Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH:9]=[O:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.N1CCCCC1.[NH2:17][C:18]1[C:27](O)=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]>[Ag-]=O.CO>[N:1]12[CH2:8][CH2:7][C:4]([C:9]3[O:10][C:27]4[C:18](=[C:19]([C:20]([O:22][CH3:23])=[O:21])[CH:24]=[CH:25][CH:26]=4)[N:17]=3)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: O=CC12CCN(CC1)CC2
Reactant: COC(=O)c1cccc(O)c1N
Agent: O=[Ag-]
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)c1cccc2oc(C34CCN(CC3)CC4)nc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.3 %

Procedure:
A mixture of quinuclidine-4-carbaldehyde (0.57 g, 4.10 mmol), piperidine (0.86 g, 1 mL, 10.10 mmol), methyl 2-amino-3-hydroxybenzoate (0.68 g, 4.10 mmol) and methanol (10 mL) was heated to reflux for 40 h. Analysis by LCMS indicated the presence of the requisite intermediate Schiff base. The solvent was removed under reduced pressure, the residue was dissolved in methylene chloride (20 ml) and silver (I) oxide (1.23 g, 5.34 mmol) was added. The reaction mixture was stirred at room temperature for 5 h. Analysis by LCMS indicated consumption of the Schiff base intermediate. The reaction mixture was filtered though diatomaceous earth (10 g) eluting with methylene chloride (50 mL) and concentrated. The crude product was purified by column chromatography (silica gel, 5 to 20% methanol in chloroform) to afford methyl 2-(quinuclidin-4-yl)benzoxazole-4-carboxylate (250 mg, 17%) as an brown solid: 1H NMR (300 MHz, CDCl3) δ 7.96 (dd, J=8.0, 1.0 Hz, 1H), 7.67 (dd, J=8.0, 1.0 Hz, 1H), 7.37 (d, d, J=8.0 Hz, 1H), 4.01 (s, 3H), 3.06-3.02 (m, 6H), 2.06-2.01 (m, 6H); MS (ESI+) m/z 287 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][NH2:8])[CH:4]=[N:3][CH:2]=1.C[Al](C)C.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]([C:36]([F:39])([F:38])[F:37])/[CH:22]=[CH:23]/[C:24]2[CH:34]=[CH:33][C:27]([C:28](OCC)=[O:29])=[C:26]([CH3:35])[CH:25]=2)[CH:17]=[C:18]([Cl:20])[CH:19]=1>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]([C:36]([F:39])([F:37])[F:38])/[CH:22]=[CH:23]/[C:24]2[CH:34]=[CH:33][C:27]([C:28]([NH:8][CH2:7][C:5]3[CH:6]=[N:1][CH:2]=[N:3][CH:4]=3)=[O:29])=[C:26]([CH3:35])[CH:25]=2)[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: NCc1cncnc1
Reactant: CCOC(=O)c1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1C
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCc1cncnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
To a stirred solution of (pyrimidin-5-yl)methanamine (0.15 g, 1.43 mmol) in CH2Cl2 (10 mL) was added drop wise trimethylaluminum (2 M solution in toluene; 0.71 mL, 1.43 mmol), and the reaction mixture was stirred at 25° C. for 30 min. A solution of ethyl 4-((E)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoate (0.3 g, 0.71 mmol) in CH2Cl2 was added drop wise to the reaction mixture at 25° C. The reaction mixture was stirred at reflux for 18 h, cooled to 25° C., quenched with 0.5 N HCl solution (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 40% EtOAc in n-hexane) to afford the title compound (0.18 g, 55%): mp 141-144° C.; 1H (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.79 (s, 2H), 7.37 (m, 2H), 7.23 (m, 2H), 7.21 (m, 1H), 6.57 (d, J=16.0 Hz, 1H), 6.40 (dd, J=16.0, 7.6 Hz 1H), 6.21 (m, 1H), 4.65 (s, 2H), 4.11 (m, 1H), 2.46 (s, 3H); ESIMS m/z 477.83 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N+:9]([O-:11])=[O:10].S(=O)(=O)(O)O.C(O)(=O)C.[I:21]I>O>[I:21][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[C:4]=1[CH3:8]
Reactant: II
Reactant: Cc1cccc(C)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(I)c(C)c1[N+](=O)[O-]
Temperature: 90 °C
Yield: 236.9 %

Procedure:
To 1,3-dimethyl-2-nitro-benzene (68.5 g, 453.2 mmol) is added sulfuric acid (27.2 mL, 510 mmol), acetic acid (543.8 mL, 9.49 mol), iodine (46 g, 181.3 mmol) and HIO4 (91.9 g, 403.3 mmol). The reaction is heated to 90° C. for 7 days. The reaction mixture is cooled to ambient temperature and water (500 mL) is added. The resulting solid is collected by filtration and washed with cold water. The solid is dried under reduced pressure at 45° C. overnight to afford the title compound as a yellow solid (119 g, 95%). 1H NMR (300.16 MHz, CDCl3): δ 7.80 (d, J=8.2 Hz, 1H), 6.85 (d, J=8.2 Hz, 1H), 2.37 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl.[CH2:13]([O:15][C:16](=[O:23])[CH2:17][CH:18]([NH2:22])[CH2:19][CH2:20][CH3:21])[CH3:14].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:13]([O:15][C:16](=[O:23])[CH2:17][CH:18]([NH:22][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[CH2:19][CH2:20][CH3:21])[CH3:14]
Reactant: CCCC(N)CC(=O)OCC
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)Nc1cc(C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.2 %

Procedure:
To a solution of 3-Fluoro-4-nitrotoluene (1.0 g, 6.5 mmol) in DMF (5 mL) were: 3-Amino-hexanoic acid ethyl ester hydrochloride (1.3 g, 6.7 mmol) and DIPEA (2.2 mL, 12.9 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was then diluted with ethyl acetate and washed with water (×4). The organic phase was then dried over Na2SO4 and concentrated. The resulting residue was purified by Combiflash using hexane and ethyl acetate (10% gradient) as an eluent to afford 1.4 g of the desired product as orange oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]#[CH:31]>C(#N)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH2:31][C:30]#[CH:29])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: C#CCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
To a solution of 200 mg (0.59 mmol) of 3-[4-chloro-2-fluoro-5-(hydroxy)phenyl]-1-methyl-6- (trifluoromethyl)-2,4 (1H,3H) -pyrimidinedione in 3 mL of acetonitrile was added 162 mg of potassium carbonate (1.18 mmol) and 131 mL (1.18 mmol) of an 80% solution of propargyl bromide in toluene. It was warmed under reflux for 2 h. The resulting mixture was filtered and the filtrate was concentrated in vacuo to give colorless oil which was flash chromatographed over silica gel, eluting with a 1:4 v:v mixture of ethyl acetate and hexane to give 204 mg of title compound as a white foam: 1H-NMR (CDCl3, 200 MHz) ppm 7.35 (d, 1H), 7.0 (d, 1H), 6.4 (s, 1H), 4.78 (d, 2H), 3.58 (s, 3H), 2.6 (d, 1H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([NH:9][C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12](O)=O)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:21]>>[CH:1]([N:4]1[C:8]2=[N:9][C:10]3[C:11]([C:12]([Cl:21])=[C:7]2[CH:6]=[N:5]1)=[CH:15][CH:16]=[CH:17][CH:18]=3)([CH3:3])[CH3:2]
Reactant: CC(C)n1nccc1Nc1ccccc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)n1ncc2c(Cl)c3ccccc3nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
A mixture of N-(1-isopropylpyrazol-5-yl)anthranilic acid (52 g, 0.212 mol) and POCl3 (436 ml, 4.68 mol) was refluxed for 3 hours, then was stirred at room temperature overnight. The excess POCl3 was removed by distillation and then the residue was poured into ice/water. The mixture was neutralized with 35% NaOH and then extracted with CH2 Cl2. The CH2Cl2 layer was separated and washed with water, then brine and then was dried over MgSO4, filtered and evaporated. The residue was dissolved in CH2Cl2 and then was purified by column chromatography on silca gel eluting with CH2Cl2 to afford 21.3 g (40.9%) of 1-isopropyl-4-chloro-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][CH2:9][CH2:10][C:11]([OH:13])=O.Cl.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:11](=[O:13])[CH2:10][CH2:9][O:8][CH3:7])=[CH:34][CH:33]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Reactant: COCCC(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCC(=O)Nc1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (0.41 ml) was added to a stirred solution of 3-methoxypropanoic acid (0.45 ml) in methylene chloride (15 ml) containing 1 drop of N,N-dimethylformamide. The mixture was stirred at ambient temperature for 3 hours. A 5 ml aliquot of this reaction mixture was added dropwise to a solution of 4-[3-(2-benzyloxyphenyl)-propyl]-benzeneamine hydrochloride (0.63 g) in dichloromethane (20 ml) containing triethylamine (0.82 ml). Stirring was containued for 16 hours. The reaction mixture was evaporated to dryness and the residue was partitioned between diethyl ether and water. The diethyl ether extract was washed consecutively with aqueous 2N HCl (20 ml), saturated aqueous sodium bicarbonate (20 ml) and brine (20 ml) then dried (MgSO4). The residue obtained on removal of the solvent was subjected to flash chromatography on silica (Merck 9385) eluted with ether, to give, after crystallisation from diethyl ether-hexane mixture, 4-[3-(2-benzyloxyphenyl)propyl]-N-(3-methoxypropionyl)-benzeneamine, m.p. 65°-6° C., yield 0.58 g (80%).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.Cl.[CH3:14][O:15][C:16](=[O:25])[C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH2:18].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH3:14][O:15][C:16](=[O:25])[C@@H:17]([NH:18][C:2](=[O:4])[C:1]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:6])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: COC(=O)[C@@H](N)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)c1ccccc1N)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.9 %

Procedure:
To a mixture of isatoic anhydride (250 mg, 1.53 mmol) and (S)-2-phenylglycine methyl ester hydrochloride (370 mg, 1.84 mmol) in DMF (5.0 mL) is added triethylamine (0.29 mL, 2.07 mmol). The mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with EtOAc (100 mL) and is washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate and concentrated to afford (S)-(2-amino-benzoylamino)-phenyl-acetic acid methyl ester (330 mg, 76%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[SH:10].[CH2:11]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[F:8][C:7]1[C:2]2[N:1]=[C:21]([C:20]3[CH:23]=[CH:24][C:17]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=3)[S:10][C:3]=2[CH:4]=[CH:5][C:6]=1[F:9]
Reactant: CCCCCCc1ccc(C=O)cc1
Reactant: Nc1c(S)ccc(F)c1F
Product: CCCCCCc1ccc(-c2nc3c(F)c(F)ccc3s2)cc1

Procedure:
2-Amino-3,4-difluorothiophenol [131105-92-5] is reacted analogously to Reference 1 with 4-hexylbenzaldehyde (commercially available, [49763-69-1]) to give 4,5-difluoro-2-(4-hexylphenyl)benzothiazoline, which is converted into 4,5-difluoro-2-(4-hexylphenyl)benzothiazole using barium permanganate by the method described in the cited literature. a-Lithiation (by means of lithium diisopropylamide analogously to J. Chem. Soc. Perkin Trans. II 1989, 2048) and quenching with hexyl bromide gives the target compound, which can be purified by chromatography and by recrystallization from acetonitrile.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[C:8]1([C@H:18]([N:20]([CH2:28][C@@H:29]2[C@@H:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:32][NH:31][CH2:30]2)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl>C1COCC1>[C:23]([O:22][C:21]([N:20]([CH2:28][C@@H:29]1[C@@H:33]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:32][N:31]([C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[CH2:30]1)[C@@H:18]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH3:19])=[O:27])([CH3:24])([CH3:25])[CH3:26]
Reactant: O=C1CCC(=O)O1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)CCC(=O)O)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Succinic anhydride was added to a mixture of 1.0 g of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate, 235 mg of triethylamine and 15 ml of THF at room temperature and stirred overnight. The reaction solution was mixed with 1 M hydrochloric acid to quench the reaction and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate and concentrated under a reduced pressure to obtain 1.72 g of crude 4-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-4-oxobutanoic acid (compound A) as a colorless amorphous substance. A 1.0 g portion of the thus obtained crude product was purified by a silica gel column chromatography (chloroform-methanol) to obtain 525 mg of 4-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-4-oxobutanoic acid as a colorless amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:33]1[CH2:32][CH2:31][N:30]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=3)[CH2:35][CH2:34]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4ccc(Cl)cc4nc3OC)CC2)c1
Yield: 91 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 91%). MS(ESI) m/z 458 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:13]=[C:12]([O:27][CH3:28])[N:11]=2)=[CH:6][C:3]=1[CH:4]=O.[CH3:29][N:30]([CH2:32][CH2:33][NH2:34])[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:49]>C(Cl)Cl.CO.CCOC(C)=O>[ClH:49].[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:13]=[C:12]([O:27][CH3:28])[N:11]=2)=[CH:6][C:3]=1[CH2:4][NH:34][CH2:33][CH2:32][N:30]([CH3:31])[CH3:29]
Reactant: CN(C)CCN
Reactant: COc1ccc(CCNc2cc(-c3ccc(F)c(C=O)c3)nc(OC)n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(CCNc2cc(-c3ccc(F)c(CNCCN(C)C)c3)nc(OC)n2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
A mixture of 2-fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzaldehyde [275 mg, 072 mmol, Example 35(j)], unsym-dimethylethylenediamine (217 μL, 1.97 mmol), sodium triacetoxyborohydride (500 mg, 2.36 mmol) and 3 Å sieves (500 mg) in DCM (7 mL) is stirred at room temperature under a nitrogen atmosphere for 5 hours. The reaction mixture is filtered and the filter cake is washed with DCM (50 mL). The combined filtrate and washings are extracted water with (50 mL) and the aqueous is extracted with DCM (50 mL). The new organic extract is washed with water (30 mL), with brine (30 mL), dried over sodium sulfate, filtered and concentrated by rotary evaporator. The resulting solid is subjected to flash column chromatography on silica (4.5 g) eluting with 0 to 7% MeOH in DCM gradient to afford a solid that is dissolved in methanol. This solution is treated with hydrogen chloride in EtOAc and concentrated to afford N-(2-fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N′,N′-dimethyl-ethane-1,2-diamine hydrochloride [300 mg, 92%, Example 13(d)]. LCMS: RT=2.04 minutes, MS: 454 (M+H). IC50=56 nM
Reaction SMILES: C([O:5][C:6](=O)[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([S:19][CH2:20][CH2:21][C:22](=[O:30])[NH:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][NH2:29])[N:16]=[C:15]([NH2:31])[N:14]=2)[C:10]([CH3:32])=[CH:9][C:8]=1[CH3:33])(C)(C)C.FC(F)(F)C(O)=O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[NH2:31][C:15]1[N:16]=[C:17]2[CH:18]=[C:13]([C:11]3[CH:12]=[C:7]([C:6](=[O:5])[NH:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][NH:23][C:22](=[O:30])[CH2:21][CH2:20][S:19]2)[C:8]([CH3:33])=[CH:9][C:10]=3[CH3:32])[N:14]=1
Reactant: Cc1cc(C)c(-c2cc(SCCC(=O)NCCOCCN)nc(N)n2)cc1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C)c2cc1C(=O)NCCOCCNC(=O)CCSc1cc-2nc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3 %

Procedure:
5-(2-Amino-6-{2-[2-(2-aminoethoxy)ethylcarbamoyl]ethylsulfanyl}pyrimidin-4-yl)-2,4-dimethylbenzoic acid tert-butyl ester (78 mg, 0.159 mmol) obtained in Step 1 above was dissolved in dichloromethane (3 ml), and then trifluoroacetic acid (1 ml) was added thereto. After this solution was stirred at room temperature for two hours, the solvent was distilled off under reduced pressure. The resulting crude product was dissolved in a mixed solvent of N,N-dimethylformamide (25 ml) and tetrahydrofuran (75 ml), and then 1-hydroxybenzotriazole (134 mg, 0.795 mmol), diisopropylethylamine (137 μl, 0.795 mmol), and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (152 mg, 2.2 mmol) were sequentially added thereto. After the solution was stirred at room temperature for 16 hours, 1-hydroxybenzotriazole (270 mg, 1.59 mmol), diisopropylethylamine (274 μl, 1.59 mmol), and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (304 mg, 1.59 mmol) were added thereto. After the solution was stirred at 50° C. for seven hours, the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate. The ethyl acetate solution was washed with a saturated aqueous sodium bicarbonate solution (twice), and dried over anhydrous sodium sulfate. After the inorganic salt was removed by filtration, the filtrate was concentrated. The resulting residue was purified by preparative thin layer silica gel chromatography (developing solvent: dichloromethane:methanol=15:1). The obtained crude product was washed with dichloromethane to yield 4-amino-20,22-dimethyl-14-oxa-7-thia-3,5,11,17-tetraazatricyclo[17.3.1.12,6]tetracosa-1(22),2(24),3,5,19(23),20-hexaene-10,18-dione (Compound 29) (2 mg) as a white solid material.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[C:48]1([CH3:66])[CH:53]=[CH:52][C:51]([C:54]([O:56][C:57]2[CH:65]=[CH:64][CH:63]=[CH:62][C:58]=2[C:59](O)=[O:60])=[O:55])=[CH:50][CH:49]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:59](=[O:60])[C:58]3[CH:62]=[CH:63][CH:64]=[CH:65][C:57]=3[O:56][C:54]([C:51]3[CH:50]=[CH:49][C:48]([CH3:66])=[CH:53][CH:52]=3)=[O:55])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: Cc1ccc(C(=O)Oc2ccccc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)c3ccccc3OC(=O)c3ccc(C)cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 2-[4-toloyloxy]benzoic acid (8.0 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][N:5]=1.Cl[CH2:12][O:13][CH3:14]>CN(C=O)C.C(OCC)(=O)C.O.[Cl-].[Na+]>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][O:13][CH3:14])=[CH:6][N:5]=1
Reactant: COCCl
Reactant: Oc1ccc(Cl)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.8 %

Procedure:
Suspend sodium hydride (3.7 g, 93 mmol) in DMF (50 mL) and add a solution of 2-chloro-5-hydroxypyridine (10 g, 77 mmol) in DMF (20 mL) dropwise over 45 min. Stir the resulting solution at room temperature for 1.5 hours. Add chloromethylmethyl ether (6.6 mL, 86 mmol) dropwise over 45 min. Stir the resulting mixture at room temperature for 12 hours. Dilute the mixture with ethyl acetate, water, and saturated aqueous sodium chloride. Isolate the organic solution and wash with three portions of water, one portion of saturated aqueous sodium chloride, dry over sodium sulfate, filter, and concentrate in vacuo. Purify the crude product by column chromatography on 330 g of silica gel eluting with a gradient from hexane to 30% ethyl acetate in hexane over 20 min and then hold at 30% ethyl acetate in hexane for 30 min to give the title compound (10.8 g, 81%) as a clear oil. MS (ES) m/z 174.0 [M+1]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])=O)C.[NH2:20][C:21]([NH2:23])=[S:22].C([O-])([O-])=O.[K+].[K+].Cl>COCCO.O>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[NH:23][C:21](=[S:22])[NH:20][C:4](=[O:3])[CH:5]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)c1ccccc1OCCOC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCO
Solvent: O
Product: COCCOc1ccccc1-c1cc(=O)[nH]c(=S)[nH]1
Yield: 60.2 %

Procedure:
To a solution of 3-[2-(2-methoxy-ethoxy)-phenyl]-3-oxo-propionic acid ethyl ester (0.5 g, 1.88 mmol) in 2-methoxyethanol (5 mL) was added thiourea (0.22 g, 2.8 mmol) and K2CO3 (0.28 g, 2 mmol). The reaction mixture refluxed 3 h. After cooling, a mixture poured into water (10 mL) and adjusted to pH 3 with concentrated HCl. A precipitate formed that was filtered and washed with water and diethyl ether to obtained 0.315 g (60%) 6-[2-(2-methoxy-ethoxy)-phenyl]-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one as a cream solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6]1.Cl.Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC>[C:11]1([N:7]2[CH2:6][CH:5]([CH2:4][CH2:3][CH2:2][N:28]3[CH2:29][CH2:30][N:25]([C:20]4[N:19]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:26][CH2:27]3)[O:9][C:8]2=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C1OC(CCCCl)CN1c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: O=C1OC(CCCN2CCN(c3ncccn3)CC2)CN1c1ccccc1
Yield: 36 %

Procedure:
Following the procedure of Example 5, a mixture of 5-(3-chloropropyl)-3-phenyl-2-oxazolidinone (4.5 g, 0.0188 mol), 1-(2-pyrimidyl)piperazine dihydrochloride (4.47 g, 0.0188 mol), potassium carbonate (15.64 g, 0.113 mol), and potassium iodide (1.0 g) in n-butanol (200 mL) gave a solid which was recrystallized from isopropanol/isopropyl ether and dried under high vacuum to give 2.49 g (36% yield), mp 92°-98° C. and 118° C.