the title compound as a tan solid: Mass spectrum (ESI, m/z): Calcd. for C27H37N5O5SSi, 572.2 (M+H), found 572.0.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([O:18]C)([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].CC(C)=O.Cl>O>[C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([OH:18])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: COC1(C)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(O)O2
Reaction time: 3.5 h

Procedure:
To a solution of (±)-6-acetoxy-2-methoxy-2,5,7,8-tetramethylchroman in 2500 ml. of acetone was added 2000 ml. of H2O followed by 16.6 ml. of concentrated aqueous HCl. Solvent was distilled from the stirred mixture until the head temperature reached 90° centigrade. The suspension was cooled in an H2O bath to 50° centigrade. At 70° centigrade, 2000 ml. of acetone was added, giving a clear solution. The solution was seeded occasionally until crystallization began. After 3.5 hours, 1500 ml. of H2O was added and the suspension was cooled in an ice bath. The solid was removed by filtration, washed with H2O and dried at 50° centigrade/0.1 mmHg. to give (±)-6-acetoxy-2-hydroxy-2,5,7,8-tetramethylchroman as a granular yellow-tan solid, sintering from 114° centigrade, m.p. 127°-132° centigrade.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:16][C:12]=2[C:11](=[O:23])[N:10]([CH:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)[C:9]1=[O:37].[ClH:38]>O1CCOCC1>[ClH:38].[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[S:16][C:12]=2[C:11](=[O:23])[N:10]([CH:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]2)[C:9]1=[O:37]
Reactant: Cc1ccsc1Cn1c(=O)n(C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)c2sc(-c3ccccc3)cc21
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccsc1Cn1c(=O)n(C2CCNCC2)c(=O)c2sc(-c3ccccc3)cc21

Procedure:
According to the procedure described for compound B92 tert-butyl 4-{1-[(3-methylthiophen-2-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (825 mg, compound B74) and a solution of hydrogen chloride in 1,4-dioxane (5.0 ml, 6.8 M) are reacted in 1,4-dioxane (25 ml) to afford the title compound as a solid.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:11][C:12]([F:22])([F:21])[C@H:13]([CH3:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Br[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH3:31])=[CH:26][CH:25]=1.C1CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C1CCCCC1.C(OCC)(=O)C>[CH2:30]([C:27]1[CH:28]=[CH:29][C:24]([CH:14]([C@@H:13]([CH3:20])[C:12]([F:21])([F:22])[F:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:25][CH:26]=1)[CH3:31]
Reactant: CCOC(=O)C[C@@H](C)C(F)(F)F
Reactant: CCc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(c1ccc(CC)cc1)[C@@H](C)C(F)(F)F
Reaction time: 0.17 h
Yield: 65 %

Procedure:
24.4 ml (24.4 mmol) of a 1 M solution of lithium hexamethyldisilazide in toluene were cooled to −10° C., and a solution of 3.0 g (16.29 mmol) of (+)-ethyl (3R)-4,4,4-trifluoro-3-methylbutanoate in ml of abs. toluene was added dropwise. The mixture was stirred for 10 min. At −10° C., a solution, prepared beforehand, of 3.92 g (21.18 mmol) of 1-bromo-4-ethylbenzene, 110 mg (0.49 mmol) of palladium(II) acetate and 404 mg (1.03 mmol) of 2′-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl in 20 ml of abs. toluene was then added dropwise. The resulting reaction mixture was then stirred first at RT for 1 h and then at 80° C. for 3 h. The mixture was then concentrated under reduced pressure and the residue was taken up in ethyl acetate and added to water. The aqueous phase was re-extracted with ethyl acetate, and the combined organic phases were washed with saturated ammonium chloride solution and saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue gave, after chromatography on silica gel (mobile phase first cyclohexane, then gradient cyclohexane/ethyl acetate 200:1→50:1), 3.051 g of the title compound (64.9% of theory, diastereomer ratio about 3:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([NH:27][C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH2:24][OH:25])=[CH:20][N:19]=2)=[O:23])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NN1CCCC1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Agent: Cl
Product: O=C(NN1CCCC1)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Yield: 23 %

Procedure:
As described for example 34b, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid (100 mg, 0.29 mmol) was converted, using 1-aminopyrrolidine hydrochloride instead of S-(+)-1-amino-2-propanol, to the title compound (31 mg, 23%), which was obtained as a white solid. MS: m/e=413.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)=[N:15][O:16][C:17]=1[CH3:18])[CH3:9].C([O:29][C:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:31])C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]([NH:12][C:13]1[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:36]3[CH:37]=[CH:38][C:33]([CH2:32][C:30]([OH:31])=[O:29])=[CH:34][CH:35]=3)=[CH:21][CH:20]=2)=[N:15][O:16][C:17]=1[CH3:18])=[O:26])[CH3:9]
Reactant: CCOC(=O)Cc1ccc(B(O)O)cc1
Reactant: Cc1onc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Product: Cc1onc(-c2ccc(-c3ccc(CC(=O)O)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl

Procedure:
Prepared according to the procedure described in Example 1, Step 3 using the following starting materials: [3-(4-bromo-phenyl)-5-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester and (4-ethoxycarbonylmethylphenyl)boronic acid, pinacol ester. Mass spectometric data [M+H]=491.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[OH:11].[C@@H]1(N)CCCC[C@H]1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:28][C:29]1[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=1>O1CCOCC1.CCOC(C)=O.[Cu]I>[F:28][C:29]1[CH:34]=[CH:33][C:32]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([OH:11])=[C:2]([CH3:1])[CH:10]=3)[CH:6]=[N:7]2)=[CH:31][CH:30]=1
Reactant: Cc1cc2[nH]ncc2cc1O
Reactant: Fc1ccc(I)cc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1O
Yield: 38 %

Procedure:
6-Methyl-1H-indazol-5-ol (5.0 g, 33.7 mmol) was dissolved in 50 mL dry dioxane in a stainless steel pressure tube. Trans-1,2-cyclohexanediamine (2.0 mL, 17 mmol) was added followed by CuI (647 mg, 3.4 mmol) and then K3PO4 12.7 g, 60 mmol). After the addition of 4-fluoro-1-iodobenzene (3.9 mL, 33.7 mmol), the reactor was sealed and heated at 100 C for 24 h. The reactor was cooled and the contents were taken up in EtOAc, filtered through a SiO2 plug with EtOAc and concentrated in vacuo. The crude product was chromatographed on SiO2 using 1:3 EtOAc/hexanes to give 3.1 g (38% yield) of 1-(4-fluorophenyl)-6-methyl-1H-indazol-5-ol. MS found: (M+H)+=242.
Reaction SMILES: [CH2:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][CH:9]([C:11](=[O:13])[CH3:12])[O:10][C:6]=2[CH:5]=1)[CH:2]=[CH2:3]>CC1C=CC=CC=1C.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Ru]>[CH:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][CH:9]([C:11](=[O:13])[CH3:12])[O:10][C:6]=2[CH:5]=1)=[CH:2][CH3:3]
Reactant: C=CCc1ccc2c(c1)OC(C(C)=O)O2
Agent: [Ru]
Agent: CC(=O)/C=C(/C)O
Solvent: Cc1ccccc1C
Product: CC=Cc1ccc2c(c1)OC(C(C)=O)O2
Temperature: 25 °C
Yield: 38.2 %

Procedure:
3.4 g of 1-(5-allylbenzo[d][1,3]dioxol-2-yl)ethanone and 68 mg (1 mol %) of ruthenium (III) acetylacetonate in 20 ml of o-xylene were stirred 2 days at 130° C., then cooled to room temperature. After concentration of the solvent in vacuum, the crude product was purified by flash chromatography on silica gel to give 1.3 g (38%) of a colorless oil.
Reaction SMILES: Br[C:2]1[N:25]=[CH:24][C:5]2[N:6]([C:21](=[O:23])[CH3:22])[C@@H:7]([CH3:20])[CH2:8][N:9]([S:10]([C:13]3[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=3)(=[O:12])=[O:11])[C:4]=2[CH:3]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[CH3:20][C@H:7]1[CH2:8][N:9]([S:10]([C:13]2[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:4]2[CH:3]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=3)[N:25]=[CH:24][C:5]=2[N:6]1[C:21](=[O:23])[CH3:22]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(=O)N1c2cnc(Br)cc2N(S(=O)(=O)c2ccc(C)cc2)C[C@@H]1C
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: C1COCCO1
Solvent: O
Product: CC(=O)N1c2cnc(-c3ccc(S(C)(=O)=O)cc3)cc2N(S(=O)(=O)c2ccc(C)cc2)C[C@@H]1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A mixture of (S)-1-(7-bromo-3-methyl-1-tosyl-2,3-dihydropyrido[3,4-b]pyrazin-4(1H)-yl)ethanone (0.010 g, 0.024 mmol), 4-(methylsulfonyl)phenylboronic acid (4.95 mg, 0.025 mmol), tris(dibenzylideneacetone)dipalladium (1.1 mg, 1.2 μmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) (1.1 mg, 2.4 μmol), and cesium carbonate (0.023 g, 0.071 mmol) in 1,4-dioxane (1.5 mL) and water (0.30 mL) were stirred at 80° C. for 2 h. The reaction mixture was filtered through Celite and concentrated to afford an orange solid. This material was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 0-100% ethyl acetate-hexane) to afford (S)-1-(3-methyl-7-(4-(methylsulfonyl)phenyl)-1-tosyl-2,3-dihydropyrido[4,3-b]pyrazin-4(1H)-yl)ethanone (0.006 g, 51%) as an off-white solid. MS (ESI, pos. ion) m/z 500.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](C(OC)=O)=[CH:2]1.[H-].[Na+].CI.[CH3:18][N:19]([CH:21]=O)[CH3:20]>O>[CH3:18][N:19]1[C:20]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:2][NH:1][CH3:9])=[CH:21]1
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CNCc1cn(C)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
Methyl 1-methyl-1H-indole-3-carboxylate NaH (60% dispersion in mineral oil, 8.56 g, 214.0 mmole) was added portionwise, allowing for gas evolution, to a solution of methyl 1H-indole-3-carboxylate (25.00 g, 142.7 mmole) in DMF (350 mL) at 0° C. When the NaH addition was complete, methyl iodide (44.4 mL, 713.5 mmole) was added at 0° C. The reaction was stirred at 0° C. for 15 minutes then at RT overnight. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were dried over K2CO3 and concentrated to afford the title compound (26.00 g, 96%) as an orange solid: MS (ES) m/e 190 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[S:19](=[O:22])(=[O:21])[CH2:20][C:11]=3[C:10]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Br-].[S:32]1[CH:36]=[CH:35][N:34]=[C:33]1[Zn+]>C1COCC1>[N:25]1([C:23]([C:10]2[C:11]3[CH2:20][S:19](=[O:22])(=[O:21])[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:12]=3[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:33]4[S:32][CH:36]=[CH:35][N:34]=4)[CH:3]=3)[N:9]=2)=[O:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O=C(c1nn(-c2cccc(Br)c2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Reactant: [Zn+]c1nccs1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(c1nn(-c2cccc(-c3nccs3)c2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1

Procedure:
1-(3-bromophenyl)-3-(morpholin-4-ylcarbonyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (100 mg, 0.20 mmol, 1 eq.) is taken in THF in and bubbled with nitrogen for 5 minutes. To this are added thiazolyl zinc bromide (2 mL), tetrakis(triphenyl phosphine)palladium(0) (12 mg, 0.010 mmol, 0.05 eq.) and the reaction mixture is heated under sealed condition at 65° C. for 4 h. The reaction mixture is filtered through a celite pad, concentrated under reduced pressure and purified by flash chromatography to afford the title compound as a pink solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.18-8.16 (d, J=7.7 Hz, 1H), 8.07 (s, 1H), 8.04-8.02 (d, J=7.7 Hz, 1H), 7.96-7.95 (d, J=3.2 Hz, 1H), 7.87-7.86 (d, J=3.2 Hz, 1H), 7.76-7.72 (t, J=7.9 Hz, 1H), 7.65-7.56 (m, 3H), 6.98-6.96 (d, J=7.7 Hz, 1H), 4.91 (s, 2H), 3.93 (m, 2H), 3.67 (m, 4H), 3.62-3.61 (m, 2H). MS (ESI+): 493.0. HPLC (max plot) 98.44%; Rt 4.02 min.