Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1.C(N(CC)CC)C.[C:25]1([CH:31]([CH2:36][C:37](Cl)=[O:38])[CH2:32][C:33](Cl)=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH2:11]([NH:10][C:8]([C:4]1[S:3][C:2]([N:1]2[C:37](=[O:38])[CH2:36][CH:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][C:33]2=[O:34])=[N:6][C:5]=1[CH3:7])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)CC(CC(=O)Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(N2C(=O)CC(c3ccccc3)CC2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a stirred solution of 2-amino-N-benzyl-4-methylthiazole-5-carboxamide (0.50 g, 2.0 mmol) in chloroform (15 mL) with triethylamine (1.8 mL, 10.0 mmol) was added 3-phenylpentanedioyl dichloride (0.45 g, 1.84 mmol). The mixture was stirred at ambient temperature for 2 h, washed with 20% hydrochloric acid solution (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was crystallized from ethyl acetate/hexane to afford a solid, which was washed with cold methanol and dried in air to afford the title compound (0.46 g, 60%): 1H NMR (300 MHz, CDCl3) δ 7.50-7.20 (m, 10H), 6.07 (br s, 1H), 4.60 (d, J=5.6 Hz, 2H), 3.60-3.50 (m, 1H), 3.13 (dd, J=17.1, 4.2 Hz, 2H), 2.95 (dd, J=17.1, 12.0 Hz, 2H), 2.68 (s, 3H); MS (ES+) m/z 420.1 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:10]=[C:11]1[NH:17][C:16]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:15]=2[NH:14][CH2:13][CH:12]1[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].O=C1NC2C=CC=CC=2NCC1NC(OC(C)(C)C)=O>>[O:10]=[C:11]1[NH:17][C:16]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:15]=2[N:14]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH:12]1[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Agent: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)c1ccccc1

Procedure:
Step 1 of Example 1 was repeated except that benzoyl chloride was used instead of pivaloyl chloride and that 2-oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine obtained from Referential Example 4 was used instead of 2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine, to thereby obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][OH:13])[CH:3]=1.[C:14]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:15][CH2:16][C:17]([CH3:19])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1C=CC=CC=1>[CH2:22]([O:21][C:14](=[O:20])[CH2:15][CH2:16][C:17]1([CH3:19])[C:3]2=[C:2]([CH3:1])[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]2[CH2:11][CH2:12][O:13]1)[CH3:23]
Reactant: Cc1cn(CCO)c2ccccc12
Reactant: CCOC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC1(C)OCCn2c1c(C)c1ccccc12
Reaction time: 12 h

Procedure:
A mixture of the intermediate of formula III, 3-methylindole-1-ethanol (29.7 g., 0.17 mole), described in Example 1, ethyl levulinate (26.96 g., 0.187 mole) and p-toluenesulfonic acid (2.25 g.) in dry benzene (650 ml.) is refluxed with stirring for 12 hr. with hydrated alkali-aluminum silicate (Molecular Sieves No. 4). The benzene solution is washed with 5% aqueous NaHCO3, followed by water. Concentrations of the solution gave a residue, which is passed through a silica gel column using 15% ethyl acetate in benzene to afford the ester, 3,4-dihydro-1,10-dimethyl-1H-1,4-oxazino[4,3-a]indole-1-propionic acid ethyl ester, as an oil, γmaxCHCl3 1730 cm-1.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4].CCCC=O.[C:13]([OH:22])(=[O:21])[C@H:14]([C@@H:16]([C:18]([OH:20])=[O:19])[OH:17])[OH:15]>C(O)(=O)C>[NH:1]1[CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:18]([C@H:16]([C@@H:14]([C:13]([O-:22])=[O:21])[OH:15])[OH:17])([O-:20])=[O:19]
Reactant: O=C(O)C1CCN1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CC(=O)O
Solvent: CCCC=O
Product: O=C(O)[C@@H]1CCN1
Product: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Temperature: 85 °C
Yield: 91 %

Procedure:
DL-AzeOH (6.14 g; 60.8 mmol) was dissolved in acetic acid (36.5 mL) at 85° C. Butyric aldehyde (0.49 g; 6.8 mmol) and D-tartaric acid (9.12 g; 60.8 mmol) were added and the mixture maintained at 85° C. for 6 hours. The reaction mixture was then gradually cooled to 0 C. The crystalline product was filtered off, washed with acetic acid and dried to yield 13.78 g (90%) of L-AzeOH-D-tartrate with a d.e. of 89%. Recrystallisation 13.78 g of the diastereomeric salt from dissolved acetic acid:water (9:1; 124 mL) yielded 11.08 g of L-AzeOH-D-tartrate with a d.e. of 99.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([O:32][P:33]([O:38][CH2:39][CH3:40])([O:35][CH2:36][CH3:37])=[O:34])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([O:32][P:33]([O:35][CH2:36][CH3:37])([O:38][CH2:39][CH3:40])=[O:34])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(N2CCC([C@@H](OP(=O)(OCC)OCC)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOP(=O)(OCC)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 30 °C
Yield: 86.4 %

Procedure:
A solution of (R)-ethyl 4-(4-((4′-chlorobiphenyl-2-yl)(diethoxyphosphoryloxy)methyl)piperidin-1-yl)benzoate (INTERMEDIATE 119, 500 mg, 0.85 mmol) in THF (10 ml) and MeOH (2.5 ml), at room temperature, was treated with a solution of lithium hydroxide (102 mg, 4.27 mmol) in water (2.5 ml). The reaction was heated to 30° C. overnight and subsequently warmed to 40° C. for about 5 hours. The mixture was allowed to cool to room temperature whereupon the volatiles were removed under reduced pressure. The concentrate was diluted with 30 ml of water, acidified with a few drops of 6N HCl to provide a white precipitate. The precipitate was collected by vacuum filtration to give the title compound (410 mg, yield: 86%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1.[C:30]([NH2:34])(=[O:33])[CH:31]=[CH2:32].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([CH3:22])=[CH:11][C:12]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:32][CH2:31][C:30]([NH2:34])=[O:33])[CH2:18][CH2:17]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: C=CC(N)=O
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2Cl)n[nH]1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCC(N)=O)CC4)cc3C)ncc2Cl)n[nH]1

Procedure:
A solution of 5-chloro-N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (41 mg, 0.1 mmol), acrylamide (24 mg, 0.33 mmol) and DIEA (87 μL, 0.5 mmol) in NMP (1 mL) was stirred at 80° C. for 10 h. LCMS at this point shows the reaction was not complete, so additional acrylamide (2×36 mg) was added and the reaction continued until LCMS shows the reaction was complete. The crude product was purified by RP-HPLC to give 3-(4-(4-(5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)piperidin-1-yl)propanamide as a white powder; ESMS m/z 483.2 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH3:40])[CH2:34]1.O>CN(C)C=O>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH3:40])[CH2:34]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: CCN1CCCC(CBr)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CC3CCCN(CC)C3)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 58.1 %

Procedure:
A stirring mixture of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt (200 mg) and potassium carbonate (236 mg) in dry N,N-dimethylformamide (2 ml) was heated with stirring at 60° C. for 1 hour. 3-(Bromomethyl)-1-ethylpiperidine (141 mg) was added and the stirring mixture heated at 50° C. for 6 hours. After 72 hours at ambient temperature heating at 50° C. was continued for a further 6 hours to complete the reaction. Water was added and the mixture extracted three times with ethyl acetate. The combined extracts were washed with water then brine, dried by passing through a phase separation cartridge and stripped to give a brown oil. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (5-35%) and the appropriate fractions combined and evaporated to remove acetonitrile. The remaining aqueous mixture was made basic with saturated sodium hydrogen carbonate, extracted three times with dichloromethane and the combined extracts dried by passing through a phase separation cartridge then evaporated to afford the title compound as a clear oil (120 mg).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:28][C:25]([CH3:27])([CH3:26])[C:22]([CH3:24])([CH3:23])[O:21]2)=[CH:16][CH:15]=1>CN(C=O)C.O>[CH3:26][C:25]1([CH3:27])[C:22]([CH3:23])([CH3:24])[O:21][B:20]([C:17]2[CH:16]=[CH:15][C:14]([CH2:13][N:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[CH:4]3)=[CH:19][CH:18]=2)[O:28]1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(Cn3ccc4ccccc43)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.5 %

Procedure:
To NaH (78 mg, 1.94 mmol) in anhydrous DMF (4 mL) under N2, at 0° C. was added indole (227 mg, 1.94 mmol) in anhydrous DMF (5 mL). The reaxtion mixture was maintained at this temperature for 10 min. 4-bromomethylphenylboronic acid pinacol ester (523 mg, 1.76 mmol) in anhydrous DMF (8 mL) was added and the reaction stirred at RT for 18 h. The reaction mixture was diluted with H2O and extracted with CH2Cl2 (×2). The organic phases were combined, washed with brine, dried (phase separation cartridge) and the solvent removed in vacuo. The crude material was purified by silica gel column chromatography eluting with isohexane and increasing the polarity to 5% EtOAc/isohexane. The compound was further purified by reverse phase preparative HPLC-MS to afford 1-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-1H-indole as an off-white solid (120 mg, 10%).
Reaction SMILES: [C:1]([SH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([CH3:17])=[CH2:16])=[CH:13][CH:12]=1>CCCCCC>[C:1]([S:9][C:15]([C:14]1[CH:18]=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=1)([CH3:17])[CH3:16])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C(S)c1ccccc1
Reactant: C=C(C)c1ccc(Cl)cc1
Solvent: CCCCCC
Product: CC(C)(SC(=S)c1ccccc1)c1ccc(Cl)cc1
Temperature: 70 °C
Yield: 34.2 %

Procedure:
Dithiobenzoic acid (6.3 g) and 4-chloro-a-methylstyrene (6 g) were combined and the mixture heated at 70° C. overnight. The residue was subjected to column chromatography (Kieselgel-60, 70-230 mesh, n-hexane as eluent) which gave the title compound as a purple solid (34.2% yield) m.p. 77-78° C. 1H-nmr (CDCl3) d (ppm): 1.97 (s, 6H, 2×CH3), 7.20-7.52 (m, 7H, ArH) and 7.86 (d, 2H. ArH). 13C-nmr (CDCl3) d (ppm): 28.4, 55.7, 126.5, 128.1, 131.9, 132.4, 142.8. 146.0. The signal due to C=S (d>220.0 ppm) was beyond the frequency range of the spectrum.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2)([O-:20])=[O:19]
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc2[nH]ncc2c1
Temperature: 120 °C
Reaction time: 6 h
Yield: 10 %

Procedure:
To a solution of the 1H-indazol-5-ol (300 mg, 2.24 mmol) obtained in Reference Example 4 in N,N-dimethylformamide (6 ml) were added 2-bromonitrobenzene (497 mg, 2.46 mmol) and potassium carbonate (402 mg, 2.91 mmol), and the resulting mixture was heated to 120° C. After 6 hours, the mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml×2). The organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 5-(2-nitrophenoxy)-1H-indazole (57 mg, 10%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.Cl.[CH3:28][C:29]1([NH2:33])[CH2:32][CH2:31][CH2:30]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([NH:33][C:29]3([CH3:28])[CH2:32][CH2:31][CH2:30]3)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: CC1(N)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(NC(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.9 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol) in DMF (2 mL) were added 1-methyl-cyclobutyl amine hydrochloride (37 mg, 0.30 mmol), diisopropylethylamine (DIPEA) (150 μL, 0.60 mmol) and 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (125 mg, 0.33 mmol). The solution obtained was stirred at room temperature for 2 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by chromatography purification (silica gel, gradient 10-20% ethyl acetate/isohexane) yielding Compound 61 as a solid (22 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:21][CH2:22][OH:23])[C:4]2[C:9]([C:10]=1[C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH3:1][C:2]1[N:3]([CH2:21][CH2:22][O:23][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[C:4]2[C:9]([C:10]=1[C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COc1ccc(C(=O)c2c(C)n(CCO)c3ccccc23)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)c2c(C)n(CCOS(=O)(=O)c3ccc(C)cc3)c3ccccc23)cc1

Procedure:
Following a procedure similar to that described above in Preparation 4A, 40 g. (0.015 mole) of 2-methyl-3-(4-methoxybenzoyl)indole in 320 ml. of THF was reacted with 61 ml. of a 2.6M solution of butyl lithium in hexane and 45.8 ml. of ethylene oxide to give 33.6 g. (72%) of 2-methyl-3-(4-methoxybenzoyl)-1-(2-hydroxyethyl)-1H-indole. Reaction of 17 g. (0.06 mole) of the latter with 72 g. (0.06 mole) of p-toluenesulfonyl chloride in 250 ml. of pyridine afforded 2-methyl-3-(4-methoxybenzoyl)-1-(2-p-toluenesulfonyloxyethyl)-1H-indole as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][NH2:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>CCO>[N+:8]([C:7]1[C:2]([NH:31][CH2:30][CH:27]2[CH2:26][CH2:25][N:24]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[CH2:29][CH2:28]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: NCC1CCN(c2ccncc2)CC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1NCC1CCN(c2ccncc2)CC1
Reaction time: 17 h
Yield: 59.3 %

Procedure:
A solution of 2-chloro-3-nitropyridine (290 mg, 1.83 mmol), triethylamine (0.26 mL) and 1-(4-pyridyl)-piperidine-4-methylamine (350 mg, 1.83 mmol) in EtOH (10 mL) was heated at reflux. After 17 h, the mixture was concentrated and the residue was purified by chromatography (SiO2, 2 to 4% (2 N NH3 in methanol) in chloroform) yielding 340 mg (60%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=2[O:7][CH2:8][CH2:9][N:10]([CH3:21])C(=O)OCC2C=CC=CC=2)[CH2:4][CH2:3]1.Br[C:27]1[C:28](=[O:46])[N:29]([C:34]2[CH:35]=[C:36]([CH:41]=[C:42]([F:45])[C:43]=2[CH3:44])[C:37]([O:39][CH3:40])=[O:38])[CH:30]=[C:31]([Br:33])[N:32]=1.C(N(CC)[CH:51]([CH3:53])[CH3:52])(C)C>O1CCOCC1>[CH2:40]([O:39][C:37]([CH2:21][NH:10][CH2:9][CH2:8][O:7][C:6]1[CH:22]=[CH:23][CH:24]=[CH:25][C:5]=1[C:2]1([NH:1][C:27]2[C:28](=[O:46])[N:29]([C:34]3[CH:35]=[C:36]([CH:41]=[C:42]([F:45])[C:43]=3[CH3:44])[C:37]([O:39][CH3:40])=[O:38])[CH:30]=[C:31]([Br:33])[N:32]=2)[CH2:3][CH2:4]1)=[O:38])[C:52]1[CH:51]=[CH:53][CH:35]=[CH:34][CH:43]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(CCOc1ccccc1C1(N)CC1)C(=O)OCc1ccccc1
Reactant: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(Br)c2=O)c1
Solvent: C1COCCO1
Product: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(NC3(c4ccccc4OCCNCC(=O)OCc4ccccc4)CC3)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 164.4 %

Procedure:
A solution of benzyl [2-[2-(1-aminocyclopropyl)phenoxy]ethyl]methylcarbamate (Preparation 4b, 68.1% w/w, 102.2 mg, 204 μmol), methyl 3-(3,5-dibromo-2-oxo-1(2H)-pyrazinyl)-5-fluoro-4-methylbenzoate (Preparation 1g, 94.5 mg, 225 μmol) and N,N-diisopropylethylamine (137 μL, 818 μmol) in 1,4-dioxane (3 mL) was heated to 90° C. (jacket temperature) in a sealed reaction tube for 3 h, before being left to stir overnight at ambient temperature. Further methyl 3-(3,5-dibromo-2-oxo-1(2H)-pyrazinyl)-5-fluoro-4-methylbenzoate (8.6 mg, 20.4 μmol) was added and the reaction mixture re-heated to 90° C. (jacket temperature) for a further 90 min. The solution was then concentrated in vacuo before being purified by preparative TLC on silica, eluting with ethyl acetate/isohexane (1:2 v/v), to afford methyl 3-[3-[1-[2-[2-[(benzyloxycarbonyl)methylamino]ethoxy]phenyl]cyclopropylamino]-5-bromo-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methylbenzoate (125.7 mg) as a white foam.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=2)[CH2:2]1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)Cl>[Br:21][C:12]1[C:7]([O:6][C@H:3]2[CH2:4][CH2:5][O:1][CH2:2]2)=[N:8][C:9]([NH2:13])=[N:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nccc(O[C@H]2CCOC2)n1
Solvent: ClCCl
Product: Nc1ncc(Br)c(O[C@H]2CCOC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-amine (intermediate 62, 33 mg, 0.182 mmol) was dissolved in DCM (4 ml), treated with NBS (35.7 mg, 0.200 mmol) and stirred at 25° C. for 1 h. The reaction solution was diluted in DCM and washed with NaOH (1 M in water) and brine. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to obtain the title compound as a white solid. (UPLC-MS 3) tR 0.67 min; ESI-MS 260.1, 262.0 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27].C(N(CC)CC)C>O1CCOCC1>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:16]2[CH:21]=[CH:20][C:19]([S:22](=[O:23])(=[O:24])[NH2:25])=[CH:18][C:17]=2[N+:26]([O-:28])=[O:27])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Temperature: 90 °C

Procedure:
Tert-butyl 4-aminopiperidine-1-carboxylate (8.63 g) was dissolved in 1,4-dioxane (250 mL), and 4-chloro-3-nitrobenzenesulfonamide (6.00 g) was added followed by triethylamine (10.60 mL). The solution was heated at 90° C. for 20 hours and then cooled. The solvent was removed under vacuum, and the material purified by flash column chromatography on silica gel using 50% ethyl acetate in hexanes, increasing to 100% ethyl acetate and increasing further to 20% methanol in dichloromethane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[NH2:10]C1C=C(O)C=CC=1F>>[NH2:10][C:7]1[CH:6]=[C:5]([OH:8])[C:4]([F:9])=[CH:3][CH:2]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: Nc1cc(O)ccc1F
Product: Nc1ccc(F)c(O)c1
Yield: 86 %

Procedure:
This compound was prepared from 4-bromo-2-fluorophenol (3.0 g, 15.71 mmol) in the manner described for 3-amino-4-fluorophenol, affording 1.79 g (86%) of 3-amino-6-fluorophenol. 1H-NMR (DMSO-d6) δ 10.42 (s, 1H), 9.69 (br s, 2H), 7.22 (dd, J=8.4, 6.6 Hz, 1H), 6.93 (dd, J=5.7, 2.1 Hz, 1H), 6.74 to 6.99 (m, 1H).
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH:12]([OH:21])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:22]1(C)[CH:27]=CC(S(O)(=O)=O)=C[CH:23]=1>CC(C)=O>[CH3:23][C:22]1([CH3:27])[O:1][CH:2]([CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5])[CH2:11][CH:12]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:21]1
Reactant: CC(C)(C)OC(=O)CC(O)CC(O)C=Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)CC1CC(C=Cc2ccccc2)OC(C)(C)O1
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl 3,5-dihydroxy-7-phenyl-6-heptenoate (5.5 g, 19 mmol) in acetone (2.3 g, 40 mmol) was added a catalyic amount of p-toluenesulfonic acid. After stirring for 2 hours, the mixture had solidified and was dissolved in excess acetone and filtered through a pad of sodium carbonate. The excess acetone was removed in vacuo and the residue crystallized from isopropyl ether to give 3.4 g of the title compound; m.p.=91°-93° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[N:22][C:21]([CH3:24])=[N:20]1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[N:22][C:21]([CH3:24])=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=1
Reactant: Cc1ccc(-n2cnc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(Br)nc1
Product: Cc1ccc(NC[C@@H]2[C@H](C)CCCN2C(=O)c2cc(C)ccc2-n2cnc(C)n2)nc1

Procedure:
The title compound was synthesized following the same general protocol as described in Example A44, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanone and 2-bromo-5-methylpyridine. ESI-MS (m/z): 419 [M+1]+.