Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Br[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:25][C:22]1[CH:23]=[CH:24][C:19]([N:8]2[CH2:7][CH2:6][C:5]3([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]3)[CH2:10][CH2:9]2)=[CH:20][CH:21]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccc(F)cc3)CC2)C1
Temperature: 120 °C
Yield: 28 %

Procedure:
Sodium t-butylate (6.24 mmol, 3.0 eq.) was added to a stirred solution of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (2.08 mmol, 1.0 eq.) and 1-bromo-4-fluorobenzene (2.08 mmol, 1.0 eq.) in toluene (15 ml) and the reaction mixture was degassed with N2. BINAP (0.12 mmol, 0.06 eq.) and Pd(OAc)2 (0.04 mmol, 0.02 eq.) were added and the reaction mixture obtained was heated at 120° C. for 12 h. The reaction mixture was filtered over Celite and the filtrate was concentrated in vacuo in order to obtain the crude product, which was purified by column chromatography (silica gel, 12% ethyl acetate in hexane), so that the desired product was achieved. Yield: 28%
Reaction SMILES: C([CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][C:9]1=O)(OC(C)(C)C)=O.[NH2:15][O:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>C(O)C>[CH:26]([O:25][C:23]([N:20]1[CH2:19][CH2:18][CH:17]([O:16]/[N:15]=[C:8]2\[CH2:9][NH:10][CH2:11][CH2:12][CH2:13]\2)[CH2:22][CH2:21]1)=[O:24])([CH3:28])[CH3:27]
Reactant: CC(C)OC(=O)N1CCC(ON)CC1
Reactant: CC(C)(C)OC(=O)C1CCCNC1=O
Solvent: CCO
Product: CC(C)OC(=O)N1CCC(O/N=C2/CCCNC2)CC1
Temperature: 65 °C
Reaction time: 0.75 h

Procedure:
3-Boc-piperidinone (0.83 mmol) and NaOAc.3H2O (30 mg) were combined in 1 mL of ethanol and heated to 65° C. for 15 minutes. 2b (167 mg, 0.83 mmol) was added and the mixture was heated at 65° C. for 18 h. The mixture was concentrated, taken up with DCM (5 mL), washed with aqueous NaHCO3 (5 mL) and the organic layer was separated and treated with TFA (5 mL). The mixture was stirred at room temperature for 45 minutes, concentrated, diluted with NaHCO3 (8 mL) and extracted with EtOAc (2×5 mL). The extracts were dried and concentrated to afford the crude 61a: LC-MS 284.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10])=O.C1(C)C=CC=CC=1.[CH3:28][NH:29][NH2:30]>O>[CH3:28][N:29]1[N:30]=[C:5]([C:4]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:2]([Cl:1])[CH:3]=2)[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]1=[O:10]
Reactant: CNN
Reactant: COc1ccc(C(=O)c2ccccc2C(=O)O)cc1Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nn(C)c(=O)c3ccccc23)cc1Cl
Yield: 68.7 %

Procedure:
A mixture of 2-(3-chloro-4-methoxybenzoyl)benzoic acid (10.46 g, 0.036 mol), toluene (50 mL) and methyl hydrazine (2.1 mL) was refluxed in the presence of a Dean Stark trap until the theoretical amount of water had been collected. The reaction mixture was cooled, and the product was collected by filtration to afford 7.42 g (68.7%) of 2-methyl-4-(3-chloro-4-methoxyphenyl)-1-(2H)-phthalazinone, m.p. 195°-195° C. An additional 1.89 g of product was also collected from the filtrate for a total of 9.31 g (86.2%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]1[O:22][CH:23]=[CH:24][N:25]=1.[NH4+].[Cl-]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:20][C:21]1[O:22][CH:23]=[CH:24][N:25]=1)[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: ClCc1ncco1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2ncco2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.2 %

Procedure:
A mixture of 5-nitroindazole (500 mg, 3.07 mmol), potassium carbonate (889 mg, 6.44 mmol) and 2-(chloromethyl)-1,3-oxazole (396 mg, 3.37 mmol) in DMF (3 mL) was stirred for 3 hours at room temperature. Saturated NH4Cl was added and the mixture was extracted with dichloromethane. After evaporation, the residue was purified on silica gel (30 to 35% EtOAc/petroleum ether) to give 5-nitro-1-(1,3-oxazol-2-ylmethyl)-1H-indazole (474 mg, 63%); NMR spectrum (CDCl3) 5.76 (s, 2H), 7.11 (s, 1H), 7.60 (d, 1H), 7.62 (s, 1H) 8.26 (s, 1H), 8.31 (d, 1H), 8.74 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:46]=[CH:45][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][N:20]4C(=O)C5C(=CC=CC=5)C4=O)[C:12](=[O:31])[N:11]([CH3:32])[C:10]=3[N:9]=[C:8]2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][C:41]([F:44])([F:43])[F:42])[CH:35]=2)=[CH:4][CH:3]=1.O.NN.Cl.C(OCC)C>C(O)C.O.C(Cl)Cl>[ClH:1].[NH2:20][CH2:19][CH2:18][CH2:17][N:13]1[C:14](=[O:16])[C:15]2[N:7]([CH2:6][C:5]3[CH:45]=[CH:46][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:8]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][C:41]([F:42])([F:44])[F:43])[CH:35]=3)=[N:9][C:10]=2[N:11]([CH3:32])[C:12]1=[O:31]
Reactant: Cn1c(=O)n(CCCN2C(=O)c3ccccc3C2=O)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: Cl
Agent: NN
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: Cn1c(=O)n(CCCN)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 145.1 %

Procedure:
Step 2 7-(4-Chlorobenzyl)-1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (1.4 g, 2.14 mmol) was slurried in ethanol (20 mL) and hydrazine hydrate (0.42 mL, 8.56 mmol) was added and the reaction was heated at reflux. The reaction at reflux changed to a clear solution then after 30 min setup as a white mass. The reaction was cooled to room temperature, diluted with water (100 mL) and extracted with DCM (3×75 mL). The combined organic extracts were dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to give an oil. The oil was purified using a 40 g silica gel flash column eluted with 10% methanol/DCM to give a light tan solid. Solid was dissolved in DCM (5 mL) and excess 1N HCl/diethyl ether was added. The solvent was removed under reduced pressure to give 1-(3-aminopropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione hydrochloride (0.87 g, 49% yield) as a tan solid. LCMS retention time=2.802 minutes and 97% purity, LCMS MH+ 524. 1H NMR (DMSO-d6) δ 7.91-8.11 (brd s, NH2 and HCl), 7.60 (t, 1H, J=8 Hz), 7.38-7.48 (m, 6H), 7.31 (d, 1H, J=12 Hz), 5.43 (s, 2H), 3.93 (t, 2H, J=8 Hz), 3.29 (s, 3H), 2.73-2.85 (m, 2H), 1.83-1.94 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[CH3:23][NH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][C:26]1([CH3:32])[CH3:31]>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:28]2[CH2:29][CH2:30][CH:25]([NH:24][CH3:23])[C:26]([CH3:32])([CH3:31])[CH2:27]2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CNC1CCNCC1(C)C
Product: CNC1CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)CC1(C)C
Yield: 54 %

Procedure:
The condensation of 5-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with 4-methylamino-3,3-dimethylpiperidine was carried out in a similar manner as described in example 1 (NorA), gave the titled product. Yield 54%, m.p 250° C., C22H29FN4O4, m/z 433 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH2:21]([NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][NH:28][CH2:27]2)[CH3:22].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH2:21]([NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:27]2)[CH3:22]
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CCNc1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCNc1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn4c3c1OCC4C)C2
Yield: 51.3 %

Procedure:
141 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 97 mg of 5-ethylaminoisoindoline, 152 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 1 to produce 109 mg of the target compound.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]#[C:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:22]([O:26][C:27]([N:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH2:30])=[O:28])([CH3:25])([CH3:24])[CH3:23]>Cl[Pd]Cl.CN(C=O)C>[C:22]([O:26][C:27](=[O:28])[N:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[N:30]1[C:8]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:14]=[C:15]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N(N)c1ccccc1
Reactant: Clc1ccccc1C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(c1ccccc1)n1c(-c2ccccc2)cc2ccccc21
Temperature: 110 °C
Yield: 85.8 %

Procedure:
Following the general procedure outlined above, a reaction tube was charged with 4.4 mg PdCl2 (5 mol %), 14.5 mg tBu3PHBF4 (10 mol %), 228.1 mg Cs2CO3 (1.4 equiv.) and 2.5 mL DMF. After stirring for 30 min at RT under a flow of argon, 1-chloro-2-phenylethynyl-benzene (106.3 mg, 1.0 equiv.) and N-phenylhydrazine carboxylic acid tert-butyl ester (145.8 mg, 1.4 equiv.) were added and the reaction was heated to 110° C. for 3 hours. After cooling to RT, the reaction mixture was quenched with 30 mL NaHCO3 (saturated aqueous) and extracted with EtOAc (2×30 mL) and the organic phase was dried by eluting through a Varian Chem Elut 12198007 cartridge. Removal of the solvents afforded the crude N-aminoindole as a dark-brown oil that was purified by flash chromatography on silica using CH2Cl2/heptane to afford 164.8 mg (86%) of Phenyl-(2-phenyl-indol-1-yl)-carbamic acid tert-butyl ester as a yellowish oil. 1H-NMR (DMSO-d6) δ 1.25 (s, 9H), 6.85 (s, 1H), 7.10-7.14 (m, 3H), 7.15-7.18 (m, 1H), 7.23 (d, 2H, J=4.0 Hz), 7.26-7.30 (m, 2H), 7.39-7.41 (m, 1H), 7.44 (t, J=7.2 Hz, 2H), 7.52 (d, 2H, J=7.9 Hz), 7.65 (d, 1H, J=7.8 Hz); 13C-NMR (DMSO-d6) δ 27.3, 82.5, 101.4, 109.2, 120.8, 121.0, 123.1, 125.3, 125.7, 127.4, 128.4, 128.7, 128.8, 130.5, 136.7, 139.7, 140.9, 152.0; HRMS (FAB): Calculated for C25H25N2O2 (M+H+) 385.1916. found 385.1917.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH3:13])[CH3:12].[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.[Cl-].[NH4+].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>[Cl:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]3([CH3:13])[CH3:12])[CH:18]=[CH:17][CH:16]=1
Reactant: CC1(C)C(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1cccc(Cl)c1
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: [Cl-]
Solvent: COCCOC
Solvent: O
Product: CC1(C)C(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0 %

Procedure:
5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.98 g, 4.07 mol) and tetrakis(triphenylphosphine)palladium(0) (0.239 g) were stirred under an atmosphere of nitrogen in dimethoxyethane (35 cm3). After 15 min., 3-chlorophenylboronic acid (1.27 g, 8.13 mol) was added, followed by potassium carbonate (3.40 g, 45 mmol) in water (15 cm3). The reaction was heated to reflux for 2 hours and then stirred at room temperature overnight. The mixture was diluted with sat. ammonium chloride and extracted with EtOAc (×3). The combined organic layers were dried (MgSO4), filtered, and evaporated. The residue was purified by column chromatography (SiO2, EtOAc:hexane, 1:3) to afford the title compound (0.284 g, 25%): mp 188-189° C.; 1H NMR (DMSO-d6) δ 3.34 (s, 6H), 6.93 (d, 1H, J=8.04 Hz), 7.38-7.35 (m, 1H), 7.53-7.43 (m, 2H), 7.61 (d, 1H, J=7.68 Hz), 7.70 (s, 2H), 10.40 (s, 1H); IR (KBr) 3420, 3150, 3050, 1700 cm−1; MS (EI) m/z 270 (M−H)−; Anal. Calc. for C16H14ClNO+0.1C4H8O2: C, 70.21; H, 5.32; N, 4.99; Found: C, 70.3; H, 5.44; N, 4.93.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2I.[C:24](=O)([O-])[O-:25].[Cs+].[Cs+].CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C>CO.[Cu]I>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2[O:25][CH3:24]
Reactant: O=C([O-])[O-]
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(C3OCCO3)ccc21
Agent: [Cu]I
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Agent: [Cs+]
Solvent: CO
Product: COc1nn(COCC[Si](C)(C)C)c2ccc(C3OCCO3)cc12
Temperature: 140 °C

Procedure:
To a microwave-flask containing 300 mg (0.672 mmol) 5-(1,3-dioxolan-2-yl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole (Example 5A), 438 mg (1.344 mmol) cesium carbonate and 32 mg (0.134 mmol) 3,4,7,8-tetramethyl-1,10-phenanthroline in methanol (4 ml) were added 13 mg (0.067 mmol) copper(I) iodide. The flask was placed in an ultrasonic bath, and argon was bubbled through for a period of five minutes. The flask was then sealed and heated to 140° C. for 2 h using microwave irradiation. The reaction mixture was filtered over celite which was washed with acetonitrile. The filtrates of a total of seven reactions at this scale were combined and purified by preparative RP-HPLC (acetonitrile/water gradient) to afford 940 mg (57% of th.) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH:15]=[CH:14][C:13]=2[O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[N:4][N:3]=1.[C:32]1([C@H:38]([NH2:40])[CH3:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16]([CH:15]=[CH:14][C:13]([O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[C:12]2[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([NH:40][C@@H:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH3:39])=[N:3][N:4]=2)=[CH:17][CH:18]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)c(-c3nnc(Cl)c4ccccc34)c2c1
Product: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)c(-c3nnc(N[C@H](C)c4ccccc4)c4ccccc34)c2c1
Temperature: 23 °C
Yield: 80.9 %

Procedure:
A solution of trifluoromethanesulfonic acid 1-(4-chlorophthalazin-1-yl)-7-methoxynaphthalen-2-yl ester (2.2 g, 4.7 mmol) in (R)-1-phenylethylamine (3.5 ml, 27 mmol) was stirred for 8 hrs at 130° C., then cooled to 23° C. The resulting viscous mixture was purified by flash chromatography on silica gel (toluene/EtOAc 5:1 to 3:1) to give 2.1 g (3.8 mmol) of the title compound as a 1:1 mixture of diastereomers as a light brown foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34](O)=[O:35])[N:21]([C@@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.[CH3:43][O:44][C:45](=[O:63])[C@@H:46]([NH2:62])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][C:57]([C:60]#[N:61])=[CH:56][CH:55]=2)=[CH:50][CH:49]=1>>[CH3:43][O:44][C:45](=[O:63])[C@@H:46]([NH:62][C:34]([C@@H:20]1[CH2:19][C:18]2[CH:17]=[C:16]3[O:37][CH2:38][C@H:13]([C:10]4[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]5[CH:39]=[CH:40][C:41]([Cl:42])=[C:2]([Cl:1])[CH:3]=5)=[CH:12][CH:11]=4)[O:14][C:15]3=[CH:24][C:23]=2[CH2:22][N:21]1[C@@H:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:26][CH3:27])=[O:35])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][C:57]([C:60]#[N:61])=[CH:56][CH:55]=2)=[CH:50][CH:49]=1
Reactant: CC[C@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Product: CC[C@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((R)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (75 mg) was coupled with (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester according to General Procedure L to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((R)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester (30 mg). LCMS (m/z): 866.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([CH:13]1[O:15][CH2:14]1)Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH:13]2[CH2:14][O:15]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: BrCC1CO1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1cc(Br)ccc1OCC1CO1
Temperature: 60 °C
Yield: 95.7 %

Procedure:
A mixture of 5-bromo-2-hydroxybenzaldehyde (10 g, 50 mmol), epibromohydrin (13.6 g, 100 mmol) and K2CO3 (10.3 g, 75 mmol) in DMF (50 ml) was heated at 60° C. for 2 h. The mixture was cooled to ambient temperature and water and EtOAc was added. The phases were separated and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography (isooctane/EtOAc) to give the title compound (12.3 g). MS m/z (rel. intensity, 70 eV) 256 (M+, 41), 201 (77), 200 (bp), 199 (84), 63 (60).
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH2:25][NH2:26])[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.[Cl:36][C:37]1[N:42]=[C:41]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)[N:40]=[C:39]([NH:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[N:38]=1.C(OC(=O)C)C.Cl>C(#N)C.C(O)(=O)C.C(OCC)(=O)C.O>[ClH:36].[F:50][C:47]1[CH:46]=[CH:45][C:44]([NH:43][C:41]2[N:42]=[C:37]([NH:26][CH2:25][C:23]3[N:22]=[CH:21][NH:20][CH:24]=3)[N:38]=[C:39]([NH:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[N:40]=2)=[CH:49][CH:48]=1
Reactant: Fc1ccc(Nc2nc(Cl)nc(Nc3ccccc3)n2)cc1
Reactant: NCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Fc1ccc(Nc2nc(NCc3c[nH]cn3)nc(Nc3ccccc3)n2)cc1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A 678 mg portion of [(1-trityl-1H-imidazol-4-yl)methyl]amine was dissolved in 10.0 ml of acetonitrile, and 0.52 ml of diisopropylethylamine and 316 mg of the 6-chloro-N-(4-fluorophenyl)-N′-phenyl-1,3,5-triazine-2,4-diamine synthesized in Reference Example 1 were added thereto and stirred at 80° C. for 3 days. After cooling down to room temperature, the reaction solution was mixed with water and extracted with ethyl acetate. The organic layer was washed with citric acid aqueous solution and saturated brine and dried using anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, and the thus obtained residue was applied to a silica gel column chromatography and eluted with chloroform:methanol (99:1) to obtain a crude product. This crude product was dissolved in 9 ml of acetic acid and 1 ml of water and stirred at 70° C. for 2 hours. After evaporation of the reaction solution under a reduced pressure, the residue was mixed with ethyl acetate and sodium bicarbonate aqueous solution in that order and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried using anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, and the thus obtained residue was applied to a silica gel column chromatography and eluted with chloroform:methanol (90:10) to obtain a crude product. This crued product was dissolved in ethyl acetate and mixed with 4 M hydrochloric acid ethyl acetate solution, and the thus formed crystals were collected by filtration and dried to obtain 306 mg of N-(4-fluorophenyl)-N′-(1H-imidazol-4-ylmethyl)-N″-phenyl-1,3,5-triazine-2,4,6-triamine hydrochloride as colorless crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([SH:6])=[CH:2]1.[CH2:7]([C:11]1([CH2:14][CH3:15])[CH2:13][NH:12]1)[CH2:8][CH2:9][CH3:10]>>[NH2:12][C:11]([CH2:14][CH3:15])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][S:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: Sc1ccsc1
Reactant: CCCCC1(CC)CN1
Product: CCCCC(N)(CC)CSc1ccsc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.3 %

Procedure:
To a solution of n-butyl lithium in hexane (194 ml 1.6M) under nitrogen at -78° C. was added diethyl ether(120 ml) and then dropwise 3-bromothiophene (28 ml). The reaction was warmed to -30° C. and then cooled to -50° C. and powdered sulfur (10 g) was added. The reaction was stirred 15 hours at room temperature and then a solution of potassium hydroxide (24 g) in 160 ml water was added and the ether layer was discarded. The aqueous layer was treated at -5° C. with 6N hydrochloric acid (125 ml) and extracted with dichloromethane and the extract was dried over magnesium sulfate. Filtration and solvent removal afforded crude 3-thiophenthiol (14.1 g). The crude 3-thiophenthiol (10 g) was combined with 2-butyl-2-ethylaziridine (12.6 g, Synthetic Example 1(f)) at 0° C. and the reaction was stirred 15 hours at room temperature. The crude reaction product was purified by column chromatography on silica using 5% methanol in diethyl ether as eluant to give the desired product as an oil (16.4 g). 1H NMR is consistent with proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[C:6]1[N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24](O)=[O:25])[CH2:19]1.[NH2:32][CH2:33][CH2:34][OH:35].CCOC(C)=O.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[C:6]1[N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:32][CH2:33][CH2:34][OH:35])=[O:25])[CH2:19]1
Reactant: NCCO
Reactant: Cn1c(=O)c2c(nc(N3CCCC(C(=O)O)C3)n2Cc2c(F)cccc2Cl)n(C)c1=O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1c(=O)c2c(nc(N3CCCC(C(=O)NCCO)C3)n2Cc2c(F)cccc2Cl)n(C)c1=O
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
A solution of 1-[7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperidine-3-carboxylic acid (30 mg, 0.066 mmol) in 1.0 mL of CH2Cl2 at room temperature was treated with polystyrene-carbodiimide (1.15 mmol/g, 104 mg, 0.12 mmol) and stirred for 30 min. The reaction mixture was treated with 2-aminoethanol (0.004 mL, 0.066 mmol), allowed to rotate overnight, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC chromatography eluting with 5:5:1/hexanes:EtOAc:MeOH to give 11 mg (33% yield) of the title compound: 1H NMR (CDCl3, 400 MHz) δ 7.26-7.14 (m, 2H), 7.00-6.93 (m, 1H), 6.17 (br s), 5.58 (d, 2H, J=1.5), 3.70 (t, 2H, J=5.1), 3.51 (s, 3H), 3.47-3.36 (m, 3H), 3.31 (s, 3H), 3.23 (br d, 1H, J=12.3), 3.12 (dd, 1H, J=12.8, 10.3), 2.97-2.88 (m, 1H), 2.42-2.32 (m, 1H), 1.94-1.86 (m, 1H), 1.82-1.45 (m, 4H); LRMS (ESI) m/z 493 (M+H+); TLC (hexanes:EtOAc:MeOH/5:5:1) Rf=0.12.