Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[NH:6][CH2:7][C:8](=[O:14])[NH:9]2.Br[CH2:16][C:17]#[N:18]>C1COCC1.[Cl-].[Na+].O>[F:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[NH:6][CH2:7][C:8](=[O:14])[N:9]2[CH2:16][C:17]#[N:18]
Reactant: O=C1CNc2c(F)cccc2N1
Reactant: N#CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCN1C(=O)CNc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%, 84 mg, 2.1 mmol) was added to a solution of 5-fluoro-3,4-dihydro-1H-quinoxalin-2-one from Example B (316 mg, 1.9 mmol) in THF (2.0 ml) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 30 mins. Bromoacetonitrile (146 μl, 2.1 mmol) was added and the mixture was stirred for 18 h. Brine was added and the mixture evaporated in vacuo. The residue was portioned between EtOAc and water, separated and the organic phase was dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant 100% pet ether then EtOAc:pet. ether 20:80); yield 183 mg, 47%.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[C:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19][CH3:20])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].[CH2:22]=O.Cl>C(O)C>[ClH:1].[C:8]([C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:21])[CH:19]([CH3:22])[CH2:20][N:2]2[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)=[CH:16][CH:17]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CCC(=O)c1ccc(C(C)(C)C)cc1
Reactant: C1COCCN1
Reactant: C=O
Agent: Cl
Solvent: CCO
Product: CC(CN1CCOCC1)C(=O)c1ccc(C(C)(C)C)cc1
Yield: 61.4 %

Procedure:
37.07 g (0.3 mole) of morpholine hydrochloride, 57.1 g (0.3 mole) of p-tert.-butyl-propiophenone and 15.01 g (0.5 mole) of paraformaldehyde were heated under reflux in 150 ml of ethanol for 1 hour. After adding 0.5 ml of concentrated hydrochloric acid, the reaction mixture was stirred under reflux for a further 15 hours. It was then concentrated, the residue was taken up in chloroform, the chloroform mixture was washed twice with water and the organic phase was dried over sodium sulphate and concentrated. The crystalline residue was suspended in hot ethyl acetate, filtered off and dried. 60 g (61.5% of theory) of p-tert.-butyl-2-methyl-3-morpholin-4-yl-propiophenone hydrochloride of melting point 189° to 91° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][CH2:6][C:5]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])([N+:8]([O-])=O)[CH2:4][O:3]1.O>C(O)C.C1COCC1.[Ni]>[NH2:8][C:5]1([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])[CH2:6][O:7][C:2]([CH3:1])([CH3:21])[O:3][CH2:4]1
Reactant: COC(=O)c1cccc(C2([N+](=O)[O-])COC(C)(C)OC2)c1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COC(=O)c1cccc(C2(N)COC(C)(C)OC2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 106.7 %

Procedure:
Under an argon atmosphere, to a solution of 2.18 g of methyl 3-(2,2-dimethyl-5-nitro-1,3-dioxan-5-yl)benzoate in 26 ml of ethanol and 7 ml of THF was added a suspension of Raney nickel (manufactured by Aldrich, 1.2 ml of a suspension was washed with water and ethanol) in 5 ml of ethanol, followed by stirring at room temperature for 7 hours under a hydrogen atmosphere of 4 atm. The reaction mixture was filtered over Celite and the liquid was concentrated under reduced pressure. To a solution of the obtained residue in 26 ml of ethanol and 7 ml of THF was added a suspension of Raney nickel (manufactured by Aldrich, 1.2 ml of a suspension was washed with water and ethanol) in 5 ml of ethanol under an argon atmosphere, followed by stirring at room temperature for 16 hours under a hydrogen atmosphere of 4 atm. The reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure to obtain 2.09 g of methyl 3-(5-amino-2,2-dimethyl-1,3-dioxan-5-yl)benzoate.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[C:6](\[Br:14])/[C:7](=[O:13])[O:8][CH:9]([CH3:12])[CH2:10][CH3:11])[C@H:3]1[C:15]([OH:17])=[O:16].[C:19]([C@@H:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)#[N:20]>>[CH3:18][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[C:6](\[Br:14])/[C:7](=[O:13])[O:8][CH:9]([CH3:12])[CH2:10][CH3:11])[C@H:3]1[C:15]([O:17][C@H:21]([C:19]#[N:20])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:23]=1)=[O:16]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CCC(C)OC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Product: CCC(C)OC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Step B of Example 43, (1R,cis,Z) 2,2-dimethyl-3-[2-bromo-3-oxo-3-(1-methylpropoxy)-1-propenyl]-cyclopropane carboxylic acid and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis,Z) 2,2-dimethyl-3-[2-bromo-3-oxo-3-(1-methypropoxy)-1-propenyl]-cyclopropanecarboxylate with a melting point of 76° C. and a specific rotation of [α]D20 =+21.5°±2° (c=0.7% in chloroform).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][C:14](S)=[N:13][C:12]=2[CH:17]=1>C1COCC1.CCOC(C)=O>[Cl:4][C:14]1[S:15][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:17][C:12]=2[N:13]=1
Reactant: COc1ccc2sc(S)nc2c1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2sc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
Sulfuryl chloride (1.64 mL) was added to a solution of 5-methoxy-2-mercaptobenzothiazole in THF (20 mL). After stirring overnight, ice water was added. The reaction mixture was allowed to warm to rt and was diluted with EtOAc (100 mL). This was washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by column chromatography (0 to 3% EtOAc in hexanes gradient), yielding 0.407 g (20%) of the title compound as a white solid. LC-MS: RT=9.05 min., [M+H]+=200.0. Rf=0.38 in 10% EtOAc/Hexanes.
Reaction SMILES: C(O)C.B([O-])([O-])O[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH3:18])=[CH:11][C:9]=2[CH:10]=1.Br[C:22]1[CH:23]=[CH:24][C:25]2[S:31](=[O:33])(=[O:32])[CH2:30][CH2:29][C:28]([C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([CH2:43][N:44]([CH3:51])[CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[CH:39][CH:38]=3)=[O:35])=[CH:27][C:26]=2[CH:52]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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.O>[CH3:51][N:44]([CH2:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]([C:28]2[CH2:29][CH2:30][S:31](=[O:33])(=[O:32])[C:25]3[CH:24]=[CH:23][C:22]([C:6]4[O:7][C:8]5[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH3:18])=[CH:11][C:9]=5[CH:10]=4)=[CH:52][C:26]=3[CH:27]=2)=[O:35])=[CH:38][CH:39]=1)[CH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1
Reactant: CCCOc1ccc2oc(OB([O-])[O-])cc2c1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCOc1ccc2oc(-c3ccc4c(c3)C=C(C(=O)Nc3ccc(CN(C)C5CCOCC5)cc3)CCS4(=O)=O)cc2c1
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
In toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) were suspended 5-propoxy-benzofuran-2-yl borate (165 mg), 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) and potassium carbonate (208 mg), and the suspension was stirred under argon atmosphere for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (47 mg), and the mixture was stirred, under argon atmosphere, at 100° C. for 8 hours and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography and recrystallized from ethanol (750 ml) to give colorless crystals of N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-7-(5-propoxybenzofuran-2-yl)-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 139) (115 mg).
Reaction SMILES: [NH2:1][C:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH2:5][OH:6])[CH2:3][OH:4].[CH2:23](C(CC)(CC)C([O-])([O-])[O-])[CH3:24].C(O)(=O)C>C(#N)C>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:2]2([CH2:5][OH:6])[CH2:3][O:4][C:23]([CH3:24])=[N:1]2)=[CH:10][CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: NC(CO)(CO)CCc1ccc(OCc2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CC#N
Product: CC1=NC(CO)(CCc2ccc(OCc3ccccc3)cc2)CO1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 2-amino-2-[2-(4-benzyloxy-phenyl)-ethyl]-propane-1,3-diol (31.1 g, 0.10 mol) in acetonitrile (2.38 l) is added triethylortho acetate (17.1 ml, 0.12 mol, 1.2 eq) and acetic acid (5.48 ml, 0.11 mol. 1.1 eq), the reaction mixture is then stirred at 80° C. for 5 hours. The reaction mixture is then concentrated under vacuum, {4-[2-(4-benzyloxy-phenyl)-ethyl]-2-methyl-4,5-dihydro-oxazol-4-yl}-methanol is isolated after crystallization with AcOEt.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N+:12]([C:15]1[C:16]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[C:17]2[CH2:23][CH2:22][CH2:21][C:18]2=[N:19][CH:20]=1)([O-:14])=[O:13].[O-]S([O-])(=S)=O.[Na+].[Na+].[OH-].[Na+]>C(Cl)Cl>[N+:12]([C:15]1[C:16]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[CH2:25]2)=[C:17]2[CH2:23][CH2:22][CH2:21][C:18]2=[N+:19]([O-:9])[CH:20]=1)([O-:14])=[O:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C1
Temperature: 25 °C
Reaction time: 67 h
Yield: 88.2 %

Procedure:
mCPBA (198 mg, 0.883 mmol) was added slowly to a solution of tert-butyl [(3S)-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (301 mg, 0.83 mmol) in DCM (1.1 mL) at 0° C. The reaction mixture was then stirred at room temperature for 67 h. The mixture was treated with aq. Na2S2O3 and 1 M NaOH, and then stirred for 30 min. at room temperature. The reaction mixture was extracted with DCM three times. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the sub-title compound (277 mg, 88%) as light orange powder, which was used without further purification. LCMS calc. for C18H22N4O5 (M+H)+: m/z=379.2. Found: 379.2.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[F:24][CH:25]([F:27])[OH:26]>>[F:24][CH:25]([F:27])[O:26][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: OC(F)F
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(OC(F)F)cc1OCC2

Procedure:
Following the procedures of the Examples herein, 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194 and difluoromethanol were reacted to give 492. LC/MS (ESI+): m/z 362.1 (M+H)
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([OH:13])=O)=[CH:7][CH:8]=2)[NH:3]1.[NH2:14][C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:19][CH:20]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:22]([NH:21][C:17]1[CH:16]=[C:15]([NH:14][C:11]([C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][C:2](=[O:1])[NH:3]3)=[CH:8][CH:7]=2)=[O:13])[CH:20]=[CH:19][CH:18]=1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(NC(=O)c2ccccc2)c1
Reactant: O=C1Cc2ccc(C(=O)O)cc2N1
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: O=C1Cc2ccc(C(=O)Nc3cccc(NC(=O)c4ccccc4)c3)cc2N1
Reaction time: 20 h

Procedure:
To a solution of 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid (0.20 g, 1.1 mmol) in DMF (1 ml) is added N-(3-amino-phenyl)-benzamide (0.26 g, 1.2 mmol), N,N-diisopropylethylamine (0.44 g, 3.4 mmol) and HATU (0.47 g, 1.24 mmol). The reaction is stirred for 20 hours and concentrated. The residue is purified by HPLC (C18 column, eluted with CH3CN—H2O containing 0.05% TFA) to give 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid (3-benzoylamino-phenyl)-amide as off-white solid. This amide (15 mg, 0.04 mmol) is then heated with 1H-pyrrole-2-carbaldehyde (6.0 mg, 0.06 mmol) in ethanol (2 ml) in the presence of 2 drops of piperidine at 80° C. for 20 hours. The mixture is concentrated and the desired compound is obtained after HPLC purification: 1H NMR (DMSO-d6) δ 6.41 (s, 1H), 6.93 (s, 1H), 7.31 (t, 1H, J=7.8 Hz), 7.44 (s, 1H), 7.48-7.51 (m, 3H), 7.54 (t, 2H, J=7.2 Hz), 7.59 (d, 1H, J=6.6 Hz), 7.70 (d, 1H, J=8.4 Hz), 7.78 (d, 1H, J=8.4 Hz), 7.92 (s, 1H), 7.98 (d, 2H, J=7.2 Hz), 8.33 (s, 1H), 10.27 (s, 1H), 10.31 (s, 1H), 11.13 (s, 1H), 13.38 (s, 1H); LC-MS: 449.1 (MH+).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([CH3:25])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:24]=[C:23]([CH3:25])[S:22][C:12]=2[N:13]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: Cc1cc2c(NCc3ccccc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example l, the reaction of benzylamine with 4-chloro-2-(pyridin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-benzylamino-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25](=O)[C:26](OC)=[O:27].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25]1[C:26](=[O:27])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: COC(=O)C(=O)c1c[nH]c2ccc(Br)cc12
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5ccc(Br)cc45)C(=O)NC3=O)c21
Temperature: 50 °C
Yield: 45.1 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (200 mg, 1.06 mmol) and methyl 2-(5-bromo-1H-indol-3-yl)oxoacetate (300 mg, 1.06 mmol) in DMF (5.4 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (1.06 mL, 1.06 mmol) at 4° C. under N2. The reaction was stirred for 20 min at this temperature, and additional KOtBu (2.12 mL, 2.12 mmol) was added. The resulting dark red solution was heated up to 50° C. overnight. The mixture was cooled to room temperature, quenched with 1N HCl (9 mL) and poured into EtOAc (300 mL). The organic layer was separated, washed with saturated aqueous NaHCO3 (150 mL), and brine (3×150 mL). The solution was dried (MgSO4), filtered, and concentrated to an orange solid. Flash chromatography (SiO2, 30% EtOAc/hexanes) gave the title compound (201 mg, 45%) as an orange solid, mp 270–290° C. dec.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH2:6][CH2:7]2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: C1COCCN1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Product: COc1cc(N2CCN(C(=O)CN3CCOCC3)CC2)ccc1Cl

Procedure:
In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), and morpholine (575 μL, 6.60 mmol, 10.00 equiv). A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-morpholin-4-yl-ethanone (24): HPLC retention time, 0.32 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 353.9, found, 354.5.
Reaction SMILES: [S:1](=[O:5])(=O)(O)[OH:2].[C:6]1([O:12][CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.P(Cl)(Cl)([Cl:16])=O.[Cl-].[Na+]>O>[CH3:13][O:12][C:6]1[CH:11]=[CH:10][C:9]([S:1]([Cl:16])(=[O:5])=[O:2])=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccccc1
Reactant: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(S(=O)(=O)Cl)cc1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
With stirring, 51.5 g (0.525 m) of 100 percent sulfuric acid was added to a mixture of 54.0 g (0.5 m) of anisole and 46.0 ml (0.5 m) of phosphorus oxychloride allowing the temperature to rise to approximately 45° C. during the addition. While attempting to maintain approximately 45° C. the temperature slowly rose to approximately 53° C. after about two hours. After stirring overnight at ambient temperature, 6.0 g of sodium chloride was added and the resulting mixture was heated to and maintained at approximately 90° for about four hours. The reaction mixture was cooled and poured onto a mixture of 500.0 g ice, 250.0 ml of water and 30.0 g of sodium chloride. The solid which formed was collected by filtration, washed with cold water and dried to obtain 96.5 g of 4-methoxybenzenesulfonyl chloride a gray-white solid. The nuclear magnetic resonance spectrum was in accord with the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2=[N:6][S:7][N:8]=[C:4]2[CH:3]=1.[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:10]=[CH:9][C:5]2=[N:6][S:7][N:8]=[C:4]2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nsnc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: BrCc1ccc2nsnc2c1
Yield: 63.5 %

Procedure:
5-Methylbenzo-2,1,3-thiadiazole (5.0 g, 33 mmol), N-bromosuccinimide (5.92g, 33.3 mmol) and catalytic 2,2′-azobisisobutyronitrile were heated at reflux for 16 hours in chloroform (75 mL). The reaction mixture was cooled and the resulting precipitate was filtered off and discarded. The filtrate was′evaporated and recrystallized from ethanol to provide 4.8 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]2[N:20]=[CH:19][C:18]3[C:13](=[C:14]([F:25])[CH:15]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=3)[C:12]2=[O:26])[C:3]=1[CH:4]=[O:5].[CH3:27][N:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([N:50]3[CH2:55][CH2:54][N:53]([CH:56]4[CH2:59][O:58][CH2:57]4)[CH2:52][CH2:51]3)=[CH:46][N:45]=2)[C:29]1=[O:60].C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:21]([C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([F:25])[CH:15]=1)[C:12](=[O:26])[N:11]([C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:2]([C:32]3[CH:31]=[C:30]([NH:43][C:44]4[CH:49]=[CH:48][C:47]([N:50]5[CH2:55][CH2:54][N:53]([CH:56]6[CH2:57][O:58][CH2:59]6)[CH2:52][CH2:51]5)=[CH:46][N:45]=4)[C:29](=[O:60])[N:28]([CH3:27])[CH:33]=3)[C:3]=1[CH:4]=[O:5])[N:20]=[CH:19]2)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cc(F)cc(Br)c3C=O)ncc2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2cc(F)cc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 70 °C
Yield: 59.9 %

Procedure:
A round-bottomed flask was charged with 2-bromo-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-fluorobenzaldehyde 102b (100 mg, 0.24 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (131 mg, 0.28 mmol), PdCl2(dppf) (25 mg, 0.03 mmol), K3PO4.3H2O (149 mg, 0.56 mmol), THF (10 mL), and H2O (5 mL). After three cycles of vacuum/argon flash, the mixture was heated at 70° C. for 6 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified on flash column chromatography eluting with 1:3 petroleum/ethyl acetate to afford 102c as a yellow solid (98 mg, 60%). LCMS: [M+H]+ 682
Reaction SMILES: C(N[C@@H](CC1C=CC=CC=1)C(=O)CCC(N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1)=O)(=O)C1C=CC=CC=1.C[O:40][C:41](=[O:74])[C@H:42]([CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)[NH:43][C:44](=[O:66])[CH2:45][CH2:46][C:47](=[O:65])[C@@H:48]([NH:56][C:57](=[O:64])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.[Li+].[OH-]>C1COCC1.CO>[C:57]([NH:56][C@@H:48]([CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:47](=[O:65])[CH2:46][CH2:45][C:44]([NH:43][C@H:42]([C:41]([OH:74])=[O:40])[CH2:67][C:68]1[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=1)=[O:66])(=[O:64])[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)CCC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Agent: O=C(CCC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CCC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)N[C@@H](Cc1ccccc1)C(=O)O
Yield: 96.7 %

Procedure:
The experimental procedure employed for the synthesis of compound 5b was followed using the (5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenyl-hexanoyl-L-phenylalanine methyl ester (200 mg, 0.4094 mmol, 1.0 eq.), 0.5N LiOH (5.0 mL) and a mixture THF-MeOH (ratio 3:2) (10 mL) was added 0.5N LiOH (5.0 mL). Work-up and column chromatography on silica gel elution with 20% MeOH-EtOAc afforded the free acid (5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenyl-hexanoyl-L-phenylalanine 5c as a yellow oil (0.187 g, 97%); IR (liquid film) ν 1720 (CO), 3100 (broad, COOH) cm−1; 1H NMR (300 MHz, CDCl3) δH 2.46 (2H, m, —CH2CO), 2.80 (2H, m, —CH2CO), 3.00-3.31 (4H, m, 2×—CH2Ph), 4.81 (1H, q, J=6.0 Hz), 4.98 (1H, ddd, J=2.5, 7.0 and 9.0 Hz, —CH—), 6.30 (1H, m, —NH), 6.94 (1H, t, J=9.3 Hz, Ar—H) and 7.10-7.74 (16H, m, Ar—H and —NH); 13C NMR (75 MHz, CDCl3) δC 29.1, 29.7, 35.3, 36.8, 37.3, 53.3, 59.5, 59.6, 67.7, 127.1 (2C), 127.2 (2C), 128.5, 128.6, 128.7, 129.2, 129.3, 129.4, 131.9, 133.5, 135.8, 136.1, 167.5, 172.0, 174.9 and 207.7; HRMS m/z calcd for C28H28N2O5 (M+) 472.19982, found 472.19982. [± The carboxylic acid and amide protons were not observed, presumably, due to rapid exchange with water in the deuteriated NMR solvent.]
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[NH:8][C:9](=[O:20])[C:10]3[N:15]([CH3:16])[N:14]=[C:13]([CH2:17][CH2:18][CH3:19])[C:11]=3[N:12]=2)=[CH:4][CH:3]=1.O.[C:24]([OH:28])(=[O:27])[CH:25]=O>[Pd].CO>[CH3:16][N:15]1[C:10]2[C:9](=[O:20])[NH:8][C:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([NH:1][CH2:25][C:24]([OH:28])=[O:27])=[CH:3][CH:4]=3)=[N:12][C:11]=2[C:13]([CH2:17][CH2:18][CH3:19])=[N:14]1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(N)cc3)nc12
Reactant: O=CC(=O)O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(NCC(=O)O)cc3)nc12
Reaction time: 3 h

Procedure:
10% w/w Palladium on charcoal (87 mg) was added to a solution of 5-(4-aminobenzyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one (870 mg, 0.00293 mol) and glyoxylic acid hydrate (260 mg, 0.0035 mol) in methanol (20 ml) and the mixture hydrogenated at room temperature at 50 p.s.i. for 3 hours.