Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].O.[CH3:4][C:5]([O:14][OH:15])([CH2:7][CH2:8][C:9]([CH3:13])([O:11]O)[CH3:10])[CH3:6].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:16]([O:15][O:14][C:5]([CH3:6])([CH3:4])[CH2:7][CH2:8][C:9]([OH:11])([CH3:13])[CH3:10])(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(CCC(C)(C)OO)OO
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(O)CCC(C)(C)OOC(=O)C(C)(C)C
Reaction time: 2 h

Procedure:
A jacketed reactor equipped with a mechanical stirrer, a thermometer and a dropping funnel was charged with 18.7 g (0.150 mole) of 45% KOH, 15.0 g of water, 27.6 g (0.120 mole) of 77.6% (wetted solid) 2,5-dimethyl-2,5-dihydroperoxyhexane and 100 ml of methylene chloride. To the resulting two liquid phase mixture at 28° to 30° C. was added 12.8 g (0.100 mole) of 94.3% pivaloyl chloride over a period of about 30 minutes. The resulting mixture was then stirred for 2.0 hours at 28° to 30° C. after which the mixture was cooled to 15° to 20° C. and was allowed to separate into phases. The upper aqueous layer was removed and was discarded. The resulting product solution was then washed with 50 ml of 20% KOH solution at 0° C. and then with 50 ml of 7.7% sodium hydrogen carbonate solution at 15° to 20° C. The methylene chloride solution was then cooled to 0° to 10° C. and was reacted with 187 g of buffered sodium sulfite solution (consisting of 7.6 g of acetic acid, 8.4 g of sodium acetate, 19 g of sodium sulfite and 152 g of water) in order to covert the 4-hydroperoxy-1,1,4,4-tetramethylbutyl peroxypivalate that was formed in the peroxidation reaction to 4-hydroxy-1,1,4,4-tetramethylbutyl peroxypivalate, the desired product. A thick emulsion resulted which required three days of storage in the refrigerator to separate into two liquid phases. The upper aqueous layer was removed and an equal volume of diethyl ether was added in order to facilitate further processing. The solution was dried over anhydrous MgSO4 and after separation of the spent desiccant by filtration the solvents were remove in vacuo at 0° to 10° C. Some solids were removed by filtration and the resulting liquid weighed 20.4 g. The assay of the product was 90.3% according to peroxyester active oxygen content. The corrected yield was 74.9%. An infrared spectrum of the product showed a broad OH band centered at 3300 to 3400 cm-1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.CC1(C)C(C)(C)OB([C:35]2[NH:39][N:38]=[CH:37][CH:36]=2)O1>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:35]4[NH:39][N:38]=[CH:37][CH:36]=4)=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CC1(C)OB(c2ccn[nH]2)OC1(C)C
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3ccn[nH]3)cc1OCC2)c1ccccc1Cl

Procedure:
Following the procedure in Example 93, 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide was coupled with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give 310. MS (ESI) 436.1
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[NH2:20][C:21]1[N:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[C:33]([N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:16](=[O:18])[CH2:15][C:12]3[CH:11]=[CH:10][C:9]([C:7]4[CH:6]=[CH:5][N:4]=[C:3]([CH:2]([F:1])[F:19])[CH:8]=4)=[CH:14][CH:13]=3)=[N:26][CH:25]=2)[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: O=C(O)Cc1ccc(-c2ccnc(C(F)F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(C(F)F)c4)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-(2-(difluoromethyl)pyridin-4-yl)phenyl)acetic acid 203-5 (30 mg, 0.11 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (28 mg, 0.13 mmol), N,N-diisopropylethylamine (99 μL, 0.57 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (65 mg, 0.17 mmol) in DMF (2 mL) was stirred at room temperature for 3 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2 N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(2-(difluoromethyl)pyridin-4-yl)phenyl)acetamide 201. MS m/z 418.2 (M+1); 1H NMR 400 MHz (MeOD) δ 8.61(d, 1H), 8.25(d, 1H), 7.91(d, 1H), 7.80-7.72(m, 4H), 7.49(d, 2H), 6.79(d, 1H), 6.73(t, 1H), 3.70(s, 2H), 3.66-3.58(m, 4H), 3.52-3.47(m, 2H), 3.45-3.40(m, 2H), 2.09(s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([CH3:15])([CH3:14])[CH2:9][CH2:8][C:7]2([CH3:17])[CH3:16])(=O)[CH3:2].[H-].[Na+].C(OP([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(OCC)=O)C>C1COCC1>[CH3:14][C:10]1([CH3:15])[CH2:9][CH2:8][C:7]([CH3:17])([CH3:16])[C:6]2[CH:5]=[C:4](/[C:1](/[CH3:2])=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:13]=[CH:12][C:11]1=2
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.3 %

Procedure:
6-Acetyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene (5.07 g) was added to a cooled (0° C.) mixture of NaH (60% oil dispersion, 1.10 g) and ethyl diethylphosphonoacetate (6.49 g) in THF (50 ml). The mixture was stirred at room temperature for 14 hours. The reaction was quenched by the addition of water and the mixture was diluted with ethyl acetate. The organic layer was washed with water and brine, dried and concentrated to give the titled compound (6.50 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:21])[C:11](N)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.N([O-])=[O:23].[Na+].C([O-])(O)=O.[Na+]>Cl.O>[NH2:21][C:10]1[C:11]([OH:23])=[N:12][C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:9]=1
Reactant: Nc1nc(-c2ccncc2)c(-c2cccc(F)c2)nc1N
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nc(-c2cccc(F)c2)c(-c2ccncc2)nc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
To a cooled solution (0° C.) of 5-(3-fluorophenyl)-6-pyridin-4-ylpyrazine-2,3-diamine (Example 72, 100 mg, 0.36 mmol) in HCl 1N (1 mL) was added dropwise a solution of sodium nitrite (35 mg, 0.50 mmol) in water (0.6 mL). The reaction was stirred for 1 h at room temperature and after this period was driven to pH7 by addition of a NaHCO3 4% solution. The suspension was filtered to leave a solid which was purified by silica gel chromatography eluting with CH2Cl2/MeOH/NH3 (50:8:1) to afford the title compound (37 mg, 36%).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]([F:26])([F:25])[C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH:15]=[O:16])[CH:14]=1)[N:11]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:10]=[CH:9]2>O1CCCC1>[F:26][C:5]([F:4])([F:25])[C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH:15]([OH:16])[CH3:1])[CH:14]=1)[N:11]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])[CH:10]=[CH:9]2
Reactant: C[Si](C)(C)CCOCn1ccc2cc(C(F)(F)F)cc(C=O)c21
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cc(C(F)(F)F)cc2ccn(COCC[Si](C)(C)C)c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methylmagnesium bromide (0.582 ml, 1.747 mmol) was added dropwise to a 0° C. solution of 5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbaldehyde (500 mg, 1.456 mmol) in tetrahydrofuran (10 ml). The reaction was stirred 30 min at 0° C. An additional portion of methylmagnesium bromide (0.58 ml, 1.75 mmol) was added. The reaction was stirred another 30 min, quenched by addition of water (10 mL), and extracted with ethyl acetate (3×10 ml). The combined organic layers were dried with magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with a gradient of 5% to 40% ethyl acetate/hexanes to give 427 mg (82%) as a yellow liquid. 1H-NMR (CDCl3, 400 MHz) δ 7.84 (d, J=1.1 Hz, 1H), 7.62 (d, J=1.0 Hz, 1H), 7.18 (d, J=3.2 Hz, 1H), 6.59 (d, J=3.3 Hz, 1H), 5.74 (d, J=11.5 Hz, 1H), 5.68 (m, 1H), 5.59 (d, J=11.4 Hz, 1H), 3.44 (dd, J=8.4, 7.8 Hz, 2H), 1.69 (d, J=6.3 Hz, 3H), 0.87 (m, 2H), −0.10 (s, 9H); LC/MS (HPLC method 4): tR=3.743 min, 382.12(MH)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=3)=[CH:12][C:11]([C:22]([OH:24])=O)=[N:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(CC)C(C)C)(C)C.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:58]3[CH2:62][C:61](=[O:63])[NH:60][CH2:59]3)=O)=N2)C=CC=1>C(O)=O>[O:63]=[C:61]1[CH2:62][N:58]([C:22]([C:11]2[CH:12]=[C:13]([C:14]3[CH:15]=[C:16]([C:20]#[N:21])[CH:17]=[CH:18][CH:19]=3)[N:9]([C:5]3[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][CH:6]=3)[N:10]=2)=[O:24])[CH2:59][NH:60]1
Reactant: N#Cc1cccc(-c2cc(C(=O)O)nn2-c2cccc(C#N)c2)c1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Product: N#Cc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(C#N)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 111A using 3.2 equivalents of N,N-diisopropylethylamine and with the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 23. 16 mg (29% of theory) of the title compound are obtained.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([NH:34]N)=[CH:33][C:28]=2[O:27][CH2:26]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([N:34]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)=[CH:33][C:28]=2[O:27][CH2:26]1
Reactant: NNc1ccc2c(c1)OCO2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccc4c(c3)OCO4)n2)c1
Yield: 10 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and benzo[1,3]dioxol-5-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for Example 91 in 10% yield. MS: M=437.3 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[N:11]=[CH:12][NH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:18]I>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[N:11]=[CH:12][N:13]([CH3:18])[CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cnc(CCNC(=O)OC(C)(C)C)c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
To a solution of [2-(1H-imidazol-4-yl)-ethyl]-carbamic acid tert-butyl ester (512 mg, 2.42 mmol) in THF (20 mL) at −10° C. was added NaH (60%, 97 mg, 2.42 mmol). After stirring at −10° C. for 30 min, MeI (0.14 mL, 2.17 mmol) was added. After stirring at −10° C. for 2.5 h, the reaction mixture was concentrated to afford a yellow oil. Purification by flash column chromatography on silica gel using 2% MeOH/CH2Cl2 afforded [2-(1-methyl-1H-imidazol-4-yl)-ethyl]-carbamic acid tert-butyl ester as a yellow oil (144 mg, 34%). Deprotection with TFA using General Procedure F gave [2-(lmethyl-1H-imidazol-4-yl)-ethyl]-amine as a yellow oil (51 mg, 25%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CS(C)=O.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S([O-])c1ccc(F)cc1
Reactant: O=Cc1cccnc1Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1cccnc1S(=O)(=O)c1ccc(F)cc1
Temperature: 100 °C
Yield: 545.7 %

Procedure:
2-Chloro-3-pyridinecarboxaldehyde (4.04 g, 2.86 mmol) and 4-fluorobenzenesulfinic acid sodium salt (5.73 g, 3.14 mmol) were dissolved in DMSO (100 ml) and the mixture was heated at 100° C. for 72 h under nitrogen. Upon cooling to ambient the mixture was diluted with water (500 ml) and extracted with EtOAc (3×). The combined organics were washed with water, brine, dried (MgSO4) and evaporated to dryness to afford 7.89 g of crude product. The crude compound was pre-absorbed onto silica and purified by dry pad suction column chromatography, eluting with heptane using an EtOAc gradient, to afford 4.14 g (41%) of the desired product as a yellow solid (plates) (MP=131-131.3° C.; IR=1691 cm−1; HPLC=7.21 min>99%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:31]([C:33]1([OH:40])[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)#[CH:32]>>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:32]#[C:31][C:33]3([OH:40])[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:20]([OH:22])=[O:21])([CH3:27])([CH3:29])[CH3:28]
Reactant: C#CC1(O)CCN(C)CC1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Product: Cc1cc2ccc(C#CC3(O)CCN(C)CC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-((4-hydroxy-1-methylpiperidin-4-yl)ethynyl)-3-methylnaphthalen-2-yl)acetic acid (79) was prepared by the method of Example 68 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 4-ethynyl-1-methylpiperidin-4-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 7.77 (d, J=9 Hz, 1H), 7.70 (br s, 1H), 7.58 (m, 3H), 7.41 (d, J=8 Hz, 1H), 7.30 (m, 2H), 5.16 (s, 1H), 3.35 (m, 4H), 2.89 (s, 3H), 2.60 (s, 3H), 2.15 (m, 4H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C31H35ClNO4: 520.2; found: 520.1.
Reaction SMILES: [CH3:1][CH:2]1[CH:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:4][N:3]1[C:17](Cl)=[O:18].[OH-].[NH4+:21]>O1CCCC1.O>[CH3:1][C@H:2]1[C@@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:4][N:3]1[C:17]([NH2:21])=[O:18]
Reactant: CC1C(Oc2cccc(C(F)(F)F)c2)CN1C(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1[C@@H](Oc2cccc(C(F)(F)F)c2)CN1C(N)=O
Reaction time: 6 h
Yield: 87 %

Procedure:
A solution of 4.02 g (0.01 mole) of crude (73%) 2-methyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride cis isomer in 20 ml of tetrahydrofuran was treated while stirring with 2 ml (0.02 mole) of 57% aqueous ammonium hydroxide. After stirring for 6 hr, the reaction mixture was diluted with 100 ml of water and the oil which separated was extracted into methylene chloride (2×50 ml). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give 4.2 g. A sample of the oil crystallized at -78° C. and was used to seed the bulk of the material. The resulting solid was recrystallized from benzene/isooctane to yield 2.35 g (87%) of white crystalline product, m.p. 107°-108° C.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]3[CH:23]=[CH:22][N:21]=[C:20]3[CH3:24])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:25]>CO.[OH-].[OH-].[Pd+2]>[ClH:25].[CH3:24][C:20]1[N:19]([C:17]2[CH:16]=[N:15][C:13]3[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=3[N:18]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Cc1nccn1-c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: Cc1nccn1-c1cnc2c(n1)OCCNC2
Temperature: 50 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
To a solution of 8-benzyl-3-(2-methyl-1H-imidazol-1-yl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (18 mg) in methanol (2.5 mL) was added 20% Pd(OH)2/C (10 mg), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 5 hr. The reaction mixture was filtered, and the filtrate was concentrated. To a solution of the obtained crude product in methanol (0.3 mL) was added 0.1 N hydrochloric acid (410 μL), and the mixture was stirred for 30 min. The reaction mixture was concentrated, and the obtained crystals were purified by recrystallization (methanol-ethyl acetate) to give the title compound (6 mg, 61%) as a pale-yellow powder.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[S:10][C:11]=2[CH:12]([NH2:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([C:7]2[C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[S:10][C:11]=2[CH:12]([NH:14][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(N)c1sc2ccccc2c1-c1ccccc1
Reactant: Clc1ncnc2[nH]cnc12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1sc2ccccc2c1-c1ccccc1
Temperature: 120 °C
Reaction time: 72 h

Procedure:
A mixture of 1-(3-phenylbenzo[b]thiophen-2-yl)ethylamine from Example 23 (160 mg, 0.63 mmol), 6-chloro-9H-purine (98 mg, 0.63 mmol) and DIPEA (0.16 mL, 0.95 mmol) in n-butanol (1.3 mL) was stirred in a sealed vial for 3 days at 120° C. After cooling to RT, the crude reaction mixture was loaded into an Isolute® SCX-2 which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-6% MeOH in DCM) and then triturated with EtOAc affording 101 (105 mg, 45%). LCMS: RT 4.33 min [M+H]+ 372.1. 1H NMR (DMSO, 400 MHz): δ 8.21 (1H, s), 8.16-8.10 (2H, m), 7.92-7.86 (1H, m), 7.66-7.54 (4H, m), 7.50-7.44 (1H, m), 7.37-7.26 (3H, m), 5.76 (1H, s), 1.50 (3H, d, J=6.94 Hz)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>O1CCCC1>[CH3:1][O:2][C:3](=[O:19])[CH:4]([CH3:20])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:8][CH2:7]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3-(N-Boc-piperidine-4-yl)-propionic acid methyl ester (2.0 g, 7.38 mmol) from above was dissolved in tetrahydrofuran (50 mL). The solution was cooled to −78° C. and sodium bis(trimethylsilyl)amide (1.0 M, 9.0 mL) was added. The mixture was stirred at −78° C. for 1 hr and methyl iodide (1.2 mL, 19.5 mmol) was added. The mixture was warmed to room temperature and stirred for 2 hrs. The mixture was extracted with ether and washed with dilute hydrochloric acid. The organic layer was dried, filtered and concentrated. The residue was purified using flash chromatography (eluting with ethyl acetate and hexanes) to give 2-methyl-3-(N-Boc-piperidine-4-yl)-propionic acid methyl ester as an oil (789 mg).
Reaction SMILES: Cl.Cl[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)=[C:8]([C:13]([NH2:15])=[O:14])[CH:9]=[N:10]2)=[CH:5][C:4]=1[I:25].[SH:26][C:27]1[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+]>CN1CCCN(C)C1=O.O>[CH3:33][N:32]([CH3:34])[C:30]([C:29]1[CH:28]=[C:27]([S:26][C:3]2[CH:12]=[C:11]3[C:6]([C:7]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)=[C:8]([C:13]([NH2:15])=[O:14])[CH:9]=[N:10]3)=[CH:5][C:4]=2[I:25])[CH:37]=[CH:36][CH:35]=1)=[O:31]
Reactant: CN(C)C(=O)c1cccc(S)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3cc(Cl)c(I)cc23)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: COc1cccc(Nc2c(C(N)=O)cnc3cc(Sc4cccc(C(=O)N(C)C)c4)c(I)cc23)c1
Temperature: 100 °C
Reaction time: 23 h
Yield: 24.6 %

Procedure:
A stirred mixture of Intermediate 63 (0.4 g), Intermediate 28 (0.16 g) and potassium carbonate (0.38 g) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 ml) was heated at 100° C. under nitrogen for 3 h. A further portion of Intermediate 28 (0.07 g) was added and the mixture stirred at 60° C. for 23 h. The cooled mixture was diluted with water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water (2×70 ml) and brine (70 ml), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with methanol followed by mass directed preparative HPLC (Method A) to give the title compound as a yellow foam (0.12 g).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:15])=[C:7]([C:10]([CH3:14])=[C:11]([Cl:13])[CH:12]=1)[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[S:24]([NH2:27])(=[O:26])=[O:25].ClCl>>[C:1]([C:5]1[C:6]([OH:15])=[C:7]([C:8]2[NH:27][S:24](=[O:26])(=[O:25])[C:18]3[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=3[N:16]=2)[C:10]([CH3:14])=[C:11]([Cl:13])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(Cl)cc(C(C)(C)C)c(O)c1C=O
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Agent: ClCl
Product: Cc1c(Cl)cc(C(C)(C)C)c(O)c1C1=Nc2cc(Cl)ccc2S(=O)(=O)N1

Procedure:
From 3-tert-butyl-5-chloro-2-hydroxy-6-methyl-benzaldehyde and 2-amino-4-chlorobenzenesulfonamide; LC-MS: m/z 413/415/417 (M+H; Cl2 isotope pattern).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([O:17]C)=[O:16])=[C:13]([CH3:19])[NH:12][C:11]3[CH2:20][O:21][CH2:22][C:23](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[Br:8].BrN1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:10]3[C:23](=[O:24])[CH2:22][O:21][CH2:20][C:11]=3[NH:12][C:13]3[CH2:19][O:16][C:15](=[O:17])[C:14]2=3)[CH:5]=[CH:6][C:7]=1[Br:8]
Reactant: COC(=O)C1=C(C)NC2=C(C(=O)COC2)C1c1ccc(Br)c(Br)c1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: O=C1COCC2=C1C(c1ccc(Br)c(Br)c1)C1=C(COC1=O)N2
Temperature: 110 °C
Yield: 46.4 %

Procedure:
The product from Example 71A (0.095 g, 0.21 mmol) in chloroform (5 mL) was treated with N-bromosuccinimide (0.037 g, 0.21 mmol) and heated to 110° C. for 16 hours. The mixture was cooled to ambient temperature and purified by chromatography on silica gel eluting with 5% methanol in dichloromethane to provide the title compound (0.043 g).