Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:13])[C:10](O)=O)=[C:4](C=O)[CH:3]=1.C([O-])(=O)C.[Na+].[OH-].[Na+]>C(OC(=O)C)(=O)C.C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:8][C:9]([CH3:10])=[CH:13][C:6]=2[CH:7]=1
Reactant: CC(Oc1ccc(Br)cc1C=O)C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1cc2cc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
A solution of 2-[(4-bromo-2-formylphenyl)oxy]propanoic acid (5.08 mmol) in acetic anhydride (6 mL) was treated with sodium acetate (15.25 mmol). The resulting solution was heated to reflux and stirred overnight. The brown reaction solution was allowed to cool to room temperature, and was diluted with toluene (10 mL). The solution was then treated with 1N aq NaOH (10 mL) and was stirred at room temperature for 20 min. The solution was then further diluted with water (50 mL) and was extracted using ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting brown residue was purified by flash chromatography (hexanes), affording the title compound as a clear oil (660 mg, 62% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.73 (d, J=2.02 Hz, 1H) 7.47 (d, J=8.59 Hz, 1H) 7.35 (dd, J=8.72, 2.15 Hz, 1H) 6.58 (s, 1H) 2.45 (d, J=1.01 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:5]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:7])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: C1COCCN1
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Product: Cc1cc(C(=O)N2CCOCC2)ccc1[N+](=O)[O-]

Procedure:
Prepared from 3-methyl-4-nitrobenzoic acid and morpholine following the method used to prepare Intermediate 29. δH (DMSO-d6) 8.03 (d, J=8.3 Hz, 1H), 7.60-7.52 (m, 1H), 7.47 (dd, J8.4, 1.9 Hz, 1H), 3.50-3.70 (m, 6H), 3.28 (m, 2H), 2.53 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[C:7]=1[C:15]1[C:16]2[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=2[N:18]=[CH:19][N:20]=1)[CH2:2][CH2:3][CH3:4].[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][C@@H:36]([NH2:39])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][C@@H:36]([NH:39][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)O)c[nH]c13)OCO2
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-butoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A71) and commercially available (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:4]=[C:5](CCl)[CH:6]=[CH:7][CH:8]=1.[OH:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24]>CS(C)=O>[C:3]1([CH2:2][O:13][N:14]2[C:15](=[O:24])[C:16]3=[CH:23][CH:22]=[CH:21][CH:20]=[C:17]3[C:18]2=[O:19])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1OCc1ccccc1

Procedure:
When the bridging group n is =NOCH2 --, an appropriately substituted or unsubstituted phenylmethyl chloride, for example, 3-trifluoromethylphenylmethyl chloride, is reacted under basic conditions with N-hydroxyphthalimide in dimethyl sulfoxide, yielding the corresponding N-(phenylmethoxy)phthalimide. The so-prepared phthalimide is in turn reacted with hydrazine monohydrate in ethanol, affording an O-(phenylmethyl)hydroxylamine, for example, O-(3-trifluorophenylmethyl)hydroxylamine. The O-(phenylmethyl)hydroxylamine is then reacted with 2,4-di[(1,1 -dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone, as described above, yielding the targeted 2,4-diamino-6-phenylmethoxyimino-5,6,7,8-tetrahydroquinazoline. Example 13 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:3]=12.[Cl:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[ClH:21].[CH2:25]([O:24][C:22]([N:18]1[CH2:19][CH2:20][C:3]2[C:4](=[N:5][C:6]3[CH:7]=[C:8]([C:12]([F:14])([F:13])[F:15])[CH:9]=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH2:16][CH2:17]1)=[O:23])[CH3:26]
Reactant: CCOC(=O)Cl
Reactant: Cc1c2c(nc3cc(C(F)(F)F)ccc13)CCNCC2
Product: CCOC(=O)N1CCc2nc3cc(C(F)(F)F)ccc3c(C)c2CC1
Product: Cl
Yield: 98 %

Procedure:
1,2,4,5-Tetrahydro-11-methyl-8-trifluoromethyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 1,2,4,5-tetrahydro-11-methyl-8-trifluoromethyl-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 155.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:3]1.Cl[CH2:37][C:38]1[CH:39]=[CH:40][C:41]2[O:46][CH2:45][C:44](=[O:47])[N:43]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:42]=2[CH:53]=1>>[CH3:52][O:51][CH2:50][CH2:49][CH2:48][N:43]1[C:42]2[CH:53]=[C:38]([CH2:37][O:1][CH:2]3[CH:7]([C:8]4[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=5)=[CH:10][CH:9]=4)[CH2:6][CH2:5][N:4]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:3]3)[CH:39]=[CH:40][C:41]=2[O:46][CH2:45][C:44]1=[O:47]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cccc(C(F)(F)F)c3)cc2)C(O)C1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4cccc(C(F)(F)F)c4)cc3)cc21

Procedure:
Analogously to Method D, 0.560 g of tert-butyl 3-hydroxy-4-{4-[3-(3-trifluoromethylphenoxy)propoxy]phenyl}piperidine-1-carboxylate and 0.339 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a yellowish oil. Rf=0.30 (1:1 EtOAc-heptane); Rt=6.15.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:22])[CH2:20][NH2:21])=[CH:15][CH:14]=2)=[CH:9]1.Cl[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>>[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH2:22][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][NH2:21])=[CH:15][CH:14]=2)=[CH:9]1
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Reactant: CC(C)(C)OC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)CC(CN)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propyl amine trifluoroacetate (prepared in example 1) and t-butyl chloroformate in a manner analogous to the procedure described in Example 1.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:35])[CH2:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]([CH:23]2[CH2:27][CH2:26][CH2:25][N:24]2C(OC(C)(C)C)=O)[CH:20]=[CH:21][CH:22]=1)=[O:16].Cl>CC(=O)OCC>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:35])[CH2:13][NH:14][C:15](=[O:16])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(C2CCCN2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.4 %

Procedure:
To a solution of tert-butyl 2-(3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)phenyl)pyrrolidine-1-carboxylate (100 mg, 0.11 mmol) in EA (10 mL) was added HCl (1M in EA, 4 mL). The reaction mixture was stirred at 25° C. for 16 h. The solvent was then removed by in vacuo and the crude product was purified by prep-HPLC to give the title compound (39.4 mg, Yield 52%). 1H NMR (CD3OD, 400 MHz): δ 7.80 (brs, 1H), 7.66 (d, J=7. Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.32-7.43 (m, 1H), 7.00-7.17 (m, 4H), 4.05-4.24 (m, 2H), 3.73-3.81 (m, 2H), 3.48-3.60 (m, 2H), 3.17-3.27 (m, 1H), 2.96-3.07 (m, 1H), 2.81-2.95 (m, 4H), 2.64-2.75 (m, 2H), 2.20-2.32 (m, 1H), 1.87-2.05 (m, 2H), 1.70-1.84 (m, 1H). LCMS (m/z): 380.2 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)[CH2:3][CH2:4][OH:5].C(Cl)Cl.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C1C=CN=CC=1)C.O>[Si:21]([O:5][CH2:4][CH2:3][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)[NH2:1])([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N[C@H](CCO)c1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC[C@@H](N)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.6 %

Procedure:
A round-bottom flask was charged with (R)-3-amino-3-(3,4-dichlorophenyl)propan-1-ol (9.25 g, 42.0 mmol, CASRN 147611-61-8), DMAP (0.513 g, 4.20 mmol) and DCM (84.1 mL) then a solution of TBDMS-Cl (6.65 g, 44.1 mmol) and DCM (10 mL) was added. The reaction was stirred at RT for 2 d. The reaction mixture was poured into water and extracted with DCM. The organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (500:8 to 500:10) to afford 10.2 g (72%) of (R)-3-(tert-butyl dimethylsilyloxy)-1-(3,4-dichlorophenyl)propan-1-amine (186): m/z (APCI-pos) M+1=334.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13]C)=[O:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.C(N)(C)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:9])([CH3:10])[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: COC(=O)C1(c2ccc(Cl)cc2)CO1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCO
Solvent: CC(C)N
Product: CC(O)(C(=O)O)c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
MCPBA (35 g, 77%, 156 mmol) was added to a solution of methyl 2-(4-chlorophenyl)-acrylate (20 g, 102 mmol) in CHCl3 (200 mL). The mixture was refluxed for 24 hours. The reaction was cooled to room temperature, diluted with chloroform (200 mL) and washed with 10% Na2S2O3, 10% NaHCO3 and water. The organic phase was dried and concentrated. The residue was subject to column chromatography, eluted by hexane/ethyl acetate (9:1) to give methyl 2-(4-chlorophenyl)oxirane-2-carboxylate. Methyl 2-(4-chlorophenyl)oxirane-2-carboxylate (2 g, 9.4 mmol) and ethanol (10 mL) and isopropylamine (1 mL, 11.7 mmol) were added to a 50 mL high pressure bomb. The mixture was heated to 90° C. for 12 hours in the bomb. After cooling, the solvent was removed, and the residue was dissolved in DCM (20 mL) and TEA (2 mL). (Boc)2O (4 g, 23.0 mmol) was added to it. The mixture was stirred at room temperature for 48 hours. The solvent was removed, and the residue was dissolved in THF (20 mL). LiOH (3M, 14 mL) was added to the mixture. The mixture was stirred at room temperature for 16 hours and refluxed for 2 hours. After cooling, the mixture was quenched with 2N HCl (21 mL). The solvent was removed and the residue was subject to column chromatography, eluted by hexane/ethyl acetate (1:1) to give 3-(tert-butoxycarbonykisopropyl)amino)-2-(4-chlorophenyl)-2-hydroxypropanoic acid. LCMS (APCI+) [M−Boc+H]+ 258.1; Rf: 3.66 min.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[C:15]([CH:17]=[C:18]([O-])[CH3:19])#[N:16].[Na+].[NH2:22]/[C:23](/[CH3:33])=[CH:24]\[C:25]([O:27][CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:26].C(O)(=O)C>CC(O)C>[C:15]([C:17]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:24]([C:25]([O:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:26])=[C:23]([CH3:33])[NH:22][C:18]=1[CH3:19])#[N:16]
Reactant: CC([O-])=CC#N
Reactant: C/C(N)=C/C(=O)OC1CCCC1
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2cccc3c(=O)cc(C)oc23)C(C(=O)OC2CCCC2)=C(C)N1

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 55.8 mg (0.53 mmol) of sodium 1-cyanoprop-1-en-2-olate, 89.9 mg (0.53 mmol) of cyclopentyl 3-aminocrotonate and 31.9 mg (0.53 mmol) of acetic acid in 5 ml of 2-propanol and heated under reflux under argon for 4 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 35 mg (16% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[C:5]([CH3:18])=[C:6]([CH:11]=[CH:12][C:13]=1[S:14]([CH3:17])(=[O:16])=[O:15])[C:7]([O:9][CH3:10])=[O:8].C#C.[CH2:21](N(CC)CC)[CH3:22].O>[Cl].C(Cl)(Cl)Cl.CCOCC>[O:1]1[CH:22]=[CH:21][C:3]([C:4]2[C:5]([CH3:18])=[C:6]([CH:11]=[CH:12][C:13]=2[S:14]([CH3:17])(=[O:15])=[O:16])[C:7]([O:9][CH3:10])=[O:8])=[N:2]1
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1C
Agent: C#C
Agent: [Cl]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(S(C)(=O)=O)c(-c2ccon2)c1C
Reaction time: 0.5 h
Yield: 3766.5 %

Procedure:
2.00 g of crude methyl 3-hydroxyiminomethyl-4-methylsulfonyl-2-methylbenzoate was dissolved in 35 ml of chloroform Chlorine gas was blown into the resulting solution, with stirring, for 30 minutes at -13~0° C. The solution was further stirred for 30 minutes at 0° C. Nitrogen gas was blown into the reaction solution to remove excessive chlorine. Chloroform was concentrated under reduced pressure to give a solid product. The obtained solid was dissolved in 50 ml of ether. Acetylene gas was blown in, with stirring, for 5 minutes at -11° C. Then 1.64 g of triethylamine dissolved in 5 ml of ether was added dropwise at -15~13.5° C. Further acetylene gas was blown in for 20 minutes at -15~13.5° C. The resulting reaction mixture was transferred to a 50 ml, stainless-steel autoclave, which was cooled beforehand, and stirred for 3.5 hours at 60~70° C. The reaction solution was cooled down, poured into water, and extracted with ethyl acetate. The organic layer was washed with water, then with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure. The obtained residue was purified by column chromatography on silica gel with benzene/ethyl acetate=9/1 to give 0. 82 g of the title compound as white crystals. m.p. 87~89° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([Mg]Br)=[N:4][CH:5]=[CH:6][CH:7]=1.C1C[O:13][CH2:12]C1.CN(C=O)C>>[CH3:1][C:2]1[C:3]([CH:12]=[O:13])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1[Mg]Br
Reactant: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cccnc1C=O
Yield: 33 %

Procedure:
3-Methyl-pyridine-2-carbaldehyde (200 mg, 33.0%) was obtained from 0.25 M 3-methyl-2-pyridinylmagnesium bromide of THF solution (20 mL, 5 mmol) with DMF (0.773 mL, 10 mmol) at room temperature under argon.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1>CN(C)C=O.C(OCC)(=O)C.C(O)CCC>[O:16]1[CH2:17][CH2:18][N:13]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)[N:11]=2)[CH2:14][CH2:15]1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: C1COCCN1
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Nc2nc(N3CCOCC3)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.6 %

Procedure:
A mixture of 2,4-dichloroquinazoline (200 mg, 1.00 mmol) and morpholine (131 mg, 1.50 mmol) in dimethylformamide (1 mL) was stirred at rt for 5 min. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and 5% aqueous lithium chloride and dried over sodium sulfate. The solvent was removed on a rotary evaporator to give a white solid. A mixture of this material and 4-aminobenzoic acid (119 mg, 0.868 mmol) in n-butanol (2.5 mL) was heated to 135° C. until the butanol was boiled off. The solid residue was collected and washed with water to give 4-(4-morpholinoquinazoline-2-ylamino)benzoic acid (303 mg, 100%) an off-white solid that was used without further purification. This material was combined with 2,6-dimethylaniline (210 mg, 1.73 mmol), Hunig's base (300 μL, 1.72 mmol) and HATU (329 mg, 0.865 mmol) in DMF (5 mL), and the mixture was heated to 65° C. overnight. The reaction was cooled to rt, diluted with ethyl acetate and extracted with water. The organic layer was washed with saturated sodium bicarbonate and concentrated on a rotary evaporator. The resulting residue was purified by preparative reverse phase HPLC to give N-(2,6-dimethylphenyl)-4-[(4-morpholin-4-ylquinazolin-2-yl)amino]benzamide (120 mg, 26%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.50 (bs, 1H), 9.70 (bs, 1H), 8.05-8.01 (m, 3H), 7.83-7.79 (m, 3H), 7.63 (d, 1H), 7.40 (t, 1H), 7.13 (s, 3H), 3.97 (bs, 4H), 3.84-3.82 (m, 4H), 2.19 (s, 6H). MS (EI) for C27H27N5O2: 454.0 (MH+).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]([C:25]2[N:26]=[C:27]([N:30]3[CH2:33][CH:32]([OH:34])[CH2:31]3)[O:28][CH:29]=2)=[O:24])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]([C:25]2[N:26]=[C:27]([N:30]3[CH2:33][CH:32]([O:34][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:31]3)[O:28][CH:29]=2)=[O:24])[CH2:22]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](OC1CN(C(=O)c2coc(N3CC(O)C3)n2)C1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OC1CN(C(=O)c2coc(N3CC(OS(C)(=O)=O)C3)n2)C1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 79.5 %

Procedure:
To a solution of 1-[4-(3-t-butyldiphenylsilyloxyazetidine-l-carbonyl)-1,3-oxazol-2-yl]-3-hydroxyazetidine (1.68 g, 3.53 mmol) (obtained as described in Reference Example 74(1)) in methylene chloride (84 ml) were added methanesulfonyl chloride (820 μl, 10.6 mmol) and triethylamine (1.49 ml, 10.6 mmol) in an ice bath and the mixture was stirred for 10 minutes and then at room temperature for 0.5 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:ethyl acetate (1:1) as the eluant to afford 1-[4-(3-t-butyldiphenylsilyloxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]-3-methanesulfonyloxyazetidine (1.56 g, yield 80%) as a pale yellow solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N+:34]([O-])=O)[CH2:24][CH:23]2[OH:37])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].[H][H]>CO.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH2:34])[CH2:24][CH:23]2[OH:37])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: [H][H]
Reactant: O=C(NC1(C(=O)NC2CCN(c3ccccc3[N+](=O)[O-])CC2O)CCCCC1)c1cc2ccccc2o1
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Yield: 98.7 %

Procedure:
4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-nitrophenyl)piperidin-3-ol (7.0 g) obtained in Step 1 was dissolved in 30 ml of methanol. The solution was stirred with 10%-palladium catalyst overnight under 30 psi hydrogen atmosphere, and then filtered and concentrated to give 6.5 g of titled compound.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:22][CH:21]=2)[CH:4]=[C:5]2[N:10]3[C@H:11]4[CH2:16][CH2:15][CH2:14][C@H:12]4[N:13]=[C:9]3[N:8]([CH3:17])[C:7](=[O:18])[C:6]=12.[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:17][N:8]1[C:7](=[O:18])[C:6]2=[C:2]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:3]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:24][CH:25]=3)[CH:4]=[C:5]2[N:10]2[C@H:11]3[CH2:16][CH2:15][CH2:14][C@H:12]3[N:13]=[C:9]12
Reactant: Nc1ccccc1
Reactant: CN1C(=O)c2c(cn(Cc3ccc(-c4ccccn4)cc3)c2Cl)N2C1=N[C@@H]1CCC[C@@H]12
Product: CN1C(=O)c2c(cn(Cc3ccc(-c4ccccn4)cc3)c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 150 °C

Procedure:
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-2-((4-Pyridin-2yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one (5.6 mg, 0.013 mmol) is placed in a Biotage microwave tube, and then aniline (0.2 mL) is added. The mixture is heated at 150° C. for an hour. The mixture is purified by a semi-preparative HPLC to give product. MS (ESI) m/z 489.3 [M+H]+.
Reaction SMILES: C(OC([N:8]([CH3:18])[C@@H:9]([CH2:13][C:14]([CH3:17])([CH3:16])C)[C:10]([OH:12])=O)=O)(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[N:25][CH:26]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[CH3:18][NH:8][C@H:9]([C:10]([NH:35][C@@H:32]1[C@@H:30]2[C@@H:29]([CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:37])([F:36])[F:19])=[CH:26][N:25]=3)[CH2:31]2)[CH2:34][CH2:33]1)=[O:12])[CH2:13][CH:14]([CH3:16])[CH3:17]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CN[C@@H](CC(C)C)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-leucine for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-(5-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 262 Step B for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.63 (s, 1H), 8.37 (d, J=7.5, 1H), 7.68 (dd, J=8.9, 2.5, 1H), 6.40 (d, J=8.9, 1H), 4.49-4.38 (m, 1H), 3.83 (d, J=10.7, 1H), 3.68 (dd, J=11.0, 7.3, 1H), 3.63-3.52 (m, 1H), 3.33 (d, J=8.2, 1H), 3.27 (dd, J=8.3, 5.9, 1H), 2.77 (h, J=8.8, 2H), 2.45 (s, 3H), 2.17 (dt, J=12.4, 7.1, 1H), 2.14-1.98 (m, 1H), 2.02-1.86 (m, 2H), 1.79-1.67 (m, 2H), 1.66-1.55 (m, 1H), 1.48-1.36 (m, 1H), 0.94 (d, J=6.6, 3H), 0.88 (d, J=6.6, 3H); MS (ESI+) m/z 399 (M+H)+.
Reaction SMILES: C[C:2](C)([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12](O)=O)[CH:7]=1)[C:3]([OH:5])=[O:4].[OH-:16].[Li+].[O:18]1[CH2:22]CCC1>>[C:22]([CH2:12][C:8]1[CH:7]=[C:6]([CH2:2][C:3]([OH:5])=[O:4])[CH:11]=[CH:10][CH:9]=1)([OH:18])=[O:16]
Reactant: [OH-]
Reactant: C1CCOC1
Reactant: CC(C)(C(=O)O)c1cccc(C(=O)O)c1
Agent: [Li+]
Product: O=C(O)Cc1cccc(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dimethyl-3-carboxyphenyl acetic acid (870 mg) in 10 ml tetrahydrofuran was treated with lithium hydroxide (8.5 ml, 0.5M solution) at 0° C. After stirring at room temperature for 4 h, all solvent was evaporated, and the residue partitioned between saturated sodium hydrogen carbonate and ethyl acetate. The aqueous layer was separated, acidified (1N HCl) and extracted with dichloromethane (2×25 ml). The combined organic layers were dried (MgSO4) and solvent removed to leave 3-(carboxymethyl)phenyl acetic acid, mp 96°-98° C.