Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:39])[C:10]1[CH:15]=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[C:12]([CH2:25][N:26]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:27][CH3:28])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:42][C:43](=[O:52])[CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[C:49](Br)[CH:50]=1)C.C(=O)([O-])[O-].[K+].[K+]>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>[CH2:1]([O:8][C:9](=[O:39])[C:10]1[CH:15]=[CH:14][C:13]([C:49]2[CH:48]=[N:47][CH:46]=[C:45]([CH2:44][C:43]([OH:42])=[O:52])[CH:50]=2)=[C:12]([CH2:25][N:26]([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])[CH2:27][CH3:28])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(Cc1cc(C(=O)OCc2ccccc2)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)Cc1cncc(Br)c1
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: [K+]
Solvent: COCCOC
Product: CCN(Cc1cc(C(=O)OCc2ccccc2)ccc1-c1cncc(CC(=O)O)c1)C(=O)OCc1ccccc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
3-[(N-Benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid benzyl ester (1.96 g, 3.7 mmol), (5-bromo-pyridin-3-yl)-acetic acid ethyl ester (0.99 g, 4.1 mmol), and potassium carbonate (1.79 g, 13.0 mmol) were combined in DME (40 mL) and H2O (30 mL), and the solution was purged with N2 for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.427 g, 0.37 mmol) was added, and the reaction was stirred at 70° C. overnight. The mixture was quenched with 1N aqueous HCl (13 mL) and extracted with EtOAc. The combined organic layers were washed with H2O, and then dried and concentrated to give 3-[(N-benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-(5-carboxymethyl-pyridin-3-yl)-benzoic acid benzyl ester.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:39]=[CH:38][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([N:12]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:13][C@H:14]([O:23][Si:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[O:16]([CH2:15][C@@H:14]([O:23][Si:24]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:29][CH3:30])[CH2:13][N:12]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH:10]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:38]=[CH:39][C:3]([CH2:2][O:1][S:48]([CH3:47])(=[O:50])=[O:49])=[CH:4][C:5]=2[CH2:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(CO)cc2C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(COS(C)(=O)=O)cc2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of N-(3-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyl-oxy)propyl]-tert-butoxycarbonylamine (1.93 g) and triethylamine (0.58 ml) in dichloromethane (40 ml) was added dropwise methanesulfonyl chloride (0.27 ml) under ice-cooling. After stirring at room temperature for 6 hours, the reaction mixture was washed successively with water, sodium bicarbonate solution, water and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo to afford crude N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-N-(3-methylsulfonyloxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-tert-butoxycarbonylamine (2.18 g), which was used without purification.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]2[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][O:8][C:4]=2[CH:3]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CC(N(C)C)=O.[Cu]I>[O:21]=[C:19]1[C:18]2[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=[O:26])[N:20]1[C:2]1[CH:15]=[CH:14][C:5]2[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)c1coc2cc(Br)ccc12
Agent: [Cu]I
Agent: [K]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1coc2cc(N3C(=O)c4ccccc4C3=O)ccc12
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 6-bromo-1-benzofuran-3-carboxylate (14.90 g, 55.4 mmol) in 200 mL of DMA was added potassium phthalimide (10.3 g, 55.4 mmol) and CuI (10.6 g, 55.4 mmol) and the mixture was stirred at 150° C. under nitrogen atmosphere overnight. The reaction mixture was concentrated under vacuum, and the residue was dissolved in DCM, filtered through Celite®. The filtration was concentrated and purified with silica gel column chromatograph to give ethyl 6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-benzofuran-3-carboxylate.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[N:22][C:21]([O:25][CH3:26])=[CH:20][CH:19]=2)(C)(C)C>ClCCl>[NH2:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[N:22][C:21]([O:25][CH3:26])=[CH:20][CH:19]=2
Reactant: COc1ccc2ncc(NC(=O)OC(C)(C)C)cc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(N)cc2n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 21.1 %

Procedure:
Trifluoroacetic acid (101 mL, 1.32 mol, 20.85 eq) is added to a stirred solution of (6-methoxy-[1,5]naphthyridine-3-yl)-carbamic acid tert-butyl ester (18.2 g, 66.11 mmol, 1.0 eq) in dichloromethane (500 mL). After 19 hours stirring at room temperature, the solution is evaporated to dryness, 6N sodium hydroxide aqueous solution is added to adjust pH to 9˜10 and a lot of solid precipitated. The mixture is extracted with dichloromethane (200 mL) and the residue is extracted with ethyl acetate (3×250 mL). Evaporation of the dichloromethane phase gives 2.44 g of product with 83% purity, which is then purified by column chromatography (silica gel, eluent: dichloromethane:petroleum ether:ethyl acetate, 25:25:2, v/v/v) to afford 6-methoxy-[1,5]naphthyridin-3-ylamino as a light yellow solid (1.95 g with 98% purity). Evaporation of the ethyl acetate phase yields additional 9.88 g of light yellow product with 99% purity. Total: 11.83 g (98% yield).
Reaction SMILES: [N:1]1[C:6]2[CH:7]3[CH2:12][NH:11][CH2:10][CH2:9][N:8]3[C:13](=[O:14])[C:5]=2[CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Br:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[Br:24][C:25]1[CH:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:28]=[CH:27][C:26]=1[S:35]([N:11]1[CH2:10][CH2:9][N:8]2[C:13](=[O:14])[C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:6]=3[CH:7]2[CH2:12]1)(=[O:37])=[O:36]
Reactant: O=C1c2cccnc2C2CNCCN12
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1c2cccnc2C2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3Br)CCN12
Temperature: 0 °C

Procedure:
To a solution of 8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-a]pyrazin-5(7H)-one (may be prepared as in Intermediate 7, 130 mg) in DCM (5 mL) was added DIPEA (0.360 mL, 2.061 mmol). The mixture was cooled to 0° C. and 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (233 mg) was added.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]([C:11]([OH:13])=[O:12])[NH:2]1.[CH3:14]OC(OC)OC.Cl>CO>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]([C:11]([O:13][CH3:14])=[O:12])[NH:2]1
Reactant: O=C(O)[C@@H]1Cc2ccccc2CN1
Reactant: COC(OC)OC
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1Cc2ccccc2CN1

Procedure:
A mixture of 1 eq. of (S)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (Aldrich Chemical Co., Milwaukee, Wis.), 5 eq. of trimethylorthoformate, methanol and catalytic HCl were allowed to heat at reflux for 5 h. Concentration in vacuo provided methyl (S)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate.
Reaction SMILES: C(O[C@H]1C2C(=CC(OCCC)=CC=2)[C@@H](N)C1)C=C.[CH2:19]([O:22][C@H:23]1[C:31]2[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=2)[C@@H:25]([NH2:33])[CH2:24]1)[CH:20]=[CH2:21].[F:34][C:35]1[CH:36]=[C:37]([CH2:42][C@H:43]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[C@H:44]2[CH2:46][O:45]2)[CH:38]=[C:39]([F:41])[CH:40]=1>>[CH2:19]([O:22][C@H:23]1[C:31]2[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=2)[C@@H:25]([NH:33][CH2:46][C@@H:44]([OH:45])[C@@H:43]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:52])([CH3:51])[CH3:53])[CH2:42][C:37]2[CH:36]=[C:35]([F:34])[CH:40]=[C:39]([F:41])[CH:38]=2)[CH2:24]1)[CH:20]=[CH2:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Reactant: C=CCO[C@@H]1C[C@H](N)c2cc(Br)ccc21
Agent: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)c2cc(Br)ccc21
Yield: 76 %

Procedure:
Step BE (1). (1S,3R)-3-(Allyloxy)-6-bromo-2,3-dihydro-1H-inden-1-amine from Step Z(1) was reacted with tert-butyl (S)-2-(3,5-difluorophenyl)-1-((S)-oxiran-2-yl)ethylcarbamate following a procedure analogous to Step AW (1) to afford 1.5 g (76% yield) of tert-butyl (2S,3R)-4-((1S,3R)-3-(allyloxy)-6-bromo-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamate. LC-MS (M+H)+ 568.97. 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (s, 9H) 1.79-1.90 (m, 2H) 2.64-2.82 (m, 4H) 3.03 (dd, J=14.09, 4.21 Hz, 1H) 3.36-3.44 (m, 1H) 3.68-3.80 (m, J=8.42, 4.03 Hz, 1H) 4.01-4.12 (m, 3H) 4.50 (d, J=9.51 Hz, 1H) 4.73 (t, J=6.04 Hz, 1H) 5.18 (dd, J=10.43, 1.28 Hz, 1H) 5.24-5.34 (m, J=17.20, 1.46 Hz, 1H) 5.92 (ddd, J=22.60, 10.52, 5.67 Hz, 1H) 6.63 (tt, J=9.01, 2.33 Hz, 1H) 6.70-6.78 (m, 2H) 7.25 (d, J=8.05 Hz, 1H) 7.39 (dd, J=7.87, 1.65 Hz, 1H) 7.49 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[Ca+2].[Br-:15].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl.CO>[Br:15][C:7]1[C:6]([CH3:9])=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[CH:8]=1
Reactant: [Br-]
Reactant: Cc1ccc(F)c(N)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(N)c(F)cc1Br
Yield: 81.7 %

Procedure:
To a slurry of 2-fluoro-5-metylaniline (6.75 g, 54 mmol) and CaCO3 (10 g, 100 mmol) in CH2Cl2 (1 L) and MeOH (400 mL) was added a solution of Benzyltrimethylammonium tribromide (22.3 g, 57 mmol) in CH2Cl2 (180 mL) and MeOH (70 mL). The solution was added dropwise and the mixture was stirred over night. The solution was a light orange/tan color. The mixture was filtered and the solvent was removed under reduced pressure. The resulting slurry was diluted with H2O (100 mL) and extracted with Et2O (3×200 mL). The mixture was purified by flash column chromatography (Hex:Et2O 2:1 to Et2O) to provide (9 g, 69.5% yield) the product as a white solid. 1H-NMR (DMSO-d6) δ 7.23 (d, J=10.8 Hz, 1H), 6.74 (d, J=10.8 Hz, 1H), 5.27 (s, 2H), 2.20 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:14]=[C:15]([S:19]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH2:32])(=[O:31])=[O:30])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([S:19]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH2:32])(=[O:30])=[O:31])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1cccc(Br)c1
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: CN(C)C=O
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1cccc(-c2cc(Cl)ccc2Cl)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol) was added to 2,5-dichlorophenylboronic acid (57 mg, 0.30 mmol) in DMF (0.25 mL) and a DMF stock solution of 0.5M 2-[(3-bromophenyl)sulfonylamino]benzenesulfonamide (0.5 mL, 0.25 mmol). The reaction mixture was stirred at RT under argon for 15 minutes before addition of 2M Na2CO3 (0.5 mL). The reaction was stirred overnight at 90° C., filtered and purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (15 mg, 13%) as a white solid.
Reaction SMILES: [CH3:1][S:2][CH:3]1[NH:6][C:5](=[O:7])[CH2:4]1.[H-].[Na+].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>CN(C)C=O.O>[CH3:1][S:2][CH:3]1[N:6]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:5](=[O:7])[CH2:4]1
Reactant: COC(=O)CBr
Reactant: CSC1CC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)CC1SC
Yield: 63.4 %

Procedure:
4-Methylthioazetidin-2-one (2.34 g, 20 mmole) was dissolved in dry dimethylformamide (40 ml) and treated at 0°-5° C. with sodium hydride (20 mmole). After 3 minutes methyl bromoacetate (3.37 g, 22 mmole) dissolved in dry dimethylformamide (20 ml) was added and the reaction mixture stirred for 3/4 hour at 0°-5° C. After diluting with water (300 ml), the mixture was extracted with ethyl acetate (3×100 ml) and the extracts combined, washed with water, dried (MgSO4) and evaporated. Chromatography of the residue on silica gel eluting with 30% ethyl acetate in petrolether provided methyl (4-methylthio-2-oxoazetidin-1-yl)acetate (2.4 g, 62%) as a mobile liquid. νmax (CHCl3): 1760 (b), 1410, 1240, 1185 cm-1 ; δ(CDCl3): 2.13 (s, 3H, SCH3); 2.95-3.75 (2H, AB of ABX, CH2); 3.88 (s, 3H, OCH3); 3.93 and 4.23 (2H, main peaks of ABq, J=18 Hz, NCH2) and 5.02 (1H, X of ABX, CH).
Reaction SMILES: C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)C[C@@H](C(C)C)[CH2:13][C:14]1[CH:19]=CC=[C:16]([OH:20])[CH:15]=1)CCC.C(OC1C=C(C=CC=1C(C)(C)C)CBr)(=O)C.[CH2:51]([O:58][C:59]1[CH:60]=[C:61]([CH:64]=[CH:65][CH:66]=1)[CH2:62]Br)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>ClCCl.CCCCCC>[CH:14]([C@@H:15]([CH2:62][C:61]1[CH:64]=[CH:65][CH:66]=[C:59]([O:58][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:60]=1)[CH2:16][OH:20])([CH3:19])[CH3:13]
Reactant: BrCc1cccc(OCc2ccccc2)c1
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1cccc(O)c1)C(C)C)NC(=O)OC(C)(C)C
Agent: CC(=O)Oc1cc(CBr)ccc1C(C)(C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)[C@H](CO)Cc1cccc(OCc2ccccc2)c1

Procedure:
The N-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxyphenyl)-octanoic acid (N-butyl)amide used as starting material is prepared analogously to Example 5a)-5l), except that in step k) instead of 3-acetoxy-4-tert-butylbenzyl bromide there is used 3-benzyloxy-benzyl bromide, so that in step i) 2(R)-isopropyl-3-(3-benzyloxy-phenyl)-propanol, Rf (dichloromethane/hexane=1:1)=0.19, is obtained directly.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:22])[CH2:7][N:8]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:4].[CH3:23][O:24][CH2:25][CH2:26]Br.[ClH:28]>O1CCCC1.C(OCC)(=O)C>[ClH:28].[NH2:8][CH:7]([CH2:26][CH2:25][O:24][CH3:23])[C:6]([O:5][CH2:3][CH3:4])=[O:22]
Reactant: COCCBr
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(N)CCOC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (1.8 g) is added to a solution of N-(diphenylmethylene)glycine ethyl ester in tetrahydrofuran under ice cooling, then the temperature is raised to room temperature, and the mixture is stirred for one hour. 2-Bromoethyl methyl ether (4.22 ml) is added to the mixture, and the whole is refluxed overnight. The reaction mixture is cooled to room temperature, 0.1 N hydrochloric acid is added thereto, and the whole is stirred for four hours. Ethyl acetate is added to the reaction mixture, and the whole is extracted with 0.1 N hydrochloric acid. The extract is basified with a saturated aqueous sodium hydrogencarbonate solution, and the whole is extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, a 4 N hydrogen chloride/ethyl acetate solution is added to the resulting residue, and the whole is concentrated under reduced pressure again to give the titled reference compound (2.67 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([Cl:12])[CH:6]=1)(=[O:3])[CH3:2].[Br:13]Br.O>C(O)(=O)C>[C:1]([NH:4][C:5]1[C:10]([Br:13])=[CH:9][C:8]([CH3:11])=[C:7]([Cl:12])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C)c(Cl)c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1cc(Cl)c(C)cc1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 48 %

Procedure:
To a solution of 4-acetamido-2-chlorotoluene (89.2 g, 0.486 mol) in glacial acetic acid (480 ml) that was stirred with an overhead mechanical stirrer and under argon was dropwise added bromine (28.5 ml) during a period of 2 h while the temperature of the reaction mixture was kept below 15° C. by using an ice-bath. Stirring was continued for a further 1.5 h after the addition of bromine, under an argon atmosphere. Then the brownish reaction mixture was poured into ice-water (1.8 lt), with the aid of water (1 lt), washed with water (6 lt), and dried in vacuo over P2O5. Purification by recrystallisation from acetonitrile afforded the desired product as a white crystals (61.5 g, 48%), mp 154-155° C.; 1H-NMR (CDCl3) 2.24, 2.32 (2×s, 6H, 2×CH3), 7.40, 7.73 (2×s, 2H, 3-H, 6-H), 7.49 (br s, 1H, CONH); MS (FAB, m/z): 262, 264, 266 [(M+H)+, 80%, 100%, 25% respectively; BrCl isotopic pattern];
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1>C(#N)C>[CH:21]1([NH:26][C:8]2[CH:9]=[CH:10][C:5]([C:3](=[O:4])[C:2]([F:13])([F:12])[F:1])=[CH:6][CH:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCC1
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1ccc(NC2CCCC2)cc1)C(F)(F)F
Temperature: 25 °C

Procedure:
To a mixture of 3.94 g of 2,2,2,4′-tetrafluoroacetophenone (20.5 mmol) and 3.35 ml triethylamine (24.0 mmol) in 40 ml of acetonitrile at 0° C. were added 5.9 ml of cyclopentylamine (59.8 mmol). The reaction was allowed to warm to room temperature and then heated to reflux for 14 h. After this time the reaction mixture was cooled to room temperature, concentrated and partitioned between water and EtOAc. The organic layer was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica (hexanes:EtOAc, 4:1) to give the title compound. 1H-NMR (CDCl3) δ 1.53-1.57 (m, 2H), 1.69-1.78 (m, 4H), 2.08-2.13 (m, 2H), 3.88-3.95 (m, 1H), 4.63 (brs, 1H), 6.60 (d, J=8.9 Hz, 2H), 7.92 (d, J=8.9 Hz, 2H). Mass Spectrum (CI+) m/e=258.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:32][CH2:31][CH2:30][C@@:10]3([C:14](=[O:15])[N:13]([C@H:16]4[CH2:21][CH2:20][C@@H:19]([O:22][Si](C(C)(C)C)(C)C)[CH2:18][CH2:17]4)[CH2:12][CH2:11]3)[CH2:9]2)=[C:4]([Cl:33])[CH:3]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+].[CH2:43]([NH:45][C:46]([C:48]1[CH:53]=[CH:52][C:51](B2OC(C)(C)C(C)(C)O2)=[CH:50][N:49]=1)=[O:47])[CH3:44]>CN(C)C=O.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>[Cl:33][C:4]1[CH:3]=[C:2]([C:51]2[CH:52]=[CH:53][C:48]([C:46]([NH:45][CH2:43][CH3:44])=[O:47])=[N:49][CH:50]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:32][CH2:31][CH2:30][C@@:10]2([C:14](=[O:15])[N:13]([C@H:16]3[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)[CH2:9]1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CC[C@]3(CCCN(c4ccc(Br)cc4Cl)C3)C2=O)CC1
Reactant: CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)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: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-c2ccc(N3CCC[C@]4(CCN([C@H]5CC[C@@H](O)CC5)C4=O)C3)c(Cl)c2)cn1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of (5S)-7-(4-bromo-2-chlorophenyl)-2-(cis-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (20 mg, 0.00004 mol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (2.0 mg), tetrakis(triphenylphosphine)palladium (1.0 mg) and potassium carbonate (14.9 mg, 0.000108 mol) in anhydrous N,N-dimethylformamide (1 mL) was added N-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (14.5 mg, 0.054 mmol). The resulting reaction mixture was heated at 150° C. and stirred overnight, followed by the removal of TBS protecting group by the addition of 1.7 M of fluorosilicic acid in water (0.10 mL) and the mixture was stirred at r.t. overnight. The reaction mixture was then directly purified by RP-HPLC to afford the desired product. LC/MS m/e 511.2 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): 8.92 (1H, d, J=2.3 Hz), 8.84 (1H, t, J=5.9 Hz), 8.26 (1H, dd, J=8.2, 2.3 Hz), 8.06 (1H, d, J=8.2 Hz), 7.89 (1H, d, J=2.2 Hz), 7.74 (1H, dd, J=8.5, 2.2 Hz), 7.30 (1H, t, J=8.5 Hz), 4.39 (1H, d, J=3.1 Hz), 3.80 (1H, m), 3.72 (1H, m), 3.24-3.44 (5H, m), 3.01 (1H, d, J=11.4 Hz), 2.63-2.74 (2H, m), 2.40-2.53 (1H, m), 1.64-1.91 (8H, m), 1.41-1.53 (3H, m), 1.20-1.32 (2H, m), 1.13 (3H, t, J=7.2 Hz).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][N:5]=[C:4](S)[N:3]=1.ClCC(O)=[O:16].Cl>O>[CH:9]([O:8][C:7]1[C:2](=[O:1])[NH:3][C:4](=[O:16])[NH:5][CH:6]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1cnc(S)nc1O
Reactant: O=C(O)CCl
Agent: Cl
Solvent: O
Product: CC(C)Oc1c[nH]c(=O)[nH]c1=O

Procedure:
60.8 g of 4-hydroxy-5-isopropoxy-2-mercapto-pyrimidine are refluxed together with 60 g of chloroacetic acid in 1.2 litres of water for 2.5 hours, during which time the precipitate dissolves completely. 200 ml of conc. hydrochloric acid are added and the mixture is refluxed for a further 7 hours. Then the reaction mixture is evaporated down to 500 ml, whereupon the desired product is obtained as a precipitate, filtered off and dried overnight at 70° C. (28.6 g; 52%).
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[N:4][C:5]([CH3:17])=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:8].C([O-])=O.[NH4+]>CO.C1COCC1.[Pd]>[CH3:17][C:5]1[N:4]=[C:3]([O:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])[CH:2]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)=[O:8]
Reactant: Cc1nc(OCc2c(-c3ccccc3)noc2C)c(Br)cc1C(=O)NC1CCOCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(OCc2c(-c3ccccc3)noc2C)ccc1C(=O)NC1CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 19.2 %

Procedure:
To a solution of 5-bromo-2-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide (150 mg, 0.37 mmol) in methanol (3 mL) and THF (3 mL) was added under an argon atmosphere palladium on charcoal (10%, 20 mg) and ammonium formate (70 mg, 1.12 mmol). The reaction mixture was stirred for 6 h at ambient temperature. Filtration over Hyflo® and washing with THF afforded the title compound (29 mg, 20%) which was obtained as a light brown semi-solid. MS: m/e=408.3 [M+H]+.