Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][NH:27][O:28][CH3:29]>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:27]([O:28][CH3:29])[CH3:26])(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: CNOC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Product: CON(C)S(=O)(=O)c1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (82 mg, 0.22 mmol), N,O-dimethylhydroxylamine hydrochloride (43 mg, 0.44 mmol) and DMAP (54 mg, 0.44 mmol) in MeCN (4 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 22 mg (25% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.41-1.55 (m, 4 H), 1.57 (s, 9 H), 2.26-2.40 (m, 1 H), 2.72 (s, 3 H), 3.30-3.37 (m, 2 H), 3.76 (s, 3 H), 3.86-3.95 (m, 2 H), 4.38 (d, J=7.42 Hz, 2 H), 7.73 (dd, J=8.6, 1.6 Hz, 1 H), 7.78 (d, J=8.2 Hz, 1 H), 8.10 (d, J=0.98 Hz, 1 H); MS (ESI) (M+H)+=396.0; Anal. Calcd for C19H29N3O4S+0.30 EtOAc (421.96): C, 57.50; H, 7.50; N, 9.96. Found: C, 57.88; H, 7.48; N, 9.95
Reaction SMILES: B([O:3][O-:4])=O.O.[Na+].[Na].[C:8]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[C:8]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:3][OH:4])=[O:23])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)CCCCCNC(=O)c1ccccc1
Reactant: O=BO[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: O=C(CCCCCNC(=O)c1ccccc1)OO

Procedure:
Perhydrolysis of the above phenolsulfonate ester to yield 6-benzoylaminoperoxycaproic acid was accomplished according to the following procedure. To 4 L of 95° F. city water was added 5.00 g (1250 ppm) of an alkaline detergent granule, 0.36 g (90 ppm) of sodium perborate monohydrate and 0.46 g (115 ppm) of the sodium salt of the phenolsulfonate ester of 6-benzoylaminocaproic acid (0.67 g of the 69% mixture described above). Perhydrolysis of the ester to form 6-benzoylamino-peroxycaproic acid was followed by analysis of the solution for available oxygen (AvO) using a conventional iodometric titration. Complete conversion of the ester to the peroxyacid would result in the formation of 4.5 ppm AvO. The results obtained for AvO versus time are tabulated below.
Reaction SMILES: N([CH:4](OC)[O:5]C)(C)C.[CH3:9][C:10]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]=1[O:24][CH3:25]>CC(N(C)C)=O.C(Cl)(Cl)Cl>[CH3:25][O:24][C:11]1[CH:12]=[C:13]([CH:19]=[C:20]([N+:21]([O-:23])=[O:22])[C:10]=1[CH2:9][CH:4]=[O:5])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1cc(OC)c(C)c([N+](=O)[O-])c1
Solvent: CC(=O)N(C)C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(OC)c(CC=O)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
13.3 ml of Me2NCH(OMe)2 was added to a solution of 4.78 g of ethyl 4-methyl-3-(methoxy)-5-nitrobenzoate in 10 ml of dimethylacetamide and the mixture was heated at 80° C. in a sealed tube for 40 minutes. The mixture was diluted with CHCl3, washed with water, dried over Na2SO4, and concentrated. The residue was purified on SiO2 column chromatography to give 4.02 g of the intended compound as a pale tan solid.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].[N+:16]([C:19]1[CH:20]=[N:21][NH:22][CH:23]=1)([O-:18])=[O:17]>CC(C)=O.O>[N+:16]([C:19]1[CH:20]=[N:21][N:22]([CH2:3][CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:23]=1)([O-:18])=[O:17]
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cnn(CCN2CCCC2)c1

Procedure:
N-(2-chloroethyl)pyrrolidine hydrochloride (752 mg, 4.42 mmol), potassium carbonate (0.534 ml, 8.84 mmol) and 4-nitro-1H-pyrazole (500 mg, 4.42 mmol) were combined in acetone (20 ml) and the reaction was stirred at reflux for 16 hours. The reaction mixture was diluted with 75 mL water and extracted with ethyl acetate (3×20 mL). The combined organics were dried (Na2SO4), filtered, and concentrated to give the title compound. MS (ESI(+)) m/e 210.9 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1)[CH3:2].Cl[CH2:11][CH:12]=O>CCO>[CH2:1]([C:3]1[CH:8]=[CH:7][N:6]2[CH:11]=[CH:12][N:9]=[C:5]2[CH:4]=1)[CH3:2]
Reactant: O=CCCl
Reactant: CCc1ccnc(N)c1
Solvent: CCO
Product: CCc1ccn2ccnc2c1
Yield: 98.6 %

Procedure:
A mixture of 4-ethylpyridin-2-amine (3.21 g, 8.19 mmol), and chloroacetaldehyde (50% aqueous solution, 2.6 ml, 10.5 mmol) in EtOH (10 ml) was refluxed vigorously for 12 hours. The reaction mixture was concentrated, and the residue was suspended in saturated aqueous sodium bicarbonate solution. The aqueous mixture was extracted with CH2Cl2 and EtOAc, and the combined organic extracts were dried over Na2SO4, filtered and concentrated to afford the desired product (1.18 g, 98% yield) as a viscous oil. MS APCI (+) m/z 147.2 (M+1) detected.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[S:22][CH:21]=[CH:20][C:18]=2[N:19]=1>C1COCC1.O>[Cl:13][C:14]1[N:15]=[C:16]([O:12][C:5]2[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=2[CH3:3])[C:17]2[S:22][CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: Clc1nc(Cl)c2sccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c(Oc2nc(Cl)nc3ccsc23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
A stirred suspension of NaH (7.8 mg, 0.19 mmol) in dry THF (1 mL) was added 2,4,6-trimethyl phenol (26.4 mg, 0.19 mmol) and stirred at room temperature for 30 min under Argon. The reaction mixture was added to a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (39.6 mg, 0.19 mmol) in dry THF (1 mL) at 0° C. and allow it to slowly warmed up to room temperature. After stirring the reaction for 4 h, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (9:1) to give the product as a white solid (32.4 mg, 56%):
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14](=[O:15])[CH2:13][C:12](C)(C)[CH2:11][C:10]1=[O:18].[C:19](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:19][O:18][C:10]1[CH2:11][CH2:12][CH2:13][C:14](=[O:15])[C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(C2C(=O)CC(C)(C)CC2=O)c(C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC1=C(c2ccc(C)cc2C)C(=O)CCC1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A solution of 10.00 g (0.0409 mol) of 2-(2',4'-dimethylphenyl)-5,5-dimethyl-1,3-cyclohexanedione, 21.42 g (0.155 mol) of anhydrous potassium carbonate, 17.59 g (0.124 mol) iodomethane, and 500 ml of anhydrous acetone was refluxed overnight. The reaction mixture was then cooled to room temperature, filtered, and the acetone removed. The residual solid was taken up in 250 ml of CH2Cl2, washed with water, 0.25 N NaOH, 1 N HCl, and water again. The solution was dried (MgSO4) and the solvent removed. The resulting solid was recrystallized from isopropyl ether to give 7.60 g (72% yield) of a white crystalline solid, m.p. 122°-23° C. The compound prepared by the above synthesis has the following structure: ##STR27##
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][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.[Br:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][C:40]=1[O:47][CH2:48][CH2:49][CH2:50][O:51][CH3:52]>>[Br:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][O:1][CH:2]2[CH:7]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:10][CH:9]=3)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:29])[CH2:3]2)=[CH:41][C:40]=1[O:47][CH2:48][CH2:49][CH2:50][O:51][CH3:52]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Reactant: COCCCOc1cc(CBr)ccc1Br
Product: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1Br

Procedure:
Analogously to Method D, 2.0 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]-phenyl}piperidine-1-carboxylate (Example 10f and 1.77 g of 1-bromo-4-bromomethyl-2-(3-methoxypropoxy)benzene are used to obtain the title compound as a slightly yellowish oil. Rf=0.34 (1:1 EtOAc-heptane); Rt=6.23.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([Cl:17])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[C:11]([Cl:17])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CO)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a stirred solution of 4-{[tert-butyl(dimethyl)silyl]oxy}-2-chlorobenzaldehyde (WO 2003051797, 1.58 g, 5.83 mmol) in methanol (5 mL) was added sodium borohydride (264 mg, 7.00 mmol) at 0° C. The mixture was stirred at room temperature for 3 h, and quenched by addition of aqueous ammonium chloride. The mixture was extracted with ethyl acetate (200 mL), and the organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (100 g) eluting with hexane/ethyl acetate (20/1 to 10/1) to afford 1.51 g (95%) of the title compound as a colorless oil:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH2:7][CH2:8][S:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:14]([C:25]([NH:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:26])[CH2:13]1)(=[O:11])=[O:10]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:29]([O:28][NH:27][C:25]([C@H:14]1[CH2:13][N:12]([S:9]([CH2:8][CH2:7][NH:6][C:2]([O:4][CH3:5])=[O:3])(=[O:11])=[O:10])[CH2:17][CH2:16][N:15]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:26])([CH3:31])([CH3:32])[CH3:30]
Reactant: CC(C)(C)ONC(=O)[C@H]1CN(S(=O)(=O)CCN)CCN1C(=O)OC(C)(C)C
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)NCCS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)NOC(C)(C)C)C1
Temperature: 0 °C
Yield: 102.9 %

Procedure:
Methyl chloroformate (132 mg) in CHCl3 (3 ml) was added dropwise to (2R)-4-(2-aminoethanesulfonyl)-N-tert-butoxy-1-tert-butoxycarbonyl-2-piperazinecarboxamide (400 mg) in pyridine (2.5 ml) with cooling on an ice bath. After stirring on the ice bath for 3 hours, the reaction mixture was concentrated in vacuo. The residue was partitioned between AcOEt and 3.6% HCl. The organic layer was washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4, and concentrated in vacuo to give 470 mg of (2R)-N-tert-butoxy-1-tert-butoxycarbonyl-4-[2-(methoxycarbonylamino)-ethanesulfonyl]-2-piperazinecarboxamide.
Reaction SMILES: [CH3:1][C:2]([OH:9])([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]#[CH:4].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[CH3:1][C:2]([OH:9])([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]#[C:4][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: C#CC(C)(O)CC(C)C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(C)(O)CC(C)C)c21

Procedure:
Using Method C above, 3,5-dimethyl-1-hexyn-3-ol (61 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 2 supra) (146 mg, 0.4 mmol) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield rac-(Z)-1,3-dihydro-4-(3,5-dimethyl-3-hydroxy-1-hexynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 87 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([SH:18])[C:15]([CH3:19])=[N:14]1.[H-].[Na+].Br[C:23]1[N:24]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:25]([C:30]#[N:31])=[C:26]([C:28]#[N:29])[N:27]=1.O>O1CCCC1>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[N:17]=[C:16]([S:18][C:23]2[N:24]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:25]([C:30]#[N:31])=[C:26]([C:28]#[N:29])[N:27]=2)[C:15]([CH3:19])=[N:14]1
Reactant: C[Si](C)(C)CCOCn1c(Br)nc(C#N)c1C#N
Reactant: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1S
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1Sc1nc(C#N)c(C#N)n1COCC[Si](C)(C)C

Procedure:
Crude 2-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-2H-1,2,3-triazole-4-thiol, prepared as in EP 350 237, (10 g) in tetrahydrofuran (50 ml) was added to a stirred suspension of sodium hydride (80%, dispersion in oil, 1.0 g) in tetrahydrofuran (50 ml) at 0°. Then a solution of 2-bromo-4,5-dicyano-1-(2-trimethylsilylethoxymethyl)-1H-imidazole (10 g) in tetrahydrofuran (100 ml) was added, dropwise, with stirring at 0°-5°. The mixture was stirred at room temperature for 20 hours and then was poured into water and extracted with ethyl acetate. Conventional work-up and purification by column chromatography gave 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-[4,5-dicyano-1-(2-trimethylsilylethoxymethyl)-1H-imidazol-2-ylthio]-5-methyl-2H-1,2,3-triazole, as a pale yellow oil, nD 24°=1.526 (compound 9a).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4Cl)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (50 mg, 55%), MS (ISP) m/z=363.5 [(M+H)+], mp 214° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 2,4-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:18](=[O:19])[CH2:17][O:16][C:15]2[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:14]1=2.C(O)(=O)C>C1COCC1.[Fe]>[NH2:24][C:21]1[CH:22]=[CH:23][C:14]2[N:13]([C:4]3[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:10])[F:11])=[CH:8][C:3]=3[O:2][CH3:1])[C:18](=[O:19])[CH2:17][O:16][C:15]=2[CH:20]=1
Reactant: COc1cc(C(F)(F)F)ccc1N1C(=O)COc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(C(F)(F)F)ccc1N1C(=O)COc2cc(N)ccc21
Temperature: 70 °C
Yield: 74.4 %

Procedure:
4-(2-Methoxy-4-(trifluoromethyl)phenyl)-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (2.1 g, 5.70 mmol) was dissolved in THF (22.81 ml) and acetic acid (17.95 ml, 314 mmol) in a 250 mL rbf, and iron (3.18 g, 57.0 mmol) was added. The flask was sealed and heated to 70° C. for 1 hr until the reaction was complete by LCMS. The reaction was cooled to RT, diluted with THF (50 mL), and filtered through Celite, washing well with 200 mL of THF. The filtrate was concentrated via rotary evaporation, and partitioned between sat. aq. sodium bicarbonate solution (50 mL) and EtOAc (50 mL). The layers were separated, and the aqueous was then extracted two times with EtOAc (2×50 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to a brown oil. The oil was loaded onto a silica column and purified by MPLC with a gradient Heptanes:EtOAc column (0-100%). Fractions were combined and concentrated to give 7-amino-4-(2-methoxy-4-(trifluoromethyl)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (1.434 g, 4.24 mmol, 74.3% yield) as an off-white foamy solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[N:21]([CH3:46])[C:22]4[C:27]([N:28]=3)=[C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:25]=[C:24]([N:35]3[C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[N:37]=[C:36]3[CH2:44][CH3:45])[N:23]=4)[C:15]([CH3:48])([CH3:47])[CH2:14]2)=[O:12])[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1([C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[N:21]([CH3:46])[C:22]4[C:27]([N:28]=3)=[C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:25]=[C:24]([N:35]3[C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[N:37]=[C:36]3[CH2:44][CH3:45])[N:23]=4)[C:15]([CH3:47])([CH3:48])[CH2:14]2)=[O:12])[CH2:9][CH2:10]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)C4(NC(=O)OC(C)(C)C)CC4)CC3(C)C)n(C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)C4(N)CC4)CC3(C)C)n(C)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of (1-{4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-3,3-dimethylpiperazine-1-carbonyl}cyclopropyl)carbamic acid tert-butyl ester in DCM (3 mL) was added TFA (2 mL) and the resulting mixture stirred at r.t. for 30 min then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-10%) affording 780 as a white foam (99 mg, 60%). LCMS (method I): RT 2.67 min, [M+H]+ 573.3. 1H NMR (CDCl3, 400 MHz): δ 8.02-8.01 (1 H, m), 7.76-7.75 (1 H, m), 7.32-7.22 (2 H, m), 4.34 (4 H, s), 3.93 (3 H, s), 3.88-3.86 (6 H, m), 3.65 (2 H, s), 3.48 (2 H, s), 3.36 (2 H, q, J=7.48 Hz), 2.57 (2 H, t, J=5.16 Hz), 1.85-1.75 (2 H, brd s), 1.45 (3 H, t, J=7.46 Hz), 1.23 (6 H, s), 1.05-0.99 (2 H, m), 0.81-0.80 (2 H, m)
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[N:5][N:4]2[CH2:8][CH2:9][CH2:10][C:3]=12.[CH3:11][O:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([C:2]2[C:6]([CH3:7])=[N:5][N:4]3[CH2:8][CH2:9][CH2:10][C:3]=23)[CH:15]=1
Reactant: COC(=O)c1ccc(C#N)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1nn2c(c1Br)CCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C#N)c(-c2c(C)nn3c2CCC3)c1
Temperature: 95 °C
Yield: 49.8 %

Procedure:
In a pressure sealed flask a suspension of 3-bromo-2-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (1.01 g, 5.0 mmol), 4-cyano-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (1.8 g, 6.25 mmol), and K3PO4 (2.65 g, 12.5 mmol) in dioxane (50 mL) was degassed by bubbling N2 for 30 m at room temperature. After the addition of tetrakis(triphenylphosphine)palladium (0.58 g, 0.5 mmol) the reaction flask was sealed and the contents heated to 95° C. for 5 h. After cooling the reaction mixture was diluted several fold with EtOAc, and washed with dilute aqueous NaHCO3 followed by brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified over normal phase silica starting with 100% DCM for 5 m and then increasing to 10% MeOH in DCM over 25 m to give the desired product as a yellow solid (0.70 g, 2.49 mmol). MS m/z 282.5 (M+H)+.
Reaction SMILES: [C:1](=[O:15])([O:12][CH:13]=[CH2:14])[O:2][C:3]1[CH:8]=CC([N+]([O-])=O)=CC=1.OCC[O:19][C:20](=[O:24])[C:21]([CH3:23])=[CH2:22].CS(C)=O.[OH-].[Na+]>O>[C:1](=[O:15])([O:12][CH:13]=[CH2:14])[O:2][CH2:3][CH2:8][O:24][C:20](=[O:19])[C:21]([CH3:23])=[CH2:22]
Reactant: C=C(C)C(=O)OCCO
Reactant: C=COC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=COC(=O)OCCOC(=O)C(=C)C

Procedure:
A solution of p-nitrophenyl vinyl carbonate, hydroxyethylmethacrylate, DMSO and sodium hydroxide is stirred at room temperature for a minimum of 12 hours. Reaction completion is monitored by G.C. The solution is drowned into water and the mixture extracted with ethyl acetate. The product solution is washed with water, dried with magnesium sulfate, then stripped to an oil under vacuum. The crude product is then purified.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH:7]2[C:5]([C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)([CH2:6]2)[CH2:4]1)=[O:2].C(=O)([O-])[O-].[CH2:20](I)[CH3:21]>C(O)C>[CH:1]([N:3]1[CH2:8][CH:7]2[C:5]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:20][CH3:21])=[CH:11][CH:10]=3)([CH2:6]2)[CH2:4]1)=[O:2]
Reactant: O=CN1CC2CC2(c2ccc(O)cc2)C1
Reactant: CCI
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOc1ccc(C23CC2CN(C=O)C3)cc1
Yield: 27.2 %

Procedure:
To a stirred mixture of 1.0 g of 3-formyl-1-(p-hydroxyphenyl)-3-azabicyclo[3.1.0]hexane and 0.7 g of potassim carbonate in 25 ml of absolute ethanol is added a solution of 3.2 g of ethyl iodide in 10 ml of absolute ethanol. The mixture is refluxed for 2 hours and then is filtered and evaporated. The residual mixture of crystals and liquid is combined with water and this is extracted with chloroform and the extract is dried over magnesium sulfate and evaporated to give 1.0 g of a colorless, viscous liquid, which crystallizes on standing. Recrystallization from hexane gives 0.31 g of 3-formyl-1 -(p-ethoxyphenyl)-3-azabicyclo[3.1.0]hexane as colorless crystals, m.p. 48°-51° C.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][CH:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[CH2:11][CH2:10][N:9]2[CH3:18])=[CH:5][CH:4]=1.[OH-].[K+]>C(O)COCCO>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[CH2:11][CH2:10][N:9]2[CH3:18])=[CH:19][CH:20]=1
Reactant: COc1ccc(CC2C3=C(CCCC3)CCN2C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: CN1CCC2=C(CCCC2)C1Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 71.7 %

Procedure:
A mixture of 253.9 g (0.935 mol) of (-)-1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline and 1.2 l. of diethylene glycol was warmed to 80°-100° and 260 g of potassium hydroxide (85% A.C.S. grade) was added. The reaction mixture was heated to 210° and stirred at this temperature under a constant stream of nitrogen for 36 hours. During this period, time to time the stop cock was removed to allow escape of water vapor. If this is not done, the desired inner temperature of 210° cannot be attained. The dark brown solution was cooled to room temperature and diluted with water (600 ml) and extracted with ether (400 ml). The aqueous solution was made acidic with concentrated aqueous hydrochloric acid and then basified with concentrated aqueous ammonium hydroxide. The aqueous suspension was extracted with ethyl acetate (4 × 250 ml). The ethyl acetate solution was washed with water and dried. Removal of the solvent gave 172.5 g (72%) of crude (-)-1-(p-hydroxybenzyl)- 2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline. For analysis, a sample of this compound was recystallized from tetrahydrofuran-heptane, mp 119°-120°, [α]25D -36.01° (c 0.98, MeOH).