Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]2[S:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:20][C:19]([C:22](Cl)=[O:23])=[CH:18][CH:17]=1>>[C:16]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:17]=[CH:18][C:19]([C:22]([N:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[S:7][C:6]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:23])=[CH:20][CH:21]=1
Reactant: c1ccc2c(c1)CNc1cccnc1S2
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2ccccc2Sc2ncccc21

Procedure:
As described for Example 26, 5,6-dihydropyrido[2,3-b][1,4]benzothiazepine is reacted with [1,1'-biphenyl]-4-carbonyl chloride to give the product as a solid.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:34]=[C:35]([NH:39][C:40](=[O:42])[CH3:41])[CH:36]=[CH:37][CH:38]=2)[CH2:29][CH2:28]1>>[C:40]([NH:39][C:35]1[CH:34]=[C:33]([CH:30]2[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][CH2:24][NH:23][C:8](=[O:9])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:28][CH2:29]2)[CH:38]=[CH:37][CH:36]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 105 was prepared from triphenylacetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.34–7.22 (m, 19H), 6.91 (d, 1H, J=7.6 Hz), 6.30 (t, 1H, J=5.6 Hz), 3.43 (dd, 2H, J=6.4, 12.0 Hz), 2.87 (d, 2H, J=12.0 Hz), 2.42 (m, 1H), 2.30 (t, 2H, J=6.8 Hz), 2.17 (s, 3H), 1.93 (t, 2H, J=11.6 Hz), 1.74–1.66 (m, 4H), 1.60–1.50 (m, 2H); ESMS m/e: 546.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]([F:15])[C:13]#[N:14])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]>C1COCC1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]([F:15])[CH2:13][NH2:14])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(C(F)C#N)c1
Solvent: C1CCOC1
Product: CCCCOc1cccc(C(F)CN)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
To a solution of 2-(3-butoxyphenyl)-2-fluoroacetonitrile (109 mg: 0.53 mmol) in dry THF (5 mL), borane tetrahydrofurane complex (2.10 mL; 2.10 mmol) is added and the reaction is stirred at 0° C. for 2 hours and then at RT for 6 hours. An LC/MS shows almost complete conversion. The reaction is quenched adding slowly few drops of EtOH and few drops of conc. HCl/EtOH (1:5) and stirring is continued for 5 min. DCM was then added, followed by 5% aqueous NaHCO3. The two phases are separated and the aqueous phase is extracted twice with DCM. The combined organic layers are dried over Na2SO4, filtered and evaporated. The crude residue is purified using a SCX cartridge (eluant: DCM/MeOH 1/1 to MeOH/conc. aq. NH3 95/5) affording 2-(3-butoxyphenyl)-2-fluoroethanamine (92 mg; 0.43 mmol; 83%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13]O)=[CH:5][CH:4]=1.S(Cl)([Cl:17])=O>ClCCl.C(OCC)(=O)C>[Cl:17][CH2:13][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2cccc(CO)c2c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc2cccc(CCl)c2c1
Yield: 84 %

Procedure:
To a solution of the compound obtained in Step A (100 g) in dichloromethane (5 ml/g) there are added 2 equivalents of thionyl chloride (126.35 g). The mixture is heated to reflux and maintained at reflux for 2 hours. After returning to ambient temperature, the solvent is evaporated off under reduced pressure. The oil obtained is taken up in ethyl acetate and washed with water and then with saturated NaCl solution. The solvent is evaporated off under reduced pressure and the crude product is purified by passing over a pad of silica (eluant: heptane). The title compound is obtained in the form of a yellow solid in a yield of 84%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Product: O=C1Cc2cc(NCc3ccccc3)ccc2N1

Procedure:
By reaction of 5-amino-2-oxindole with benzaldehyde using the procedure of Example 1, the title compound was prepared.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[O-].[Na+].[C:14]([CH:17]([CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25]C)=[O:24])[C:18](OC)=[O:19])(=O)[CH3:15]>CO>[CH3:15][C:14]1[N:9]=[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[NH:10][C:18](=[O:19])[C:17]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24]
Reactant: CCCC(C(=O)OC)C(C(C)=O)C(=O)OC
Reactant: N=C(N)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 119.9 %

Procedure:
To a solution of benzamidine hydrochloride (9.2 g; 50 mmol) in methanol (46 mL) was slowly added a solution of sodium methoxide (25%) (23 mL; 100 mmol) and dimethyl 2-acetyl-3-propylsuccinate (60%) (19.2 g; 50 mmol). The reaction mixture was heated at reflux for 18 h, and after cooling, the white precipitate was filtered and washed with a small volume of methanol. The solid was dried and carefully added to a cold hydrochloric 12N solution (25 mL). The suspension was stirred for one minute at 0° C., filtered and washed with a small amount of methanol. The precipitate was dried under reduced pressure over phosphorus pentoxide to provide 17.16 g of the expected 2-(4-methyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)pentanoic acid as a white powder which was used without further purification. ESI/APCI(+): 287 (M+H); ESI/APCI(−): 285 (M−H). 1H NMR (DMSO-d6) δ 8.08 (2H, d, Harom.); 7.70 (1H, m, Harom.); 7.60 (2H, m, Harom.); 3.76 (1H, m, CHα); 2.48 (3H, s, CH3); 1.98 (1H, m, CHβ); 1.72 (1H, m, CHβ′); 1.14 (2H, m, CH2γ); 0.87 (3H, t, CH3δ).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH2:10][C@@H:9]4[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[CH:4][N:3]=[CH:2]1>C(Cl)Cl>[O:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH:10]=[C:9]4[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[CH:4][N:3]=[CH:2]1
Reactant: CCCN(CCC)[C@@H]1Cc2c(-c3cnco3)ccc3c2[C@H](CN3)C1
Solvent: ClCCl
Product: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(-c4cnco4)c(c23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
A mixture of (-)(2aR,4S)-6-(5-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (300 mg, 0.9 mmol) and 0.5 g of HnO2 in 50 ml of methylene chloride was stirred at room temperature for 16 hours. The oxidant was removed by filtration through celite. The crude product obtained after filtering and removing the solvent was purified by flash chromatography, using ethyl acetate as eluent, to provide 100 mg of title compound. Recrystallization from hexane gave 60 mg of pure title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.C([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27]O)[CH2:23][CH2:22]1)C1C=CC=CC=1>C1COCC1.C([Li])CCC>[NH:21]1[CH2:26][CH2:25][CH:24]([CH2:27][O:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([Cl:11])[C:2]([NH2:1])=[CH:3][C:4]=2[O:12][CH3:13])[CH2:23][CH2:22]1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: OCC1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1C(=O)OCC1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.1 %

Procedure:
1,1-carbonyldiimidazole (0.8 g., 0.005 mol) was added to a solution of 4-amino-5-chloro-2-methoxy-benzoic acid (1 g, 5 mmol) in THF (20 ml) and the reaction mixture was stirred at room temperature for about 30 minutes. The solvent was evaporated and the residue was taken up in H2O and extracted into ethyl acetate (3×20 ml). The organic phases were collected, dried and evaporated to dryness. The obtained solid residue was dissolved in THF (10 ml) and dropped into a solution of 1-benzylpiperidin-4-yl-methanol [J. Med. Chem. (1992), 35, 4344], (1 g, 5 mmol) in THF (10 ml) and butyllithium (1.6 M in hexane; 3 ml), maintained at 0° C. The reaction mixture was further stirred at room temperature for 1 hour. The solvent was evaporated and the residue was taken up into H2O and extracted into ethyl acetate. The organic extracts were dried and evaporated to give the desired product as a pale yellow oil, (1.63 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl>CN(C)C=O.O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[N:8]2[CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2/C1=C/c1cccc(Cl)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
To a solution of E/Z 6-Bromo-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one (5.3 g, 16 mmol) prepared in example 157a in N,N-dimethyl-formamide (50 mL) at 0° C. was added NaH (60% in mineral oil) (0.64 g, 16 mmol), followed by the dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (2.65 g, 16 mmol) in tetrahydrofuran (40 mL). The reaction mixture was stirred at 0° C. for 0.5 h, then poured into ice-water. The crude was extracted with ethyl acetate twice. The combined organic layer was dried over Na2SO4. The solvent was removed and the residue was purified by chromatography (hexanes) to give E/Z-6-Bromo-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one as a yellow oil (Yield 4.5 g, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].COC1C=CC=CC=1OC1C=CC=CC=1N.NC1SC=CN=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1ccccc1O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: COc1ccccc1Oc1ccccc1N
Agent: Nc1nccs1
Product: COc1ccccc1Oc1ccccc1[N+](=O)[O-]
Yield: 80.7 %

Procedure:
2-(2-Methoxyphenoxy)-1-nitrobenzene (0.99 g, 81%) was prepared from 2-methoxyphenol (0.68 g, 5.5 mmol) and 1-fluoro-2-nitrobenzene (0.71 g, 5.0 mmol) following the general procedure A. This was reduced to 2-(2-methoxyphenoxy)aniline (0.63 g, 73%) following general procedure B. N-2-(2-Methoxyphenoxy)phenyl-N′-(thiazol-2-yl)urea (110 g, 65%) was prepared from 2-(2-methoxyphenoxy)aniline (108 mg, 0.5 mmol) and 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure D.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.N1C=CC=CC=1>>[F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(C#N)c(F)c1
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1ccc(O)cc1F
Temperature: 170 °C

Procedure:
A mixture of 2-fluoro-4-methoxy-benzonitrile (500 mg, 0.246 mmol) and pyridine hydrochloride (2.0 g, 17.2 mmol) is heated at 170° C. for 5 hours. The reaction is partitioned between ethyl acetate and 1N hydrochloric acid. The organic phase is washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 2-fluoro-4-hydroxy-benzonitrile.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[CH:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=2)[N:4]([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:3]=1.CN(C)C(=N)N(C)C.Cl.[N+:35]([CH3:38])([O-:37])=[O:36]>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH2:38][N+:35]([O-:37])=[O:36])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=2)[N:4]([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C=Cc1ccc2c(C)cn(CCCc3ccccc3)c2c1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Product: COC(=O)CC(C[N+](=O)[O-])c1ccc2c(C)cn(CCCc3ccccc3)c2c1
Temperature: 65 °C

Procedure:
A stirred solution of methyl 3-(3-methyl-1-{3-(phenyl)propyl}-1 H-indol-6-yl)-propenoate (0.263 g, Reference Example 39) in nitromethane (5 ml) was treated with tetramethylguanidine (0.091 g). The mixture was heated to 65° C. for 2 hours then treated with a further aliquot of tetramethylguanidine (0.091 g). After heating at 65° C. for a further hour the reaction mixture was cooled to room temperature then poured into hydrochloric acid (20 ml, 1N) then extracted three times with ethyl acetate (25 ml). The combined extracts were dried over magnesium sulphate then evaporated. The residue was subjected to preparative layer chromatography on silica using a mixture of ethyl acetate and hexane (1:2, v/v) as eluent to yield the title compound (0.296 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[CH2:13]([NH2:16])[CH2:14][CH3:15].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C1COCC1.C1COCC1.O>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:16][CH2:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: CCCN
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCNC(=O)Nc1cccc(N)c1

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with N-3-aminophenyl-N'-propylurea to generate the title compound. The N-3-aminophenyl-N'-propylurea was prepared by sequentially treating commercial 3-nitrophenylisocyanate with PrNH2 in THF at 20° C. followed by reduction with Na2S2O4 in THF/H2O at 100° C.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:17](/B(O)O)=[CH:18]\[CH2:19][CH2:20][CH2:21][CH3:22].[ClH:26]>CCOCC>[ClH:26].[CH:17](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:18]\[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCC/C=C/B(O)O
Reactant: OCCCCNc1ccc2ncc(Br)n2n1
Agent: Cl
Solvent: CCOCC
Product: CCCC/C=C/c1cnc2ccc(NCCCCO)nn12
Yield: 51 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2. The free base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (61 mg, 51%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 7.87 (s, 1H), 7.85 (d, J=9.8 Hz, 1H), 7.15 (,J=9.8 Hz, 1H), 6.93 (dt, J=7.0, 16.2 Hz, 1H), 6.66 (d, J=16.2 Hz, 1H), 3.62 (t, J=6.5 Hz, 2H), 3.43 (t, J=7.0 Hz, 2H), 2.37-2.32 (m, 2H), 1.82-1.76 (m, 2H), 1.69-1.64 (m, 2H), 1.56-1.50 (m, 2H), 1.47-1.41 (m, 2H), 0.96 (t, J=7.3 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 157.1, 139.1, 133.3, 130.1, 120.9, 120.7, 117.7, 114.3, 62.6, 42.6, 34.2, 32.3, 31.2, 25.9, 23.3, 14.3; HPLC tR=11.2 min (Luna), 98.3%; ES-MS: (M+H)=289 m/z.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]1[N:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][N:17]=1)=O>CC(O)=O>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]1[N:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][N:17]=1
Reactant: CCOC(=O)c1cnc(N2CCC[C@H]2C(=O)Nc2ccccc2N)nc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(N2CCC[C@H]2c2nc3ccccc3[nH]2)nc1
Temperature: 90 °C
Yield: 64.9 %

Procedure:
AcOH (2 mL) was added to compound 500 (117 mg, 0.329 mmol) and the solution was heated at 90° C. for 30 minutes. The solvent was evaporated under reduced pressure. The residue was then partitioned between ethyl acetate and water and the pH adjusted to pH=10. The organic phase was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 50-100% EtOAc in hexanes to afford title compound 501 (72 mg, 65%). MS (m/z): 338.4 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.CC(N(C)C)=O.[C:21]1([NH:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=[C:2]([NH:30][CH2:29][CH2:28][NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1
Reactant: NCCNc1ccccc1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: Clc1cc(NCCNc2ccccc2)nc(N2CCOCC2)n1
Temperature: 75 °C
Reaction time: 20 h

Procedure:
To a solution of 4-(4,6-dichloropyrimidin-2-yl)morpholine (prepared as described in Method 22; 932 mg, 4.0 mmol) and DMA (0.7 mL, 4.0 mmol) in ACN (40 mL), neat N1-phenyl-ethane-1,2-diamine (0.523 mL, 4.0 mmol) was slowly added. The reaction mixture was stirred at 70-80° C. under nitrogen. After 20 hours, the reaction mixture was cooled down, and the solvent was removed under reduced pressure. The crude product was partitioned between EtOAc (120 mL) and 0.1 M NaHCO3 (50 mL). The organic layer was washed with additional 0.1 M NaHCO3 (2×50 mL), brine (50 mL), dried, filtered and concentrated to give N1-(6-chloro-2-morpholinopyrimidin-4-yl)-N2-phenylethane-1,2-diamine, as an off-white solid (1.29 g, 96%). LC/MS (m/z): 334.0 (MH+), Rt 1.94 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[CH:14][C:15]2[NH:20][CH:19]([CH3:21])[O:18][C:17]([CH3:23])([CH3:22])[C:16]=2[CH:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH:19]([CH3:21])[O:18][C:17]([CH3:23])([CH3:22])[C:16]=3[CH:24]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC1Nc2ccc(Br)cc2C(C)(C)O1
Product: CC1Nc2ccc(-c3cccc(Cl)c3)cc2C(C)(C)O1

Procedure:
Prepared according to the coupling procedure for Example 17 from 3-chlorophenyl boronic acid and 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine. A orange solid: mp 144-146° C.; 1H-NMR (CDCl3) δ 7.50 (t, 1H, J=1.78 Hz), 7.40 (dt, 1H, J=7.61, 1.45 Hz), 7.33 (t, 1H, J=7.76 Hz), 7.29-7.22(m, 4H) 6.72 (d, 1H, J=8.24 Hz), 4.90 (q, 1H, J=5.45 Hz), 1.62 (s, 3H), 1.59 (s, 3H), 1.46 (d, 3H, J=5.5 Hz); MS (ES) m/z 288/290 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C@H:8]([NH:11][S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.[CH3:18][S:19]([O-:21])=[O:20].[Na+]>CS(C)=O.[NH4+].[Cl-].C([O-])(O)=O.[Na+].CCOC(C)=O.[Cu]I>[CH3:18][S:19]([C:2]1[CH:7]=[C:6]([C@@H:8]([NH:11][S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1)(=[O:21])=[O:20]
Reactant: CC[C@@H](NS(=O)C(C)(C)C)c1ccnc(Br)c1
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC[C@H](NS(=O)C(C)(C)C)c1ccnc(S(C)(=O)=O)c1
Temperature: 130 °C

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid [(R)-1-(2-bromo-pyridin-4-yl)-propyl]-amide (6.00 g, 18.8 mmol) in DMSO (240 ml) was added sodium methanesulfinate (6.77 g, 56.4 mmol) and copper (I) iodide (10.7 g, 56.4 mmol) The mixture was then heated at 130° C. for 45 minutes. The reaction was diluted with saturated aqueous NH4Cl (90 mL), saturated NaHCO3 (10 mL), and EtOAc (150 mL), and sonicated for 10 minutes to dissolve all the solids. The phases were separated and the organic layer was washed with a 9:1 mixture of saturated NH4Cl-saturated NaHCO3 (100 mL). The combined aqueous phases were extracted with EtOAc (150 mL). Combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc in hexanes to afford 2-methyl-propane-2-sulfinic acid [(S)-1-(2-methanesulfonyl-pyridin-4-yl)-propyl]amide as a clear thick oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+]([O-])=O)=[C:4]2[O:15][CH2:14][CH2:13][O:12][C:5]2=[C:6](C(=O)C)[C:7]=1[Cl:8].O1C2C=CC=CC=2OCC1>>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]2[O:15][CH2:14][CH2:13][O:12][C:5]=2[CH:6]=1
Reactant: CC(=O)c1c(Cl)c(Cl)c([N+](=O)[O-])c2c1OCCO2
Agent: c1ccc2c(c1)OCCO2
Product: Clc1cc2c(cc1Cl)OCCO2

Procedure:
The 5',6'-dichloro-2',3'-ethylenedioxy-4'-nitroacetophenone can be prepared by chlorinating 1,4-benzodioxane to give 6,7-dichloro-1,4-benzodioxane and then acetylating. The chlorination can be carried out by treating the benzodioxane with chlorine gas in acetic acid at 0 to 20° C. and requires 1 to 8 hours. The acetylation can be effected by reacting the 6,7-dichloro-1,4-benzodioxane with acetyl chloride in the presence of a Lewis acid in a suitable solvent (e.g., 1,2-dichloroethane, carbon disulfide, nitrobeanzene, etc.) at 20 to 40° C. and requires 24 to 48 hours.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]#[N:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:17][OH:18].C(N(CC)CC)C>C(O)C>[NH2:15]/[C:14](=[N:17]\[OH:18])/[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCCCC1C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCCC1/C(N)=N/O
Yield: 95 %

Procedure:
In a 16 mL vial, N-boc-2-cyanopiperidine (500 mg, 2.38 mmol) was dissolved in ethanol (6.7 mL), then hydroxylamine hydrochloride (231 mg, 3.33 mmol) and triethylamine (0.56 mL, 4.05 mmol) were added. The reaction mixture was stirred at reflux for 5 h, cooled and concentrated. The residue was taken up in EtOAc and water. The two layers were separated and the aqueous phase extracted with EtOAc. The combined organics were dried on Na2SO4 and concentrated to give the product as a white solid (550 mg, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH3:21][O:22][CH2:23][C:24](Cl)=[O:25]>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:24](=[O:25])[CH2:23][O:22][CH3:21])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: COCC(=O)Cl
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Product: COCC(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 99.9 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added 2-methoxyacetyl chloride (0.43 g, 4.0 mmol). The stirred mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.69 g (100%) of product as an off-white solid: mp 246–248° C.; 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 10.30 (s, 1H), 8.70 (d, J=8.4 Hz, 1H), 7.86 (t, J=7.8 Hz, 1H), 7.63 (d, J=7.3 Hz, 1H), 5.17 (dd, J=5.2 and 12.7 Hz, 1H), 4.11 (s, 2H), 3.49 (s, 3H), 2.98–2.84 (m, 1H), 2.66–2.47 (m, 2H), 2.12–2.07 (m, 1H); 13C NMR (DMSO-d6) δ 172.67, 169.66, 169.02, 168.25, 166.61, 136.48, 135.91, 131.24, 124.35, 118.31, 116.04, 71.40, 59.10, 48.96, 30.91, 21.94; Anal. Calcd. For C16H15N3O6: C, 55.65; H, 4.38; N, 12.17. Found: C, 55.58; H, 4.40; N, 12.08.