Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O.[C:22]([O:26][C:27]([N:29]1[CH2:38][C:37]([CH3:40])([CH3:39])[C:36]2[C:31](=[CH:32][C:33]([NH2:41])=[CH:34][CH:35]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:22]([O:26][C:27]([N:29]1[CH2:38][C:37]([CH3:40])([CH3:39])[C:36]2[C:31](=[CH:32][C:33]([NH:41][C:15](=[O:17])[C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[NH:12][CH2:11][C:7]3[C:6]4[C:10](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=4)[NH:9][CH:8]=3)=[CH:34][CH:35]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C(C)(C)C1
Reactant: O=C(O)c1ccccc1NCc1c[nH]c2c(F)cccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3NCc3c[nH]c4c(F)cccc34)ccc2C(C)(C)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-[(7-fluoro-1H-indol-3-ylmethyl)-amino]-benzoic acid (Step A, 200 mg, 0.70 mmol), 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (194 mg, 0.70 mmol), TBTU (247 mg, 0.80 mmol), and DIEA (0.25 mL, 1.4 mmol) in CH2Cl2 (5 mL) was stirred at RT under N2 atmosphere for 16 h. The mixture was diluted with CH2Cl2 (5 mL) and extracted with water (2×10 mL). The crude material was purified with flash chromatography (SiO2, 15% EtOAc/hexane) to give a yellow solid. MS (ES+) 543.1. (M+H)+. Calc'd for C32H35FN4O3-542.24.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].Br[CH2:12][Si:13]1(C2C=CC=CC=2)[CH2:18][CH2:17][CH:16]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][Si@H:13]2[CH2:14][CH2:15][C@H:16]([C@H:19]3[CH2:24][CH2:23][C@H:22]([CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29])[CH2:21][CH2:20]3)[CH2:17][CH2:18]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: C=CCCC[C@H]1CC[C@H](C2CC[Si](CBr)(c3ccccc3)CC2)CC1
Reactant: CCOc1ccc(O)cc1
Product: C=CCCC[C@H]1CC[C@H]([C@H]2CC[Si@H](COc3ccc(OCC)cc3)CC2)CC1

Procedure:
The general procedure of Example 39 was repeated using 4-ethoxyphenol and trans-4-(4-bromomethyl-4-phenyl-4-silacyclohexyl)-1-(4-pentenyl)cyclohexane, thereby obtaining the intended product.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([OH:10])(=[O:9])[CH3:8].[CH2:11]([C:18]1[C:23]([I:24])=[CH:22][CH:21]=[C:20]([N:25]2[CH2:29][C@H:28]([O:30][CH3:31])[C@@H:27](OS(C3C=CC=C([N+]([O-])=O)C=3)(=O)=O)[CH2:26]2)[N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CS(C)=O>[CH2:11]([C:18]1[C:23]([I:24])=[CH:22][CH:21]=[C:20]([N:25]2[CH2:29][C@H:28]([O:30][CH3:31])[C@H:27]([O:9][C:7](=[O:10])[CH3:8])[CH2:26]2)[N:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)O
Reactant: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@@H]1OS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OC(C)=O
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To a mixture of 7.9 g of cesium carbonate and 15 ml of dimethyl sulfoxide was added 4.2 ml of acetic acid. After foaming ceased, a mixture of 14.4 g of 2-benzyl-3-iodo-6-[(3S,4S)-3-(3-nitrobenzenesulfonyl)oxy-4-methoxypyrrolidin-1-yl]pyridine and 35 ml of dimethyl sulfoxide was added and the resultant mixture was heated under stirring under nitrogen atmosphere in an oil bath at 70° C. for 6 hours. After the reaction mixture was cooled, it was extracted with ethyl acetate-water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (10–15% ethyl acetate/hexane), to give 7.5 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[N+](N[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:20][N:19]=1)([O-])=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[CH:20][N:19]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1CCCCN
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCCCc3ncc(Br)cc3C)[nH]c2=O)cn1
Yield: 63.3 %

Procedure:
5-Bromo-2-(4-aminobutyl)-3-methylpyridine (2.12 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (3.18 g) were refluxed in pyridine (12 ml) for 9.5 hrs. The pyridine was removed in vacuo and the residue was re-evaporated with n-propanol (2×50 ml), triturated with chloroform, filtered and the solution was chromatographed on silica in chloroform-methanol (10:1). The product was crystallised from ethanol-ether to give 2-[4-(5-bromo-3-methylpyrid-2-yl)-butylamino]-5-(6-methylpyrid-3-yl-methyl)-4-pyrimidone (2.44 g) m.p. 151°-152° C.
Reaction SMILES: CS([O:5][CH:6]([CH:17]([CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=O)=O.[CH3:38][N:39]([CH:41](O)[CH2:42][CH2:43][CH3:44])[CH3:40].[H-].[Na+].O>C1(C)C=CC=CC=1>[CH2:18]([CH:17]([CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:6]([O:5][CH2:44][CH2:43][CH2:42][CH2:41][N:39]([CH3:40])[CH3:38])[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(CCC/C=C\CCCCC)OS(C)(=O)=O
Reactant: CCCC(O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(CCC/C=C\CCCCC)OCCCCN(C)C
Temperature: 115 °C
Reaction time: 50 h
Yield: 12.7 %

Procedure:
A solution of the mesylate 61 (1.09 g, 2.01 mmol) in toluene (30 mL) was successively treated with N,N-dimethylaminobutanol (1.34 mL, 10.1 mmol) and NaH (442 mg as a 60% dispersion in oil, 11.1 mmol). Once gas evolution ceased the reaction mixture was brought to reflux (115° C. bath temp.) and stirred (50 h). The reaction mixture was then cooled (rt) and poured into cold water and then extracted with EtOAc. The combined organics were washed with water and brine, dried (Na2SO4), filtered, concentrated and purified via chromatography (100% EtOAc) to yield 4-(((6Z,16Z)-12-((Z)-dec-4-en-1-yl)docosa-6,16-dien-11-yl)oxy)-N,N-dimethylbutan-1-amine 62 (143 mg, 13%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.41-5.30 (m, 6H), 3.46-3.35 (m, 2H), 3.19-3.14 (m, 1H), 2.34 (t, 2H), 2.24 (s, 6H), 2.10-1.93 (m, 12H), 1.60-1.09 (m, 35H), 0.90 (t, 9H). Rf 0.54 (10% MeOH—CH2Cl2).
Reaction SMILES: C1S[CH:5]([C:6]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:7]=2[NH:16][S:17]([CH3:20])(=[O:19])=[O:18])SCC1.CC[O:24]C(C)=O.CCCCCC.C1C([N+]([O-])=O)=CC([N+]([O-])=O)=C(O)C=1>CN(C)C=O.CC(C)=O.[Cu]=O.[Cu](Cl)Cl>[CH3:20][S:17]([NH:16][C:7]1[CH:8]=[CH:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:6]=1[CH:5]=[O:24])(=[O:19])=[O:18]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)c(C2SCCCS2)c1
Agent: Cl[Cu]Cl
Agent: O=[Cu]
Agent: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NS(C)(=O)=O)c(C=O)c1
Yield: 79 %

Procedure:
A sample of 2-(methanesulfonylamino)-5-(methoxycarbonyl)benzaldehyde trimethylene mercaptal (7.66 g, 0.022 mol) dissolved in N,N-dimethylformamide (4.35 mL) and acetone (39.13 mL) was added over a 5-min period through a dropping funnel to a solution of copper (II) oxide (2.09 g, 0.026 mol), copper (II) chloride (7.0 g, 0.055 mol) in acetone (174.0 mL) and heated at reflux. After 2 h at reflux, thin-layer chromatography analysis (SiO2, EtOAc:hexane 1:1) showed disappearance of the starting material and the appearance of a new slightly higher Rf spot which gave a positive result when sprayed with 2,4-DNP. Upon cooling, the reaction was filtered through Celite and the cake was washed with 10% ethanol in dichloromethane. Water (125 mL) and dichloromethane (150 mL) were added to the filtrate. The layers were partitioned and the water layer extracted 2×100 mL dichloromethane. The combined organic layers were washed twice with water (100 mL), dried (Na2SO4), and filtered. Concentration of the filtrate gave a beige solid which was dried in vacuo to give 4.48 g (79%) of 2-(methanesulfonylamino)-5-(methoxycarbonyl)benzaldehyde, mp 161°-163° C. (ethanol).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[CH2:22][CH:21]([CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:26][CH2:25]3)[C:19](=[O:20])[C:14]2=[CH:15][C:16]=1[O:17][CH3:18]>C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[CH2:22][CH:21]([CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:28][CH2:29]3)[C:19](=[O:20])[C:14]2=[CH:15][C:16]=1[O:17][CH3:18].[C:1]([O-:8])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5]
Reactant: O=C(O)CCC(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Product: O=C([O-])CCC(=O)[O-]
Temperature: 25 °C

Procedure:
Succinic acid (1.18 g, dissolved in 35 ml of absolute ethanol) is slowly added to a solution of Donepezil (3.79 g) in ethyl acetate (70 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 169.1° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:26])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20]COC)=[C:16]([O:24][CH3:25])[CH:15]=2)=[C:5]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:4]=1[CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36].Cl.CO>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:26])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:24][CH3:25])[CH:15]=2)=[C:5]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:4]=1[CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36]
Reactant: COCOc1ccc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2OCC(=O)OC)cc1OC
Agent: Cl
Solvent: CO
Product: COC(=O)COc1c(CCC(C)C)c(OC)cc(OC)c1C(=O)CCc1ccc(O)c(OC)c1
Reaction time: 0.17 h
Yield: 83.9 %

Procedure:
Then, 15.5 g of 1-(4,6-dimethoxy-2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(3-methoxy-4-methoxymethoxyphenyl)-1-propanone was dissolved in 25 ml of methanol, and 23 ml of hydrochloric acid/methanol was added to the solution and the mixture was heated and fluxed for 10 minutes. After the reaction, the solvent was removed by distillation, and the obtained solid was dissolved in a small amount of ethyl acetate and crystallized by diethyl ether/hexane to obtain 11.9 g (yield=84%) of 1-(4,6-dimethoxy-2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(4-hydroxy-3-methoxyphenyl)-1-propanone in the form of a white solid.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]([C:15]3[N:16]=[N:17][S:18][C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[Cl:27])=[CH:13][C:12]([Br:28])=[CH:11][N:10]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:28][C:12]1[CH:13]=[C:14]([C:15]2[N:16]=[N:17][S:18][C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[Cl:27])[C:9]([NH2:8])=[N:10][CH:11]=1
Reactant: COc1ccc(CNc2ncc(Br)cc2-c2nnsc2-c2cccc(Cl)c2Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(Br)cc1-c1nnsc1-c1cccc(Cl)c1Cl
Temperature: 40 °C
Reaction time: 72 h
Yield: 36.9 %

Procedure:
To a solution of N-(4-methoxybenzyl)-5-bromo-3-(5-(2,3-dichlorophenyl)-1,2,3-thiadiazol-4-yl)pyridin-2-amine (0.128 mmol) in CH2Cl2 (2 mL) was added TFA (3 mL). The mixture was heated at 40° C. for 20 hours then at RT for 3 d. The volatiles were evaporated and the residue purified by preparative reversed-phase HPLC to afford 5-bromo-3-(5-(2,3-dichlorophenyl)-1,2,3-thiadiazol-4-yl)pyridin-2-amine as a colorless oil (0.019 g, 37% yield). Using the same procedure, 5-bromo-3-(5-(2,3-fluorophenyl)-1,2,3-thiadiazol-4-yl)pyridin-2-amine and 5-bromo-3-(5-(3-chloro-2-fluorophenyl)-1,2,3-thiadiazol-4-yl)pyridin-2-amine can be produced from 1-(5-bromo-2-chloropyridin-3-yl)-2-(2,3-difluorophenyl)ethanone and 1-(5-bromo-2-chloropyridin-3-yl)-2-(3-chloro-2-fluorophenyl)ethanone, respectively.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:22]>CO>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH2:22])[N:11]=2)=[CH:15][CH:16]=1
Reactant: N
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Solvent: CO
Product: COc1ccc(N(C)c2nc(N)nc3ccccc23)cc1

Procedure:
Title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (10 mg, 0.033 mmol) and 7 M ammonia in methanol (1 mL) by a procedure similar to Example 10 (5 mg, 50%). 1H NMR (CDCl3): 7.44 (m, 2H), 7.16 (m, 2H), 6.96-6.95 (m, 2H), 6.88 (dd, J=8.4 and 1.5 Hz, 1H), 6.72 (ddd, J=8.7, 6.6 and 1.8 Hz, 1H), 3.86 (s, 3H), 3.72 (s, 3H).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:32])[CH2:15][NH:16][C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]2)=O)=[CH:10][CH:9]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:32][C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:20]3)=[N:16][CH:15]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)NCC(=O)c2ccc(F)cc2)C1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC(c2ncc(-c3ccc(F)cc3)o2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.6 %

Procedure:
Dry pyridine (0.24 mL, 2.74 mmol) was added dropwise to a solution of tert-butyl 3-((2-(4-fluorophenyl)-2-oxoethyl)carbamoyl)piperidine-1-carboxylate (500 mg, 1.37 mmol) in dry CH2Cl2 (12 mL) at 0° C., followed by trifluoromethanesulfonic anhydride (0.5 mL, 2.74 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 3 h. The reaction mixture was diluted with CH2Cl2 and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by purified by column chromatography (silica gel 60-120 mesh, eluent 12-15% EtOAc in petroleum ether) to afford tert-butyl 3-(5-(4-fluorophenyl)oxazol-2-yl)piperidine-1-carboxylate (150 mg, yield 32%). 1H NMR (400 MHz, DMSO-d6) δ 7.75-7.72 (dd, J=9.0 Hz, 5.3 Hz, 2H), 7.55 (s, 1H), 7.33-7.29 (t, J=8.8 Hz, 2H), 3.99-3.90 (m, 1H), 3.69-3.60 (m, 1H), 3.02 (m, 1H), 2.12-2.07 (m, 1H), 1.82-1.76 (m, 2H), 1.64-1.57 (m, 1H), 1.51-1.42 (m, 2H), 1.35 (s, 9H). MS (ESI) m/z: Calculated for C19H23FN2O3: 346.17. found: 347.2 (M+H)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21][NH:22]C(=O)C)[CH:11]=3)=[CH:9][C:2]=12.N1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(CC)=O>[N:22]1([CH2:21][CH2:20][CH2:19][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([C:8]3[NH:7][C:3]4=[N:4][CH:5]=[CH:6][N:1]=[C:2]4[CH:9]=3)=[CH:11]2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: CC(=O)NCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: c1ccc2c(c1)c(-c1cc3nccnc3[nH]1)cn2CCCN1CCOCC1
Temperature: 25 °C

Procedure:
A mixture of 3-[3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-indol-1-yl]-propylbromide [250 mg, Reference Example 4], morpholine (0.5 mL), potassium carbonate (100 mg) and potassium iodide (2 crystals) in ethyl methyl ketone was heated at reflux for 2 hours. The mixture was then allowed to cool to ambient temperature over 16 hours then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (9:1, v/v) to give a yellow glass which was triturated with ethyl acetate and pentane to give the title compound (40 mg) as a yellow solid, m.p. 180-185° C. MS: 362 (MH+).
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[CH:11][NH:12][C:13]1[N:17]([CH2:18][CH3:19])[N:16]=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4]([OH:20])=[C:14]2[CH:15]=[N:16][N:17]([CH2:18][CH3:19])[C:13]2=[N:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccnn1CC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(cnn2CC)c1O
Temperature: 25 °C

Procedure:
(1-Ethylpyrazol-5-yl-amino)methylenemalonate diethyl ester (180 mmol from previous reaction) was dissolved in diphenyl ether (200 mL), and the resulting solution was placed in a preheated oil bath at 255° C. The reaction solution was heated for 5 h, and then the diphenyl ether was removed via distillation. The resulting brown reaction mixture was cooled to room temperature and poured to hexane (1 L). Cooling this solution to −78° C., followed by filtration of the resulting precipitate afforded the title compound as a beige colored needle shaped solid that was >90% pure by HPLC and was used directly (25 g, 60% for 2 steps). A portion was recrystallized using ethanol-H2O to afford a white solid: mp 85-86° C.; LRMS (m/z) 236 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:30])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH:16]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:15]2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:30])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][C:17](=[O:20])[CH:16]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:15]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC1CN(CCn2c(=O)cnc3ccc(F)cc32)CCC1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CN(CCn2c(=O)cnc3ccc(F)cc32)CCC1=O
Reaction time: 1 h
Yield: 67.8 %

Procedure:
To a solution of racemic 1,1-dimethylethyl ({1-[2-(7-fluoro-2-oxo-1(2H)-quinoxalinyl)ethyl]-4-hydroxy-3-piperidinyl}methyl)carbamate (2.0 g, 4.76 mmol) in dry dichloromethane (120 mL) was added Dess-Martin periodinane (1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one, 3.03 g, 7.12 mmol) in portions over 5 min. The mixture was stirred for 1 h, then 10% aqueous sodium sulphite (70 mL) and aqueous sodium bicarbonate (60 mL) were added and stirring continued for 0.5 h. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The organic fractions were dried and evaporated and the residue was chromatographed on silica, eluting with 50-100% ethyl acetate/hexane, to give the product (1.35 g, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][CH:15]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[CH2:14][CH2:13]1
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCC(=O)CC1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1N1CCC(N2CCN(C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(2-methoxy-5-nitrophenyl)piperidin-4-one (Preparation Example 502) (296 mg), 1-methylpiperazine (0.20 mL) and 1,2-dichloroethane (11 mL), sodium triacetoxyborohydride (385 mg) was added and stirred overnight at room temperature. After addition of water and saturated aqueous sodium hydrogen carbonate, the reaction liquid was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=100:0 to 10:1) to give 1-[1-(2-methoxy-5-nitrophenyl)piperidin-4-yl]-4-methylpiperazine (0.40 g) as a brown oil.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:21][N:22]=[C:23]=[O:24].C(=O)([O-])[O-].[K+].[K+].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>O1CCCC1.C(O)C.C(OC(C)C)(C)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[CH3:21][NH:22][C:23](=[O:24])[O:20][C:17]1[CH:16]=[CH:15][C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][N:9]2[CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:19][CH:18]=1
Reactant: Oc1ccc(C2CCCN2CCN2CCOCC2)cc1
Reactant: CN=C=O
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CNC(=O)Oc1ccc(C2CCCN2CCN2CCOCC2)cc1
Yield: 57.7 %

Procedure:
To a solution of 4-{1-[2-(4-morpholinyl)ethyl]-2-pyrrolidinyl}phenol (0.92 g) in dry tetrahydrofuran (50 ml) was added methyl isocyanate (0.22 ml) at ambient temperature, with stirring, over ten mins. Milled potassium carbonate (0.55 g) was added and the reaction mixture was stirred for 2 days and filtered through a pad of celite. The filter cake was washed with ethyl acetate and the combined filtrates concentrated. The residue was purified by flash column chromatography (silica gel, 10% methanol/ether). The appropriate fractions were collected and concentrated. The residue was dissolved in dichloromethane and washed with water (5-6 times). The combined aqueous layers were back-extracted with ether, and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. Fumaric acid (2.02 equivalents) in absolute ethanol and diisopropyl ether was added to the residue to yield (0.55 g, 57.7%) of product. mp 119°-121° C.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl-].[Li+].Br[C:9]1[C:10]([O:17][CH3:18])=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=1.[N:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[N:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C1COCC1.[Cl-].[Na+].O>[CH3:34][C:31]([O:30][C:28]([N:19]([C:9]1[C:10]([O:17][CH3:18])=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=1)[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:29])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: COc1ncc(Br)c(OC)n1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ncc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(OC)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Isopropylmagnesium chloride-lithium chloride complex (1.3 M in THF, 18.3 mL, 23.7 mmol) was added dropwise to a cold (0° C.) solution of 5-bromo-2,4-dimethoxypyrimidine (4 g, 18.3 mmol) in THF (50 mL), under argon. The reaction mixture was allowed to warm to rt and stirred for 1 h at this temperature. Di-tertbutyl azodicarboxylate (4.2 g, 18.3 mmol) was added portionwise. The reaction mixture was stirred for 1 h at rt, diluted with brine, and extracted with EtOAc. The organic layers were combined, washed with brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc, 9:1→7.3) to provide 6.78 g of the title compound. tR: 1.08 min (LC-MS 4); ESI-MS: 371.3 [M+H]+ (LC-MS 4); Rf=0.55 (hexane/EtOAc, 1:1).