Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][C:23]2[S:27][CH:26]=[CH:25][CH:24]=2)[CH2:9]1)C1C=CC=CC=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1(C)C=CC=CC=1>[CH2:32]([O:31][C:29]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][C:23]2[S:27][CH:26]=[CH:25][CH:24]=2)[CH2:9]1)=[O:30])[CH3:33]
Reactant: c1ccc(CN2CCOC(COc3ccccc3Cc3cccs3)C2)cc1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCOC(COc2ccccc2Cc2cccs2)C1
Yield: 85.7 %

Procedure:
To a solution of 3.8 g of 4-benzyl-2-[2-(2-thenyl)phenoxymethyl]-morpholine in 30 ml of toluene was added 1.2 g of ethyl chloroformate, and the mixture was heated under reflux for 6 hours. After cooling, the insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give 3.1 g of crude 4-ethoxycarbonyl-2-[2-(2-thenyl)-phenoxymethyl]morpholine as an oil. The oil was dissolved in 40 ml of ethanol, and a solution of 3.2 g of barium hydroxide in 50 ml of water was added, and the mixture was heated under reflux for 8 hours. After cooling, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The remaining oil was extracted with two 70 ml portions of 5% hydrochloric acid, and the combined water layer was made alkaline with sodium hydroxide. The liberated oil was extracted with benzene, and the benzene extract was dried over potassium carbonate. Then the benzene was distilled off to give 1.6 g of 2-[2-(2-thenyl)phenoxymethyl]-morpholine as an oil. A solution of the oil (1.6 g) in 15 ml of isopropyl ether was added to a solution of 0.65 g of maleic acid in 7 ml of ethanol to give 2.1 g of colorless crystals. The crystals were recrystallized from a mixture of methanol and isopropyl ether (1:1) to give 1.5 g of 2-[2-(2-thenyl)phenoxymethyl]morpholine maleate as colorless crystals, melting at 155°-156° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:20])=[C:4]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(#N)C.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.C1COCC1>[Br:1][C:2]1[C:3]([Cl:20])=[C:4]2[C:10]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)c(Br)cnc21
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(Br)c(Cl)c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
5-Bromo-4-chloro-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (916 mg, 2 mmol), 2-methoxyphenyl boronic acid (321 mg, 2.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (74 mg, 0.1 mmol), and 2 mL of 2M Na2CO3 (aq) were dissolved in 10 mL of acetonitrile and 10 mL of THF under an atmosphere of nitrogen. The mixture was heated at 60° C. with rapid stirring under N2 for 2 h. Sodium sulfate was added to the reaction mixture and the slurry was filtered over Celite and concentrated. The crude product was purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes to afford the title compound (452 mg, 1.02 mmol, 51% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.74 (s, 1H), 7.37 (m, 1H), 7.23 (dd, J=7.5 Hz, J2=1.5 Hz, 1H), 7.05 (dd, J=8 Hz, J2=1 Hz, 1H), 6.98 (td, J=7.5 Hz, J2=1 Hz, 1H), 5.63 (s, 2H), 3.67 (s, 3H), 3.56 (t, J=8 Hz, 2H), 0.82 (t, J=8 Hz, 2H), −0.09 (s, 9H). MS: m/z 467.1/469.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH2:11][CH:10]([CH2:12]OS(C)(=O)=O)[O:9][N:8]=2)=[CH:4][CH:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[Na+]>CN(C)C=O>[N:18]([CH2:12][CH:10]1[O:9][N:8]=[C:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:11]1)=[N+:19]=[N-:20]
Reactant: CS(=O)(=O)OCC1CC(c2ccc(Br)s2)=NO1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CC(c2ccc(Br)s2)=NO1
Temperature: 75 °C
Yield: 97.6 %

Procedure:
Methanesulfonic acid 3-(5-bromo-thien-2-yl)-4,5-dihydro-isoxazol-5-ylmethyl ester (9 g, 26.4 mmol) was added to dimethyl formamide (25 ml) followed by addition of sodium azide (3.4 g, 52.8 mmol). The mixture was heated to 75° C. for five hours and then added to aqueous sodium chloride (100 ml) followed by extraction with ethyl acetate (3×200 ml). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to yield the desired product (7.4 g).
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[N:7]=[CH:6][C:5]=1[CH2:15][C:16]([O-:18])=[O:17]>C1COCC1>[CH3:3][C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[N:7]=[CH:6][C:5]=1[CH2:15][C:16]([OH:18])=[O:17]
Reactant: Cc1cc(-n2cnnn2)ncc1CC(=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(-n2cnnn2)ncc1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of lithium hydroxide (1 N, 4.75 ml) was added to a stirred mixture of [4-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]acetate (1.00 g, 4.29 mmol) in THF (10 ml) and the mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH ˜3-4 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to provide [4-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]acetic acid which was used directly in the next step without further purification. LC-MS (IE, m/z): 206 [M+1]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:9][CH2:8][O:7][CH2:6]2)[CH2:4][C:3]([C:10]2[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([OH:16])[CH:15]=2)=[N:2]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[CH3:28]>CN(C)C=O.O>[CH2:27]([O:16][C:14]1[CH:15]=[C:10]([C:3]2[CH2:4][C:5]3([CH2:9][CH2:8][O:7][CH2:6]3)[O:1][N:2]=2)[CH:11]=[CH:12][C:13]=1[O:17][CH3:18])[CH3:28]
Reactant: CCBr
Reactant: COc1ccc(C2=NOC3(CCOC3)C2)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C2=NOC3(CCOC3)C2)ccc1OC
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of the compound No. 73 (1 eq) in dimethylformamide (10 mL), was added potassium iodide (0.1 eq) and potassium carbonate (2 eq). The reaction mixture was stirred at room temperature and ethyl bromide (2 eq) was added. The reaction mixture was stirred for overnight at room temperature. The reaction mixture was cooled and diluted with water, extracted with ethylacetate and washed with saturated solution of sodium chloride. The organic solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography to furnish the title compound. Yield=90%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:25]2[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])=[CH:27][CH:26]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21](=[O:24])(=[O:23])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].Cl.O1CCOCC1>O>[Cl:1][C:2]1[C:3]([C:25]2[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:26]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21](=[O:24])(=[O:23])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]1=[O:14]
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCS(=O)(=O)C4)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCS(=O)(=O)C4)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A mixture of the compound obtained in Example 114 (200 mg), 10% aqueous hydrochloric acid (3 ml) and dioxane (5 ml) was stirred at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature and poured into water. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4) and the solvent was distilled off under reduced pressure to obtain (4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7,7-dioxido-5,8-dihydro-6H-thiopyrano-[4′,3′:4,5]-thieno[2,3-b]pyridin-4-yl}phenoxy)acetic acid (130 mg, 72%). It was recrystallized from acetone-hexane. Colorless prisms. Melting point 260–261° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[C:21]([F:24])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.[N+](C1C=CC(OC(=O)[NH:48][C:49]2[CH:54]=[CH:53][C:52]([N:55]3[CH2:60][CH2:59][O:58][CH2:57][CH2:56]3)=[CH:51][CH:50]=2)=CC=1)([O-])=O>>[N:55]1([C:52]2[CH:51]=[CH:50][C:49]([NH:48][C:6]([N:8]3[CH2:9][CH2:10][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([O:25][CH2:26][CH2:27][CH2:28][N:29]6[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]6)=[C:21]([F:24])[CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:12][CH2:13]3)=[O:7])=[CH:54][CH:53]=2)[CH2:56][CH2:57][O:58][CH2:59][CH2:60]1
Reactant: CN1CCN(CCCOc2cc3ncnc(C4CCN(C(=O)OC(C)(C)C)CC4)c3cc2F)CC1
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CN1CCN(CCCOc2cc3ncnc(C4CCN(C(=O)Nc5ccc(N6CCOCC6)cc5)CC4)c3cc2F)CC1

Procedure:
The title compound was prepared from 4-{6-Fluoro-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid tert-butyl ester, prepared in the previous step, and (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride, prepared as described in Example 66a, using essentially the protocol given for Example 170c. 1H-NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 7.74 (d, 1H), 7.44 (d, 1H), 7.27 (m, 2H), 6.88 (m, 2H), 6.32 (s, 1H), 4.27 (m, 4H), 3.86 (m, 4H), 3.54 (tt, 1H), 3.18-3.08 (m, 6H), 2.58 (t, 2H), 2.64-2.35 (br, 8H), 2.30 (s, 3H), 2.12 (m, 4H), 1.96 (m, 2H). LC/MS (ESI): calcd mass 591.3, found 592.4 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH2:10][C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[OH:12][CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[C:14]1[CH:18]=[CH:17][S:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)c1ccsc1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CCO)c1ccsc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (±)-2-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)propanoic acid (E4) in THF at 0° C. is added BH3-THF dropwise. The solution is allowed to warm to room temperature and stirred for an additional 2 hours. The solution is cooled to 0° C., quenched with AcOH (10%)/MeOH, and evaporated. Column chromatography (SiO2, EtOAc) gives pure tert-butyl 3-hydroxy-1-(thiophen-3-yl)propylcarbamate (E73A).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=2)[CH2:12][CH2:11]1
Reactant: Nc1ccc(Cl)nn1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc(N)nn2)CC1
Temperature: 170 °C
Yield: 78 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 6-chloro-pyridazin-3-amine (1.3 g, 10 mmol) and 1-methylpiperazine (15 mL). The reaction mixture was heated at 170° C. for 3 h. It was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was washed with CH3CN (20 mL) to afford 342a as a yellow solid (1.5 g, 78%). MS: [M+H]+ 194. 1H NMR (500 MHz, DMSO) δ 7.12 (d, J=9.0 Hz, 1H), 6.74 (d, J=9.0 Hz, 1H), 5.72 (s, 2H), 3.27 (t, J=4.5 Hz, 4H), 2.40 (t, J=4.5 Hz, 4H), 2.20 (s, 3H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[N:8]=[C:9]2[NH:17][CH:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]2[C:11](=[O:13])[CH:12]=1.[OH-].[Na+]>ClCCCl.O.C(OCC)(=O)C>[Cl:3][C:7]1[N:8]=[C:9]2[NH:17][CH:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]2[C:11](=[O:13])[CH:12]=1
Reactant: O=c1cc(O)nc2n1CCC(C(F)(F)F)N2
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCCl
Product: O=c1cc(Cl)nc2n1CCC(C(F)(F)F)N2
Temperature: 65 °C
Yield: 81.6 %

Procedure:
136 mL (1440 mmol) of phosphorus oxychloride are added, at room temperature and under an argon atmosphere, to a suspension of 68.10 g (290 mmol) of 2-hydroxy-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 950 mL of 1,2-dichloroethane. The mixture obtained is then heated at 65° C. for 3 hours. After cooling, the reaction mixture is evaporated to dryness under reduced pressure. The residue obtained is taken up in 140 mL of cold water and 430 mL of ethyl acetate. 32% sodium hydroxide is added to the mixture obtained, to pH=5. The resulting organic phase is separated out and then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 60 g of 2-chloro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in the form of an orange solid, the characteristics of which are as follows:
Reaction SMILES: Cl.CC(C)([S@]([NH:7][CH:8]([C:10]1[CH:11]=[C:12]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[CH:13]=[C:14]2[C:19]=1[O:18][C:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[CH:16][C:15]2=[O:26])[CH3:9])=O)C>O1CCOCC1>[NH2:7][CH:8]([C:10]1[CH:11]=[C:12]([C:27]([N:29]([CH3:30])[CH3:31])=[O:28])[CH:13]=[C:14]2[C:19]=1[O:18][C:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[CH:16][C:15]2=[O:26])[CH3:9]
Reactant: CC(N[S@](=O)C(C)(C)C)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Cl
Solvent: C1COCCO1
Product: CC(N)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
Hydrogen chloride in dioxane 4M (15 mL, 60.1 mmol) was added to 8-(1-((R)-1,1-dimethylethylsulfinamido)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (2.7 g, 6.0 mmol) dissolved in dioxane (40 mL). The resulting white suspension was stirred at RT for 1 hour, collected by filtration, washed with diethyl ether and dried. It was dissolved into a 5% methanolic ammonia (7 N) sol. in DCM (200 mL) and stirred for 5 minutes. The precipitate (NH4Cl) was removed by filtration and the filtrate was concentrated to dryness to afford 8-(1-aminoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (single enantiomer, 1.85 g, 89%) as an off-white solid. Mass Spectrum: M+H+ 346. [α]D20°: +35° in acetonitrile.
Reaction SMILES: [CH2:1]([Zn]CC)C.C(O)(C(F)(F)F)=O.ICI.[CH2:16]=[C:17]1[CH2:22][CH2:21][CH:20]([CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:19][CH2:18]1.[Cl-].[NH4+]>C(Cl)Cl>[CH2:1]1[C:17]2([CH2:22][CH2:21][CH:20]([CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:19][CH2:18]2)[CH2:16]1
Reactant: C=C1CCC(CNC(=O)OCc2ccccc2)CC1
Reactant: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ICI
Product: O=C(NCC1CCC2(CC1)CC2)OCc1ccccc1
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
Diethyl zinc (25 mL, 1M hexane solution) was slowly added to 100 mL of anhydrous DCM at −40° C. under nitrogen, and further slowly added TFA (2.85 g, 0.025 mol) and reacted for 0.5 h, then diiodomethane (6.67 g, 0.025 mol) was slowly added thereto. The reaction was continued for 0.5 h, then Compound 8-4 (3 g, 0.012 mol) was dissolved in 20 mL of anhydrous DCM and added dropwise to the reaction mixture under nitrogen, reacted overnight at −5° C., added saturated ammonium chloride solution to quench the reaction, followed by liquid separated, the organic phase was concentrated and purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give Compound 8-5 as a white solid (2.85 g, yield 86.9%).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][CH:5]1[C:10](=[O:11])[NH:9][CH:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:19])[NH:6]1.[OH-].[Na+].Cl>CO>[CH2:12]([CH:8]1[C:7](=[O:19])[NH:6][CH:5]([CH2:4][C:3]([OH:20])=[O:2])[C:10](=[O:11])[NH:9]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)CC1NC(=O)C(Cc2ccccc2)NC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC1NC(=O)C(Cc2ccccc2)NC1=O
Reaction time: 2 h

Procedure:
In 1,000 l of a 50% aqueous methanol solution was suspended 55 g of the 5-benzyl-3,6-dioxo-2-piperazine acetic acid methyl ester obtained in Example 1, and 42 g of a 20% aqueous sodium hydroxide solution was added to the suspension at room temperature under stirring. Then, the hydrolysis was conducted at room temperature for two hours to form an aqueous solution. Thereafter, conc. hydrochloric acid was added dropwise to the aqueous solution, which had been removed with methanol under reduced pressure by distillation, to adjust its pH at 1. The resulting mixture was stirred at room temperature for one hour and the crystal thereby deposited was filtered, washed with water and dried to obtain 5-benzyl-3,6-dioxo-2-piperazine acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:10]=1[N:9]([C:16]1[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([F:13])[CH:15]=1)[CH:8]=[CH:7]2
Reactant: COc1ccc(B(O)O)cc1F
Reactant: COc1ccc(Cl)c2[nH]ccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-n2ccc3c(OC)ccc(Cl)c32)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.7 %

Procedure:
To a solution of 7-chloro-4-(methyloxy)-1H-indole (D11) (1.15 g, 6.35 mmol) in dichloromethane (20 mL) was added 3-fluoro-4-methoxyphenylboronic acid (2.2 g, 12.9 mmol), triethylamine (1.8 mL, 12.9 mmol), copper (II) acetate (2.3 g, 12.7 mmol) and powdered 4A molecular sieves (2.0 g). The reaction mixture was stirred at room temperature in the presence of air for 3 days. Further quantities of 3-fluoro-4-methoxyphenylboronic acid (440 mg), triethylamine (0.36 mL) and copper acetate (440 mg) were added and the mixture stirred at room temperature in the presence of air for a further 16 hours. The mixture was filtered and the solid washed with dichloromethane. The filtrate was concentrated at reduced pressure. The product was partially purified by silica gel chromatography eluting with 2-35% dichloromethane in hexane. The resulting product was partially dissolved in dimethylsulphoxide and acetonitrile. The undissolved solid was collected by filtration to yield the title compound (D12) (440 mg). The filtrate was concentrated at reduced pressure and the product purified by MDAP to yield a further batch of the title compound (D12), (143 mg).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:15][C@H:16]1[CH2:18][O:17]1>C(O)C>[O:17]1[CH2:18][C@H:16]1[CH2:15][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: ClC[C@H]1CO1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C[C@@H]2CO2)CC1
Reaction time: 5 h
Yield: 73.3 %

Procedure:
Tert-butyl piperazine-1-carboxylate 7a (3.72 g, 20 mmol) was dissolved in 40 mL of ethanol followed by the addition of (R)-2-chloromethyl-oxirane (1.85 g, 20 mmol). The reaction solution was stirred for 5 hours and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-[[(2R)-oxiran-2-yl]methyl]piperazine-1-carboxylate 7b (3.55 g, yield: 74.0%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][C@@H:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1.[C:48]1([N:54]=[C:55]=[O:56])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][C@@H:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:55]([NH:54][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:56])[CH2:41]1
Reactant: O=C(C[C@@H]1CCCNC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCCN(C(=O)Nc2ccccc2)C1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 40 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-piperidin-3-yl]acetamide bis(trifluoroacetate) and phenyl isocyanate as the starting materials in 40% yield. LCMS for C32H33ClN7O2 (M+H)+: m/z=582.2.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22]([O:24]C)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[OH-].[Na+].Cl>CO.O1CCCC1>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22]([OH:24])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: COC(=O)c1cccc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.2 %

Procedure:
Methyl 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate (from step 1) (2.90 g, 6.91 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (12 mL). 4N NaOH (4.3 mL, 17.27 mmol) was added. The resulting mixture was stirred for 1.5 hours at room temperature. The reaction was acidified (pH-2) with 4N HCl. The precipitate was collected by filtration to afford an off white solid (2.36 g, 84%). 1H NMR (400 MHz, DMSO-d6) δ 8.01 (dt, J=1.441, 7.65 Hz, 1H), 7.76 (app t, J=1.68 Hz, 1H), 7.69-7.53 (m, 3H), 7.36-7.14 (m, 2H), 6.69 (s, 1H), 5.32 (s, 2H), 1.93 (s, 3H). ES-HRMS m/z 406.0662 (M+H C20H14ClF2NO4 requires 406.0652).