Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>C(O)CC.O>[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:14]=[C:13]([C:15]([OH:24])([C:20]([F:21])([F:22])[F:23])[C:16]([F:17])([F:19])[F:18])[CH:12]=[C:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[CH:3]=2)=[CH:28][CH:27]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C(O)(C(F)(F)F)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCO
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C(O)(C(F)(F)F)C(F)(F)F)c2)cc1
Temperature: 85 °C

Procedure:
To a mixture of tert-butyl 3-bromo-5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzoate (1.2 g, 2.8 mmol) from Example 2.11 step B, (4-methylphenyl)boronic acid (0.5 g, 3.7 mmol), Pd[P(Ph3)]4 (0.16 g, 0.14 mmol), and K2CO3 (1.2 g, 8.5 mmol) under N2 was added 28 mL of degassed n-Propanol/water (4:1). The reaction was heated to 85° C. overnight. The mixture was cooled to room temperature, filtered over celite and concentrated. The crude material was taken up in EtOAc and sat. NaHCO3. The organic layer was extracted (3×) and washed with brine. The final organic layer was dried over Na2SO4, filtered and concentrated to 1.0 g of crude material. Purification using automated flash chromatography (SiO2, 120 g, 0-5% MeOH/DCM) gave, upon concentration, title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]([O:29]CC)=[O:28])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]([OH:29])=[O:28])[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cc3cc(C(=O)O)ccc3nc2-c2ccc(OC)cc2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
A solution of ethyl 2,3-bis(4-methoxyphenyl)quinoline-6-carboxylate (83 mg, 0.20 mmol, 1.00 equiv) and sodium hydroxide (40 mg, 1.00 mmol, 5.00 equiv) in methanol (10 mL) and water (1 mL) were placed in a 25-mL round-bottom flask and stirred for 3 h at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum, diluted with 10 mL of H2O, and the pH adjusted to 4-5 with 1N HCl. The resulting solids were collected by filtration and dried in an oven under reduced pressure. The crude product (80 mg) was purified by Flash-Prep-HPLC (CH3CN/H2O; Detector, UV 254 nm), affording 60 mg (78%) of 2,3-bis(4-methoxyphenyl)quinoline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([C:18](=[O:23])N(OC)C)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[C:31]([NH:32][C:33](=[O:35])[CH3:34])=[CH:30][CH:29]=[CH:28][N:27]=1>>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])[C:18](=[O:23])[CH2:25][C:26]1[C:31]([NH:32][C:33](=[O:35])[CH3:34])=[CH:30][CH:29]=[CH:28][N:27]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C
Reactant: CC(=O)Nc1cccnc1C
Product: CC(=O)Nc1cccnc1CC(=O)[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 2 with [(R)-2-(2,5-Difluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (4.85 mmol; 1.67 g) and N-(2-Methylpyridin-3-yl)acetamide (12.12 mmol; 1.82 g) gives the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[C:15]([C:16]([O:18]C)=O)=[CH:14][S:13][CH:12]=1)=[O:9].Cl.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1>>[F:36][C:22]([F:21])([F:35])[C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]3[C:16](=[O:18])[C:15]4=[CH:14][S:13][CH:12]=[C:11]4[NH:10][C:8]3=[O:9])[CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: COC(=O)c1cscc1NC(=O)NCCCCCBr
Agent: Cl
Product: O=c1[nH]c2cscc2c(=O)n1CCCCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 96.7 %

Procedure:
The title compound was prepared by the procedure in Example 18 starting with 10.13 g (29 mmol) of the N-(5-bromopentyl)-N'-(4-carbomethoxythien-3-yl]urea of Example 12 and 15.47 g (58 mmol) of 1-(3-trifluoromethylphenyl)piperazine hydrochloride. There was obtained 13.08 g (96%) of the known 3-[5-[4-(3-trifluoromethylphenyl)piperazin-1-yl]pentyl]thieno[3,4-d]pyrimidine-2,4-dione (J. Press and R. Russell, U.S. Pat. No. 4,670,560) which was crystallized from CH2Cl2 /hexane to afford a white solid, mp 118°-123° C.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1.C(O)C>[C:17]1([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Nc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2cccc3ccccc23)cc1
Temperature: 60 °C

Procedure:
First, 5.0 g (29 mmol) of 4-bromoaniline, 5.0 g (29 mmol) of 1-naphthylboronic acid, and 0.45 g (1.5 mmol) of tri(ortho-tolyl)phosphine were put into a 500-mL three-neck flask, and the air in the flask was replaced with nitrogen. Then, 100 mL of toluene, 50 mL of ethanol, and 31 mL of a potassium carbonate aqueous solution (2 mol/L) were added to this mixture. The mixture in the flask was stirred and degassed while reducing pressure in the flask. Then, after the mixture was heated at 60° C., 66.2 mg (0.29 mmol) of palladium(II) acetate was added to the mixture. The mixture was refluxed at 80° C. for 2.3 hours. After the reflux, toluene and water were added to the mixture, an organic layer and an aqueous layer were separated, and the aqueous layer was extracted twice with toluene. The extract and the organic layer were combined, washed with a saturated saline solution, and dried with magnesium sulfate. The mixture was subjected to gravity filtration to remove magnesium sulfate. Then, the filtrate was concentrated to give an oily substance, which was subjected to suction filtration through Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), and alumina to obtain a filtrate. The resulting filtrate was concentrated to give 2.5 g of an oily substance, which was an object, in a yield of 40%.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:16][CH2:15][N:14]([C:17]([C:19]4[S:27][C:26]5[CH2:25][CH2:24][NH:23][CH2:22][C:21]=5[CH:20]=4)=[O:18])[CH2:13][CH2:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:37][O:38][C:39]1[CH:44]=[C:43]([CH3:45])[C:42]([S:46](Cl)(=[O:48])=[O:47])=[C:41]([CH3:50])[CH:40]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH3:50])[C:42]([S:46]([N:23]2[CH2:24][CH2:25][C:26]3[S:27][C:19]([C:17]([N:14]4[CH2:15][CH2:16][C:11]5([CH2:28][CH2:29][N:8]([C:5]6[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=6)[CH2:9][CH2:10]5)[CH2:12][CH2:13]4)=[O:18])=[CH:20][C:21]=3[CH2:22]2)(=[O:47])=[O:48])=[C:43]([CH3:45])[CH:44]=1
Reactant: O=C(c1cc2c(s1)CCNC2)N1CCC2(CC1)CCN(c1ccncc1)CC2
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCc3sc(C(=O)N4CCC5(CC4)CCN(c4ccncc4)CC5)cc3C2)c(C)c1
Reaction time: 15 h

Procedure:
(9-(Pyridin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)(4,5,6,7-tetrahydrothieno[3,2-c]-pyridin-2-yl)methanone hydrochloride (89 mg, 0.208 mmol) was dissolved in dichloromethane (5 ml) and cooled, and triethylamine (0.07 ml, 0.52 mmol) was added thereto. At 0° C., a solution of 4-methoxy-2,6-dimethylbenzenesulfonyl chloride (50 mg, 0.208 mmol) in dichloromethane (5 ml) was added dropwise, and then stirring was carried out for 15 h at room temperature. Saturated sodium hydrogen carbonate solution (10 ml) was added, the mixture was stirred for 15 min. and the phases were separated. The aqueous phase was extracted with dichloromethane (30 ml), and then the combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/methanol/-ammonia (25% aq.), 400:20:1). Yield: 70 mg (56%). MS, R=3.4 min; m/z=595.3 [MH]+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][C:22]([CH2:24][C:25]2[CH:32]=[CH:31][C:28]([CH2:29][OH:30])=[CH:27][CH:26]=2)=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][C:22]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([CH:29]=[O:30])=[CH:31][CH:32]=2)=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(NC(=O)Cc2ccc(CO)cc2)c2ccccc2N2CCCCC2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(NC(=O)Cc2ccc(C=O)cc2)c2ccccc2N2CCCCC2)cc1
Reaction time: 12 h

Procedure:
One-half gram (1.2 m mol) of 4-{N-[α-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl}-benzyl alcohol was added to a suspension of 0.4 gm (1.5 m mol) of pyridinium chlorochromate in 2 ml of chloroform. After 12 hours at ambient temperature, ether was added, the mixture was filtered, and the concentrated filtrate was purified by column chromatography on silica gel [eluant: toluene/ethyl acetate (5:1)].
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([N:18]([C:28]([C:30]1[S:31][CH:32]=[C:33]([Br:35])[CH:34]=1)=[O:29])[O:19]C(C1SC=C(Br)C=1)=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](=[O:8])[O-:7])(C)C.C([O-])([O-])=O.[K+].[K+]>CO>[Br:35][C:33]1[CH:34]=[C:30]([C:28]([N:18]([OH:19])[CH:10]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:9][NH:5][C:6](=[O:8])[O:7][C:12]([CH3:17])([CH3:13])[CH3:11])=[O:29])[S:31][CH:32]=1
Reactant: CC(C)(C)N(CC(Cc1ccccc1)N(OC(=O)c1cc(Br)cs1)C(=O)c1cc(Br)cs1)C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(Cc1ccccc1)N(O)C(=O)c1cc(Br)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
To a solution of 1,1-dimethylethyl[2-([(4-bromo-2-thienyl)carbonyl]{[(4-bromo-2-thienyl)carbonyl]oxy}amino)-3-phenylpropyl]carbamate in MeOH (5 mL) was added K2CO3 (1.0 g, 7.3 mmol). The mixture was stirred at RT for 2 h. The mixture was concentrated under vacuum and purified on silica gel (EtOAc/Hexane, 30%) to give the title compound (410 mg, 37% for two steps) as an off white solid: LC-MS (ES) m/z=456 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]>CO.[Pd]>[CH2:6]([O:5][C:3](=[O:4])[C:2]([CH3:8])([O:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)[CH3:1])[CH3:7]
Reactant: CCOC(=O)C(C)(C)Oc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(C)(C)Oc1ccc(N)cc1
Yield: 68 %

Procedure:
The title compound (1.2 g, 68%) was prepared from ethyl 2-methyl-2-(4-nitrophenyloxy)propanoate (2 g, 7.9 mmol) by hydrogenation with 10% Pd/C (1 g) in methanol at 50 psi and room temperature for 2 h.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([CH3:24])=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:27][CH2:26]3)=[CH:16][C:15]=2[F:32])[CH2:10][CH:9]1[CH3:33])C1C=CC=CC=1>[Pd].C(O)(=O)C>[CH3:33][CH:9]1[NH:8][CH2:13][CH2:12][N:11]([C:14]2[C:23]([CH3:24])=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:26][CH2:27]3)=[CH:16][C:15]=2[F:32])[CH2:10]1
Reactant: Cc1c(N2CCN(Cc3ccccc3)C(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To 7-(4-benzyl-3-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.30 g) are added acetic acid (10 ml) and 10% Pd-C (50 mg), and the mixture is subjected to catalytic reduction at 70° C. under atmospheric pressure for one hour. After the catalytic reduction, the reaction mixture is cooled and the catalyst is removed by filtration. The filtrate is concentrated, and to the residue is added water, and the mixture is adjusted to about pH 7.5 with sodium hydrogen carbonate, and then is extracted with dichloromethane. The dichloromethane is distilled off, and to the residue is added diethyl ether, and the resulting precipitates are separated by filtration and recrystallized from ethanol to give 7-(3-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.16 g), as pale yellow powder, m.p. 206°-208° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:15][C:14]2[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][C:9](=S)[C:8]=2[N:7]=1)=[O:5])[CH3:2].FC(F)(F)S(OC)(=O)=O.[CH3:30][O:31][CH2:32][CH2:33][C@H:34]1[CH2:39][NH:38][CH2:37][CH2:36][NH:35]1>C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:15][C:14]2[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[N:10]=[C:9]([N:38]3[CH2:37][CH2:36][NH:35][C@@H:34]([CH2:33][CH2:32][O:31][CH3:30])[CH2:39]3)[C:8]=2[N:7]=1)=[O:5])[CH3:2]
Reactant: COCC[C@H]1CNCCN1
Reactant: CCOC(=O)c1nc2c(s1)Nc1ccccc1NC2=S
Agent: COS(=O)(=O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCOC)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine 10-thioxo-9,10-dihydro-4H-3-thia-1,4,9-triaza-benzo[f]azulene-2-carboxylic acid ethyl ester (3.59 g, 11.76 mmol) in 25 mL CH2Cl2 and add methyl trifluoromethanesulfonate (2.41 g, 14.7 mmol) dropwise at 0° C., stir at 0° C. for half hour, and warm to RT. After 2 h, concentrate the reaction mixture under reduced pressure, mix with (S)-2-(2-methoxy-ethyl)-piperazine (0.1.47 g, 10.2 mmol) in 20 mL pyridine and heat to 100° C. After 4 hours, cool the reaction to RT, and concentrate to a residue. Purification by flash chromatography (twice) on silica gel using a gradient (100% CH2Cl2 to 100% mixed solvent of (CH2Cl2: 2N NH3/MeOH=20:1)) over 55 min. gives the title compound: mass spectrum (electrospray) (m/e): C20H25N5O3S, Calc. Mass (M+1): 416.1756, Found: 416.1748. 1H NMR (400 MHz, CDCl3): δ 7.05-6.98 (m, 2H), 6.91-6.85 (m, 1H), 6.65-6.62 (m, 1H), 5.51 (br, 1H), 4.40 (q, 2H, J=7.5 Hz). 4.10 (br, 2H), 3.51 (t, 2H, J=6.0 Hz), 3.32 (s, 3H), 3.30-3.00 (m, 4H), 2.79-2.72 (m, 1H), 1.79-1.66 (m, 2H), 1.38 (t, 3H, J=7.5 Hz).
Reaction SMILES: FC1C=CC=CC=1C=O.[Br:10][C:11]1[CH:12]=[C:13]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[O:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[C:19](F)[C:16]=1[CH:17]=O.O.[NH2:30][NH2:31]>CS(C)=O>[Br:10][C:11]1[CH:12]=[C:13]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[O:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]2[C:16]=1[CH:17]=[N:30][NH:31]2
Reactant: NN
Reactant: O=Cc1c(F)ccc(Cl)c1Oc1cc(Cl)cc(Br)c1
Agent: O=Cc1ccccc1F
Solvent: CS(C)=O
Solvent: O
Product: Clc1cc(Br)cc(Oc2c(Cl)ccc3[nH]ncc23)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 2-(3-bromo-5-chlorophenoxy)-3-chloro-6-fluorobenzaldehyde fluorobenzaldehyde (4.5 kg; 12.36 moles; 1.0 eq.) in DMSO (18 L) was degassed, after which hydrazine monohydrate (6.192 kg; 123.7 moles; 10.0 eqs.) was added over 20 minutes at room temperature. The reaction solution was degassed again, stirred at room temperature for 15 minutes, heated to 73° C., and then aged for 16 hours. After the mixture was cooled to room temperature, isopropanol (15 L) and then water (40 L) were added, and the resulting mixture cooled to room temperature, filtered under pressure, and washed with isopropanol:water (1:2; 10 L), water (12 L), and heptane (12 L). The title product as a solid was obtained after drying at 30° C.-35° C. under vacuum for four days.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([N:12]2C(=O)[C:19]3[C:14](=[CH:15]C=CC=3)[C:13]2=O)[C:4](=[O:23])[C:3]=1[C:24]1[NH:29][C:28]2[S:30][CH:31]=[C:32]([CH2:33][O:34][CH2:35][O:36][CH3:37])[C:27]=2[S:26](=[O:39])(=[O:38])[N:25]=1.C1(C=O)CC1>CN(C)C(=O)C>[CH:14]1([CH:13]=[N:12][N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([OH:1])=[C:3]([C:24]3[NH:29][C:28]4[S:30][CH:31]=[C:32]([CH2:33][O:34][CH2:35][O:36][CH3:37])[C:27]=4[S:26](=[O:38])(=[O:39])[N:25]=3)[C:4]2=[O:23])[CH2:15][CH2:19]1
Reactant: COCOCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(N3C(=O)c4ccccc4C3=O)c1=O)N2
Agent: O=CC1CC1
Solvent: CC(=O)N(C)C
Product: COCOCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(N=CC3CC3)c1=O)N2
Temperature: 25 °C
Yield: 73.4 %

Procedure:
The product of Example 350D (94 mg, 0.22 mmol) was reacted with cyclopropanecarbaldehyde (0.162 mL, 2.2 mmol) in N,N-dimethylacetamide (1 mL) in a sealed tube at 120° C. for 90 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and filtered to give the title compound (78.9 mg, 75%).
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([O:28][CH3:29])=[CH:20][C:3]=1[CH2:4][N:5]1[C@H:9]([C:10]([CH3:18])([CH3:17])[O:11][SiH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][CH2:7][C:6]1=[O:19].[CH2:30]([O:37][C:38]1[C:43](B(O)O)=[CH:42][CH:41]=[CH:40][N:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)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>[CH2:30]([O:37][C:38]1[C:43]([C:2]2[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([O:28][CH3:29])=[CH:20][C:3]=2[CH2:4][N:5]2[C@H:9]([C:10]([CH3:18])([CH3:17])[O:11][SiH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][CH2:7][C:6]2=[O:19])=[CH:42][CH:41]=[CH:40][N:39]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1cc(CN2C(=O)CC[C@H]2C(C)(C)O[SiH2]C(C)(C)C)c(Br)cc1C(C)(C)C
Reactant: OB(O)c1cccnc1OCc1ccccc1
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: CO
Solvent: ClCCl
Product: COc1cc(CN2C(=O)CC[C@H]2C(C)(C)O[SiH2]C(C)(C)C)c(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Yield: 75 %

Procedure:
step 2—A sealed tube containing 104 (141 mg, 0.29 mmol), 2-benzyloxy-pyridin-3-yl boronic acid (100 mg, 0.44 mmol), Na2CO3 (92 mg, 0.87 mmol) and Pd(PPh3)4 (33 mg, 0.029 mmol) in a mixture of MeOH (1.5 mL) and DCM (0.5 mL) was irradiated in a microwave synthesizer at 100° C. for 30 min. The reaction mixture was diluted with DCM, filtered through a pad of CELITE and the filtrate was concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 40% EtOAc/hexanes to afford 128 mg (75%) of (S)-1-[2-(2-benzyloxy-pyridin-3-yl)-4-tert-butyl-5-methoxy-benzyl]-5-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-2-one (106).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH3:13].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:12][S:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:13][Br:14])[CH:4]=1)(=[O:11])=[O:10]
Reactant: Cc1cc(OS(C)(=O)=O)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)Oc1ccc(Cl)c(CBr)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
To a solution of the product from step A (61.3 g, 301 mmol) in 500 ml of carbon tetrachloride was added N-bromosuccinimide (80.3 g, 451 mmol) and 2,2-azobisisobutyronitrile (7.40 g, 45.0 mmol). The reaction was stirred at 80° C. for 2.5 hr, concentrated in vacuo, and then suspended in 30% EtOAc/Hexane (300 mL). The solution was filtered and concentrated to give crude product. The crude product was purified by silica gel chromatography (20% EtOAc/Hexane) to provide the title product as a yellow oil
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15](O)[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:27][C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1.O>C(#N)C>[Br:27][C:28]1[CH:29]=[C:30]([S:34]([N:11]2[C:10](=[O:13])[N:9](/[CH:14]=[CH:15]/[C:16]([F:19])([F:18])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:12]2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=c1n(S(=O)(=O)c2cccc(Br)c2)nc(-c2ccc(Cl)cc2)n1/C=C/C(F)(F)F

Procedure:
500 mg (1.63 mmol) of the compound from Example 5A were dissolved in 10 ml of acetonitrile, and 449 mg (3.25 mmol) of potassium carbonate and 415 mg (1.63 mmol) of 3-bromobenzenesulfonyl chloride were added. The mixture was heated under reflux for 2 h. For work-up, 10 ml of water were added and the mixture was extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 8:1→5:1→1:1). This gave 285 mg (34% of theory) of the target compound.
Reaction SMILES: [CH3:1][C@@H:2]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:3]=O.Cl.[CH3:17][O:18][C:19](=[O:22])[CH2:20][NH2:21].C1COCC1>CO>[CH2:8]([O:7][C:6]([NH:5][C@H:2]([CH3:1])[CH2:3][NH:21][CH2:20][C:19]([O:18][CH3:17])=[O:22])=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@H](C=O)NC(=O)OCc1ccccc1
Reactant: COC(=O)CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CNC[C@@H](C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
A 1000 mL round bottom flask was charged with benzyl (1R)-1-methyl-2-oxoethylcarbamate (59.4 mmol) and 347 mL of anhydrous methanol. The resulting mixture was cooled to 0° C. and glycine methyl ester hydrochloride (29.3 g, 237.6 mmol) was added. After 10 minutes, 1.0 M NaCNBH4 in THF (95 mL, 95.0 mmol) was added and the reaction was allowed to warm to 22° C. overnight. The reaction mixture was then concentrated, redissolved in diethyl ether (200 mL) and placed in a separatory funnel. The organic phase was washed with saturated NaHCO3 (200 mL) and separated. The basic aqueous layer was washed twice with diethyl ether (2×200 mL), and the combined organic layers were washed with brine (2×200 mL), dried with Na2SO4 and concentrated. Silica gel chromatography using 2:1 hexanes/ethyl acetate with gradual polarization to 1:1 hexanes/ethyl acetate provided the desired product as a clear oil in 75% yield (12.5 g, 44.6 mmol).