Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[N:25]1([C:30]([C:32]2[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=2)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([C:30]([N:25]4[CH2:26][CH2:27][CH2:28][CH2:29]4)=[O:31])[CH:37]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Reactant: O=C(c1cccc(B(O)O)c1)N1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOCc1nc2c(N)nc3cc(-c4cccc(C(=O)N5CCCC5)c4)cnc3c2n1CC(C)(C)O
Temperature: 110 °C
Yield: 27.5 %

Procedure:
A suspension of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (1.2 g, 3.0 mmol), (3-pyrrolidinylcarbonylphenyl)boronic acid (0.800 g, 3.65 mmol), potassium carbonate (1.4 g, 10.0 mmol), dichlorobis(triphenylphosphine)palladium(II)(0.021 g, 0.030 mmol), DME (13 mL), and water (7 mL) was stirred under a nitrogen atmosphere in a pressure vessel. The vessel was then sealed and heated at 110° C. for 16.5 hours and allowed to cool to room temperature. The volatiles were removed under reduced pressure. The residue was diluted with methanol, and silica gel was added. The mixture was concentrated under reduced pressure. The residue was purified by automated flash chromatography (FLASH 40+M silica cartridge, eluting with 10% to 25% methanol in ethyl acetate). The resulting material was concentrated twice from acetonitrile and then triturated with acetonitrile (100 mL) to provide a solid. The solid was isolated by filtration, washed with acetonitrile, and dried in a vacuum oven at 65° C. to provide 403 mg of 1-{4-amino-2-(ethoxymethyl)-7-[3-(pyrrolidin-1-ylcarbonyl)phenyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}-2-methylpropan-2-ol as a white solid, mp 185-187° C.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]([CH3:20])[C:10](=[O:21])[CH:9]=1.[CH3:22][O-:23].[Na+]>O1CCCC1>[CH3:22][O:23][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]([CH3:20])[C:10](=[O:21])[CH:9]=1
Reactant: Cn1c(N2CCOCC2)nc(-c2ccncc2F)cc1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cnccc1-c1cc(=O)n(C)c(N2CCOCC2)n1
Temperature: 60 °C
Yield: 63.8 %

Procedure:
A suspension of 6-(3-fluoropyridin-4-yl)-3-methyl-2-(morpholin-4-yl)-3H-pyrimidin-4-one obtained in Example 6-1 (0.60 g, 2.07 mmol), and sodium methoxide (1.37 g, 25.4 mmol) in tetrahydrofuran (15 ml) was heated at 60° C. for 3 hours. The resulting suspension was partitioned between chloroform and brine and the aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish 6-(3-methoxypyridin-4-yl)-3-methyl-2-(morpholin-4-yl)-3H-pyrimidin-4-one (0.40 g, 1.32 mmol, 64%) as white crystals.
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:29](=[O:30])[N:6]2[C:7]([C:13]([O:15]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:14])=[C:8]([CH2:11][Cl:12])[CH2:9][S:10][C@H:5]12)=[O:2].FC(F)(F)C(O)=O.C(OC(C)C)(C)C.CCCCCC>ClCCl.C1(OC)C=CC=CC=1>[CH:1]([NH:3][C@@H:4]1[C:29](=[O:30])[N:6]2[C:7]([C:13]([OH:15])=[O:14])=[C:8]([CH2:11][Cl:12])[CH2:9][S:10][C@H:5]12)=[O:2]
Reactant: O=CN[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Solvent: COc1ccccc1
Solvent: CCCCCC
Solvent: CC(C)OC(C)C
Product: O=CN[C@@H]1C(=O)N2C(C(=O)O)=C(CCl)CS[C@H]12
Temperature: 5 °C
Reaction time: 1.2 h
Yield: 82.1 %

Procedure:
To a solution of benzhydryl 7β-formamido-3-chloromethyl-3-cephem-4-carboxylate (27.34 g) in a mixture of dichloromethane (137 ml) and anisole (27 ml) was added dropwise trifluoroacetic acid (54 ml) and the mixture was stirred at 5° C. for 1.2 hours. The mixture was added dropwise to a cooled mixture of diisopropyl ether (2 l) and hexane (2 l) and the resulting precipitates were collected by filtration, washed with a mixture of diisopropyl ether and hexane to give 7β-formamido-3-chloromethyl-3-cephem-4-carboxylic acid (14.03 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](C)(C)[O:18][SiH2]C(C)C)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[NH:27][N:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C=C2C(=CC=1)N(C(OC(C)(C)C)=O)C(C1C3C(=CC=CC=3)NN=1)=C2)=[O:36].CC(=CC)C.OP([O-])(O)=O.[Na+].Cl([O-])=O.[Na+]>ClCCl.C(O)(C)(C)C.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:36])=[O:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[NH:27][N:26]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)[SiH2]OC(C)(C)c1ccc2c(c1)cc(-c1n[nH]c3cc(Cl)ccc13)n2C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)n1c(-c2n[nH]c3ccccc23)cc2cc(C=O)ccc21
Agent: [Mn+4]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2n[nH]c3cc(Cl)ccc23)cc2cc(C(=O)O)ccc21
Reaction time: 1 h

Procedure:
A solution of the alcohol 4-3 (210 mg, 0.528 mmol) in dichloromethane was treated with manganese dioxide (229 mg, 2.64 mmol) and heated to reflux where it remained for 1 h. Five additional equivalents of manganese dioxide were added and the reaction was maintained at reflux for 1 h. The excess manganese dioxide was filtered through Celite and the filter cake was washed with ethyl acetate (40 ml) and methanol (40 ml). The filtrate was concentrated in vacuo to a brown oil (4-4). A solution of the tert-butyl 5-formyl-2-(1H-indazol-3-yl)-1H-indole-1-carboxylate (4-4, 1.2 g, 3.3 mmol), 2-methyl-2-butene (19.9 ml, 188.2 mmol), a 1.9M solution of sodium phosphate monobasic (1.73 ml, 6.6 mmol), and sodium chlorite (597.3 mg, 6.60 mmol) were stirred in t-Butanol for 1 h. 3 additional equivalents of both solid sodium phosphate monobasic and sodium chlorite were added to the reaction over a 3 h period, and the reaction was mixed for 24 h. The t-Butanol was removed in vacuo and the residual yellow solid was dissolved in ethyl acetate (150 ml) and washed twice with a 98:2 mixture of 10% sodium bisulfite:10% potassium bisulfate (2×75 ml). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to afford 1-(tert-butoxycarbonyl)-2-(1H-indazol-3-yl)-1H-indole-5-carboxylic acid (4-5); 1H NMR(500 MHz, CDCl3) δ 8.47 (s, 1H), 8.40 (d, 1H, J=8.8 Hz), 8.17 (d, 1H, J=8.8 Hz), 7.68 (d, 1H, J=8.1 Hz), 7.56 (d, 1H, J=8.3 Hz), 7.46 (t, 1H, J=8.3 Hz), 7.23 (t, 1H, J=7.8 Hz), 6.99 (s, 1H), 1.14 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]([CH2:21][C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:29][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([Cl:28])[CH:25]=1)[CH2:21][N:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=2)[CH:4]=1)(=[O:11])=[O:10]
Reactant: O=Cc1ccc(F)cc1
Reactant: NCc1cccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2cc(Cl)cc(Cl)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1cccc(CNCc2ccc(F)cc2)c1)N(Cc1ccc(F)cc1)Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
To a solution of 3-(aminomethyl)-N-(3,5-dichlorobenzyl)-N-(4-fluorobenzyl)benzenesulfonamide (290 mg, 0.64 mmol) in CH2Cl2 (6 mL) was added 4-fluorobenzaldehyde (0.07 mL, 0.64 mmol). The resulting mixture was stirred at rt. for 1 h. To the mixture was added sodium triacetoxyborohydride (217 mg, 1.02 mmol) under N2 atmosphere. The resulting mixture was stirred at rt for 20 h. To the reaction mixture was added saturated aq NaHCO3 solution and the mixture was stirred for 20 minutes. The mixture was concentrated. The residue was diluted with ethyl acetate and saturated aq NaHCO3 solution. The organic layer was washed with brine and dried over MgSO4. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel eluting with 100% CH2Cl2 to 25% ethyl acetate in CH2Cl2 to obtain the desired product as a colorless oil (0.16 g, 45%). 1H NMR (CDCl3): δ 7.86 (s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.33-7.29 (m, 2H), 7.16-7.15 (m, 1H), 7.09-6.99 (m, 4H), 6.94-6.89 (m, 2H), 6.85-6.84 (m, 2H), 4.32 (s, 2H), 4.25 (s, 2H), 3.89 (s, 2H), 3.78 (s, 2H), 1.77 (bs, 1H); MS (ESI): [M+H]+=561.0.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>[Pd].C1COCC1.CO>[NH2:16][C:12]1[CH:11]=[C:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH:15]=[CH:14][CH:13]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A round-bottom flask containing tert-butyl methyl(3-nitrophenyl)carbamate (19) (8.8 g, 34.9 mmol), 10% palladium on charcoal (880 mg), and THF-MeOH (80 mL/80 mL) was evacuated and flushed with hydrogen three times. The mixture was stirred vigorously overnight under an atmosphere of hydrogen. The catalyst was removed by filtration through a pad of Celite, and the filtrate evaporated to afford tert-butyl 3-aminophenyl(methyl)carbamate (20) 7 g as yellow solid (yield 91%). LC-MS (ESI): m/z (M+1) 223.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:17]=2[CH3:16])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: Cc1ccncc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccncc1-c1nc2cc(F)cc(F)c2c(Cl)c1C

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 4-methylpyridine-3-boronic acid (0.28 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 45 h to give 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpyridin-3-yl)quinoline as a brown solid. Mass Spectrum (ESI) m/e=305.0 (M+1).
Reaction SMILES: B(F)(F)F.CCOCC.[CH:10]1([C@@H:13]2[O:21][CH2:20][C:16]3=[N:17][O:18][CH2:19][C@@H:15]3[CH2:14]2)[CH2:12][CH2:11]1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1I.C([Li])CCC>C1(C)C=CC=CC=1>[CH:10]1([C@@H:13]2[O:21][CH2:20][C@:16]3([C:26]4[CH:25]=[CH:24][C:23]([F:22])=[CH:28][C:27]=4[F:29])[NH:17][O:18][CH2:19][C@@H:15]3[CH2:14]2)[CH2:12][CH2:11]1
Reactant: C1O[C@@H](C2CC2)C[C@H]2CON=C12
Reactant: Fc1ccc(I)c(F)c1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1ccc([C@]23CO[C@@H](C4CC4)C[C@H]2CON3)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Boron trifluoride diethyl etherate (2.97 mL, 24.1 mmol) was added drop-wise to a solution of rel-(3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C18) (1.67 g, 9.99 mmol) in toluene (150 mL) at an internal temperature of −72.5° C. The reaction mixture was stirred at −73° C. to −76° C. for 30 minutes, then treated with 2,4-difluoro-1-iodobenzene (98%, 1.37 mL, 11.2 mmol) in one portion. While the reaction temperature was maintained below −73° C., n-butyllithium (2.5 M in hexanes, 4.24 mL, 10.6 mmol) was added in a drop-wise manner over 15 minutes. The reaction mixture was stirred at −73° C. to −75° C. for 1 hour, then was quenched with saturated aqueous ammonium chloride solution (350 mL) at −74° C. and allowed to warm to room temperature. The resulting mixture was extracted with ethyl acetate (400 mL), and the aqueous layer was extracted with additional ethyl acetate (250 mL and 100 mL); the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 30% ethyl acetate in heptane) afforded the product as a white solid after azeotroping twice with dichloromethane. Yield: 2.16 g, 7.68 mmol, 77%. GCMS m/z 281 [M+]. 1H NMR (400 MHz, CDCl3) δ 7.88-7.98 (m, 1H), 6.84-6.93 (m, 1H), 6.79 (ddd, J=11.9, 8.6, 2.4 Hz, 1H), 6.34 (br s, 1H), 4.04 (br d, J=12.7 Hz, 1H), 3.83 (d, J=12.5 Hz, 1H), 3.72 (d, J=7.0 Hz, 1H), 3.54 (dd, J=6.8, 5.1 Hz, 1H), 2.99-3.08 (m, 1H), 2.86-2.95 (m, 1H), 1.99 (br dd, J=13.8, 6.8 Hz, 1H), 1.56-1.68 (m, 1H), 0.88-1.00 (m, 1H), 0.51-0.64 (m, 2H), 0.37-0.47 (m, 1H), 0.24-0.33 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:29][CH2:28][CH2:27][C@@:3]1([CH3:30])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C@H:16]([O:21][CH3:22])[CH2:17][C:18]([OH:20])=[O:19])[CH3:14])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5].N1C=CC=CC=1.FC(F)(F)C(O[C:42]1[C:47]([F:48])=[C:46]([F:49])[C:45]([F:50])=[C:44]([F:51])[C:43]=1[F:52])=O>ClCCl>[CH3:1][N:2]1[CH2:29][CH2:28][CH2:27][C@@:3]1([CH3:30])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C@H:16]([O:21][CH3:22])[CH2:17][C:18](=[O:20])[O:19][C:42]1[C:43]([F:52])=[C:44]([F:51])[C:45]([F:50])=[C:46]([F:49])[C:47]=1[F:48])[CH3:14])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCN1C)C(C)C
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCN1C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 125.1 %

Procedure:
To a cooled solution (0° C.) of #203 (7.0 g, 10.77 mmol, 1 eq.) in dichloromethane (15 mL) was added dropwise pyridine (3.41 g 43.08 mmol, 4 eq.) followed by a solution of pentafluorophenyl trifluoroacetate (6.03 g, 21.54 mmol, 2 eq.) in dichloromethane (7 mL). The mixture was stirred at room temperature for one hour, and the solvent was concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 1 to 10% methanol in dichloromethane) to afford compound #204 (8 g, 82% over two steps) as yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3cnccn3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step A was prepared from {3-[(4-pyrazin-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13b, and benzenesulfonyl chloride following the method described in Example 3, Step B 1H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.60 (m, 1H), 8.49 (m, 1H), 7.87 (m, 4H), 7.61-7.51 (m, 3H), 7.26-7.08 (m, 3H), 6.75 (m, 1H), 6.63 (m, 1H), 6.58 (m, 1H), 4.38 (s, 2H), 4.34 (s, 2H), 4.31 (s, 2H), 1.47 (s, 9H); MS 546 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:50])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:48][CH3:49])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([F:47])[C:37]=4[C:38]([NH:40][CH3:41])=[O:39])[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[OH-].[Na+].O>O1CCOCC1.CCOC(C)=O.C1COCC1>[CH3:50][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:48][CH3:49])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([F:47])[C:37]=4[C:38]([NH:40][CH3:41])=[O:39])[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CNC(=O)c1c(F)cc(F)cc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(F)cc(F)cc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)[nH]c2nccc1-2
Temperature: 120 °C
Reaction time: 0.15 h
Yield: 90.3 %

Procedure:
To a suspension of 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,6-difluoro-N-methylbenzamide (0.950 g, 1.07 mmol) in 1,4 dioxane (10 mL) in a microwave vessel was added 6 N NaOH (10 ml) and water (3 mL). The resulting mixture was stirred in the microwave at 120° C. for 9 min. The reaction mixture was diluted with EtOAc and THF and the organic layer was washed with water and a saturated brine solution. Combined organic layers were dried over sodium sulfate and all solvents were removed under reduced pressure and purified via chromatography on SiO2 to afford 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4,6-difluoro-N-methylbenzamide (0.532 g, 0.966 mmol) as a beige solid. (ESIMS (M+H)+=551). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 6 H) 2.83 (d, J=4.40 Hz, 3 H) 3.06-3.12 (m, 2 H) 3.33 (s, 2 H) 3.76 (s, 2 H) 4.05-4.23 (m, 2 H) 6.25 (dd, J=3.39, 1.74 Hz, 1 H) 6.80-6.94 (m, 1 H) 6.93-7.04 (m, 2 H) 7.80 (s, 1 H) 8.41-8.54 (m, 2 H) 8.54-8.64 (m, 1 H) 10.79 (s, 1 H) 11.33 (br. s., 1 H)
Reaction SMILES: Br[C:2]1[C:3]([O:36][CH3:37])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:38]([O:45][C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>C(#N)C.C1COCC1.O.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([C:24]([NH:23][C@@H:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:4]=[C:3]([O:36][CH3:37])[C:2]([C:49]4[CH:50]=[CH:51][C:46]([O:45][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:47][CH:48]=4)=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:35])=[CH:26][CH:27]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CCCCCCCOc1ccc(B(O)O)cc1
Reactant: COc1nc(-c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC(C)(C)C)cc2)ncc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)OC(C)(C)C)cc3)nc2OC)cc1
Temperature: 110 °C
Yield: 94.9 %

Procedure:
Prepared using General Procedure 10: A mixture of tert-butyl (S)-3-(4-(5-bromo-4-methoxypyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoate (18.0 mg, 0.031 mmol), (4-(heptyloxy)phenyl)boronic acid (10.0 mg, 0.042 mmol) and sodium carbonate (8.97 mg, 0.084 mmol) in acetonitrile (0.80 mL), THF (0.80 mL) and H2O (0.40 mL) was degassed for 10 min. Pd(dppf)Cl2:CH2Cl2 (3.09 mg, 0.003 mmol) was added and the reaction mixture heated at 110° C. in a microwave for 30 min. Once cooled, the reaction was diluted with NaHCO3 (5 mL) and extracted with EA (3×5 mL). The combined organics were dried over MgSO4 and concentrated. The residue was purified by column chromatography (EA:hexanes) to afford 20.0 mg (60%) of tert-butyl (S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-4-methoxypyrimidin-2-yl)phenyl)propanoate as pale yellow solid. LCMS-ESI (m/z) calculated for C42H53N3O5: 679.8; no ion observed, tR=13.83 min. (Method 2).
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][N:4]1[C:9](=[O:10])[C:8]([CH:11]([CH2:13][CH3:14])[CH3:12])=[N:7][N:6]=[C:5]1SC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[NH2:3][N:4]1[C:9](=[O:10])[C:8]([CH:11]([CH2:13][CH3:14])[CH3:12])=[N:7][N:6]=[C:5]1[NH:2][CH3:1]
Reactant: CN
Reactant: CCC(C)c1nnc(SC)n(N)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: CCC(C)c1nnc(NC)n(N)c1=O
Reaction time: 4 h

Procedure:
Monomethylamine was passed for 4 hours into a boiling solution of 42.8 g of 4-amino-6-sec.-butyl-3-methylthio-1,2,4-triazin-5 (4H)-one of which 12 ml of glacial acetic acid and 1 g of p-toluenesulfonic acid had been added, and the mixture was then boiled for a further 4 hours under reflux. The solvent was largely evaporated off in vacuo and the oily residue was taken up in methylene chloride and repeatedly shaken with 10% strength sodium carbonate solution. The organic phase was separated off and concentrated by evaporation. 38.6 g (98% of theory) of 4-amino-6-sec.-butyl-3-methylamino-1,2,4-triazin-5 (4H)-one which gradually solidified, remained. The product was purified further by recrystallization from carbon tetrachloride. Melting point = 117° C.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH:18][N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25].C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH:18][N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1C=CCCCCCCCCCCO
Reactant: CCCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOCCCCCCCCCCC=CN1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
0.14 mole of butyl bromide and 0.14 mole of N-hydroxy dodecenylsuccinimide are dissolved in 100 milliliters of dimethylformamide. 50 milliliters of triethylamine are added and the mixture is stirred overnight at room temperature. The solvent is then removed under vacuum and the reaction product is water washed until salt free and then dried. A yield of 85% of N-butoxy dodecenylsuccinimide is recovered.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:41]=[CH:40][C:9]2[N:10]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23](=[O:33])NCC3C=CC(Cl)=CC=3)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([NH:49][CH:50]([CH3:52])[CH3:51])=[CH:45][CH:44]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:41]=[CH:40][C:9]2[N:10]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23](=[O:33])[N:49]([C:46]3[CH:47]=[CH:48][C:43]([Cl:42])=[CH:44][CH:45]=3)[CH:50]([CH3:52])[CH3:51])[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)Nc1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)NCc4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)N(c4ccc(Cl)cc4)C(C)C)ccc3c1)n2C1CCCCC1

Procedure:
The title compound was prepared as described for Compound 546c using Compound 546a in place of 4-chloro-N-methylaniline. MS: 595.27 (M+H+).