Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](Cl)=[N:6][CH:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>CCCCO.CCOC(C)=O>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: Cn1c(Cl)ncc(Br)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cn1c(Nc2ccccc2)ncc(Br)c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
A mixture of 5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one (0.510 g, 2.282 mmol), aniline (0.271 ml, 2.967 mmol) and NaHCO3 (0.767 g, 9.129 mmol) in n-BuOH (15 mL) was stirred at 60° C. for 16 hours. The reaction mixture was cooled to room temperature and then diluted with EtOAc. The EtOAc layer was washed with H2O and saturated aqueous NaCl. The aqueous phase was re-extracted with EtOAc (1×). The combined EtOAc layers were dried (Na2SO4), filtered and concentrated to yield the desired product (0.636 g, 99%) as a pale yellow solid that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.95 (br s, 1H), 7.94 (s, 1H), 7.47 (m, 2H), 7.35 (m, 2H), 7.14 (m, 1H), 3.53 (s, 3H). LRMS (ESI pos) m/e 280, 281 (M+, Br pattern).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].O>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]3)=[CH:18][CH:17]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: COc1ccc(-c2ccc3[nH]c(C(=O)O)cc3c2)cc1
Yield: 92 %

Procedure:
The general procedure described in Example 3 was used with 5-chloro-1H-indole-2-carboxylic acid (194 mg, 1.00 mmol), 4-methoxyphenylboronic acid (207 mg, 1.50 mmol), Pd(OAc)2 (2.2 mg, 0.010 mmol, 1 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (10.0 mg, 0.020 mmol, 2 mol %), K2CO3 (414 mg, 3.00 mmol), water (2.0 mL), 12 h, 80° C. The product was isolated as a light yellow solid (246 mg, 93%). Mp=>230° C. 1H NMR (400 MHz, d6-DMSO) δ: 11.81 (s, 1H), 7.84 (s, 1H), 7.58 (d, 2H, J=8.8 Hz), 7.49 (m, 2H), 7.13 (d, 1H, J=1.6 Hz), 6.99 (d, 2H, J=8.4 Hz), 3.78 (s, 3H). 13C NMR (125 MHz, d6-DMSO) δ: 162.7, 158.3, 136.3, 133.7, 132.2, 129.0, 127.7, 127.5, 123.7, 119.1, 114.3, 112.8, 107.7, 55.1. IR (neat, cm−1): 4320, 1700, 1183. Anal. Calcd for C16H13NO3: C, 71.90; H, 4.90. Found: C, 71.94; H, 4.93.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[N+:13]([C:16]1[C:21]([O:22][CH3:23])=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=[C:18]([C:27]([F:30])([F:29])[F:28])[C:17]=1Cl)([O-:15])=[O:14]>>[Cl:8][C:7]1[C:2]([NH:1][C:17]2[C:18]([C:27]([F:30])([F:29])[F:28])=[CH:19][C:20]([N+:24]([O-:26])=[O:25])=[C:21]([O:22][CH3:23])[C:16]=2[N+:13]([O-:15])=[O:14])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:10])[F:11])[CH:6]=1
Reactant: Nc1ncc(C(F)(F)F)cc1Cl
Reactant: COc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Product: COc1c([N+](=O)[O-])cc(C(F)(F)F)c(Nc2ncc(C(F)(F)F)cc2Cl)c1[N+](=O)[O-]

Procedure:
In accordance with the process of Preparation 8 except using 1.9 g. of 2-amino-3-chloro-5-trifluoromethylpyridine and 2.8 g. of 2,4-dinitro-3-methoxy-6-trifluoromethylchlorobenzene, the reaction was carried out for 3 hours. The reaction mixture was treated as the process of Preparation 6 to obtain 1.4 g. of the object oily compound.
Reaction SMILES: COC1C=CC=CC=1[C:9]1[CH:14]=[C:13]([N+]([O-])=O)[CH:12]=[CH:11][C:10]=1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][C:22]=1C1C=CC=CC=1OC)(=[O:20])=[O:19].[OH-].[Na+].[CH2:40]([OH:42])C>>[CH3:40][O:42][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:18]([C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=1)(=[O:19])=[O:20]
Reactant: COc1ccccc1-c1cc([N+](=O)[O-])ccc1S(=O)(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1OC
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1S(=O)(=O)c1ccc(N)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a stirred slurry of 2-methoxyphenyl-4-nitrophenyl sulfone (12.36 g, 4.2 mmol) and 90 mL of absolute ethanol was added stannous chloride dihydrate (47.4 g, 21 mmol) in one portion. The mixture was heated to 50° C. where an exothermic reaction caused the solution to strongly reflux. The mixture was allowed to stir at ambient temperature for 30 min., poured onto ice-water and made strongly basic by the addition of 350 mL of 15% NaOH. The mixture was extracted with methylene chloride (3×275 mL), the extracts dried (MgSO4), filtered, and the solvent removed in vacuo to yield a white solid which was recrystallized from ethyl acetate-hexane. After cooling the solid was filtered to yield the title benzenamine (5.38 g, 49%) as a white solid; mp 206°-208° C. 1H-NMR (300 MHz, d6 -DMSO): 3.75 (s, 3H, OCH3), 6.10 (s, 2H, NH2), 6.56-6.61 (m, 2H, aromatic), 7.07-7.13 (m, 2H, aromatic), 7.49-7.61 (m, 3H, aromatic), 7.90 (dd, 1H, J =8.1 & 1.7 Hz, aromatic). MS (CI, CH4): 264 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13]([C:24](O)=[O:25])[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:27][N:28]([CH3:39])[S:29]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:24]([OH:25])[C:13]3[C:12](=[C:17]([C:18]([NH:36][C:35]4[CH:37]=[CH:38][C:32]([S:29](=[O:31])(=[O:30])[N:28]([CH3:27])[CH3:39])=[CH:33][CH:34]=4)=[O:20])[CH:16]=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)S(=O)(=O)c1ccc(N)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(Cl)c(Cl)c3)nc12
Product: CN(C)S(=O)(=O)c1ccc(NC(=O)c2cc([N+](=O)[O-])cc3c(O)nc(Nc4ccc(Cl)c(Cl)c4)nc23)cc1

Procedure:
The title compound was prepared in a manner analogous to Example 1 from 2-((3,4-dichlorophenyl)amino)-4-hydroxy-6-nitroquinazoline-8-carboxylic acid and 4-(N,N-dimethyl)sulfamoylaniline. 1H NMR (300 MHz, DMSO-d6):. 11.87 (s, 1H), 10.45 (s, 1H), 8.90 (d, J=2.7 Hz, 1H), 8.80 (d, J=2.7 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.65 (d, J=8.7 Hz, 2H), 7.54 (d, J=8.7 Hz, 2H 2.64 (s, 6H). MS (APCI+): m/z 577, 579.
Reaction SMILES: [CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:25]3[C:20](=[C:21]([F:26])[CH:22]=[CH:23][CH:24]=3)[C:19](=[O:27])[N:18]([NH:28][CH2:29][CH2:30][CH3:31])[C:17]=2[CH2:32]Br)=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[F-:34].[K+]>O>[CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:25]3[C:20](=[C:21]([F:26])[CH:22]=[CH:23][CH:24]=3)[C:19](=[O:27])[N:18]([NH:28][CH2:29][CH2:30][CH3:31])[C:17]=2[CH2:32][F:34])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCCNn1c(CBr)c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c2cccc(F)c2c1=O
Reactant: [F-]
Agent: [K+]
Solvent: O
Product: CCCNn1c(CF)c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c2cccc(F)c2c1=O

Procedure:
3-Bromomethyl-8-fluoro-1-oxo-2-propylamino-1,2-dihydro-isoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide (27 mg, 0.052 mmol) N,N-Dimethylformamide (2 mL) and potassium fluoride (0.015 g, 0.26) were stirred at room temperature overnight. The reaction mixture was poured into water. The mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by preparative HPLC to give the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[N:18][CH:19]=1.N1(C=O)CC[O:24][CH2:23]C1>C1COCC1>[Cl:13][C:14]1[CH:19]=[N:18][C:17]([F:20])=[C:16]([CH:15]=1)[CH:23]=[O:24]
Reactant: Fc1ccc(Cl)cn1
Reactant: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cc(Cl)cnc1F
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 73.8 %

Procedure:
To a cold (0° C.) solution of diisopropylamine (12.8 mL, 91.2 mmol) in THF (100 mL) was added butyllithium (31.9 mL of 2.5 M, 79.8 mmol) over 5 min. After 5 min, the reaction was cooled to −78° C. for 15 min. Then 5-chloro-2-fluoro-pyridine (10.0 g, 76.0 mmol) was slowly added over 5 min. The reaction was kept at −78° C. for an additional 1.5 hr. Then, morpholine-4-carbaldehyde (17.5 g, 152.1 mmol) was added rapidly. The mixture was stirred for a further 2 min and quenched with 10% citric acid and the mixture was allowed to warm to room temperature. The pH was adjusted to 5-6 with additional citric acid solution. The mixture was extracted with dichloromethane (3×200 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated. Flash chromatography (SiO2, 0-25% EtOAc-Hexanes, gradient elution) provided the desired product as an off-white crystalline solid (8.95 g, 74% yield). LC-MS shows the mass for the desired product and the corresponding hydrate: 1H NMR (300 MHz, CDCl3) δ 10.28 (d, J=8.4 Hz, 1H), 8.41 (t, J=1.4 Hz, 1H) and 8.25 (dd, J=2.7, 7.8 Hz, 1H) ppm; LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, RT=2.45 min, (M+H) 159.91.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N+:6]([O-:13])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].[CH3:22]I>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:22])[C:7](=[O:12])[N+:6]([O-:13])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)[n+]1[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)[n+]([O-])c(-c2ccccc2)c2cc(Cl)ccc21
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
To a suspension of 5 g (0.018 mole) of 6-chloro-4-phenyl-2(1H)quinazolinone 3-oxide and 125 ml of N,N-dimethylformamide was added, at room temperature, 0.96 g of sodium hydride (50% in oil). The temperature rose to 30° and the stirring was continued for approximately 30 minutes to effect salt formation To this mixture was added, dropwise, 6 g (0.042 mole) of methyl iodide. Stirring was continued for approximately 2 hours and the solid was collected by filtration, washed with water and with 10 ml of 1N HCl to give 3.98 g (78%) of product identified as 6-chloro-1-methyl-4-phenyl-2(1H)-quinazoline 3-Oxide: mp 253°-254°. 1H nmr (CF3CO2H) δ 3.12 ppm (s, 3H); δ 6.5-7.3 (m, 8H, aromatic).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[C:7]([NH:10][C:11]1[S:12][C:13]([S:17](Cl)(=[O:19])=[O:18])=[C:14]([CH3:16])[N:15]=1)(=[O:9])[CH3:8].C(N(CC)CC)C>C1COCC1>[C:7]([NH:10][C:11]1[S:12][C:13]([S:17]([N:1]2[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]2)(=[O:18])=[O:19])=[C:14]([CH3:16])[N:15]=1)(=[O:9])[CH3:8]
Reactant: OC1CCNC1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)N2CCC(O)C2)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 68.3 %

Procedure:
To a stirred solution of (RS)-3-pyrrolidinol (0.51 g, 5.85 mmol) in THF (12 ml) was added at 0° C. (ice water bath) commercially available 2-acetamido-4-methylthiazole-5-sulfonyl chloride (1.0 g, 3.93 mmol) and triethylamine (0.6 ml, 4.32 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by flash chromatography on silica gel (dichloromethane/MeOH) and subsequent crystallization (dichloromethane/MeOH/hexane) to yield (RS)-1-(2-acetamido-4-methyl-thiazole-5-sulfonyl)-pyrrolidin-3-ol (0.82 g, 68%) as a white solid. MS (ISP) 306.3 [(M+H)+]; mp 241° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:32])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[C@H:28]([CH2:29][OH:30])[CH2:27][O:26][C:25]5=[O:31])=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:33]I>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:32])[C:7]([N:10]3[CH2:11][CH2:12][N:13]([C:16]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[C@H:28]([CH2:29][O:30][CH3:33])[CH2:27][O:26][C:25]5=[O:31])=[CH:22][CH:23]=4)=[O:17])[CH2:14][CH2:15]3)=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CI
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)cc2)CC1
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)cc1
Yield: 86.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-3-{4-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-4-hydroxymethyloxazolidin-2-one (655 mg) described in Example 299 and methyl iodide (255 mg), the title compound (583 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1>[CH2:26]([O:25][C:23](=[O:24])[NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2)[CH3:27]
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 80 °C
Yield: 27.9 %

Procedure:
To a stirred mixture of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.41 g, 1.3 mmol) in tetrahydrofuran (10 mL), was added ethyl chloroformate (0.45 mL, 4.7 mmol) and heated at 80° C. for three hours. The mixture was quenched with a few drops of methanol. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-carbamic acid ethyl ester as a white solid (130 mg, 27% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.26 min (99.2%); mp, 284-286° C. (decomposed); 1HNMR (DMSO-d6) 1.26 (t, J=7 Hz, 3H, CH2CH3), 2.15-2.19 (m, 1H, CHH), 2.58-2.90 (m, 6H, CHCH2, CH3), 4.16 (q, J=7 Hz, 2H, CH2CH3), 5.31 (dd, J=6, 11 Hz, 1H, CH), 7.23-8.24 (m, 3H, Ar), 11.08 (s, 1H, NH), 11.30 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.28, 20.72, 23.28, 30.53, 56.70, 60.99, 107.14, 113.36, 119.59, 135.73, 140.00, 147.95, 152.66, 154.73, 169.31, 172.54. LCMS MH=359; Anal Calcd For C17H18N4O5+0.8H2O: C, 54.78; H, 5.30; N, 15.03. Found: C, 54.67; H, 4.99; N, 14.80.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][CH:9]2[C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.[NH2:37][C:38]1[NH:39][C:40]2[CH:46]=[C:45]([C:47]#[N:48])[CH:44]=[CH:43][C:41]=2[N:42]=1>CN(C=O)C>[C:47]([C:45]1[CH:44]=[CH:43][C:41]2[N:42]=[C:38]([NH:37][C:11]([CH:9]3[CH2:10][CH:8]3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[O:13])[NH:39][C:40]=2[CH:46]=1)#[N:48]
Reactant: O=C(O)C1CC1c1cccc(F)c1
Reactant: N#Cc1ccc2nc(N)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc(NC(=O)C3CC3c3cccc(F)c3)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(3-Fluoro-phenyl)-cyclopropanecarboxylic acid 2 (90 mg, 0.50 mmol) was dissolved in 10 ml DMF. 115 mg (0.6 mmol) 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and 81 mg (0.6 mmol) 1-Hydroxybenzotriazole (HOBT) were added. The mixture was stirred for 30 min at room temperature (RT). Then 97 mg (0.5 mmol) 2-Amino-3H-benzoimidazole-5-carbonitril hydrochloride 1 were added to the mixture, which was stirred for 16 h at RT. After removing the solvent in vacuo, 20 ml water were added, whereupon the mixture was extracted 3 times with 50 ml acetic acid ethylester. The organic phases were combined, dried with sodium sulfate, and evaporated to dryness. The residue was separated via preparative HPLC. The resulting clean fractions were concentrated and lyophilized. 91 mg (57%) of a colorless, amorphous solid 3 were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:13]([OH:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.OC(C(F)(F)F)=O.[NH2:47][C@@H:48]([CH2:66][C:67]1[CH:72]=[CH:71][C:70]([O:73][CH3:74])=[CH:69][CH:68]=1)[C:49]([NH:51][C@@H:52]([CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:53]([C@@:55]1([CH3:58])[CH2:57][O:56]1)=[O:54])=[O:50].CCN(C(C)C)C(C)C>CN(C=O)C>[OH:15][C@@H:13]([CH3:14])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([NH:47][C@@H:48]([CH2:66][C:67]1[CH:68]=[CH:69][C:70]([O:73][CH3:74])=[CH:71][CH:72]=1)[C:49]([NH:51][C@@H:52]([CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:53]([C@@:55]1([CH3:58])[CH2:57][O:56]1)=[O:54])=[O:50])=[O:12]
Reactant: C[C@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1ccc(C[C@H](N)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)O)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Reaction time: 0.08 h

Procedure:
To (2S,3S)-2-((tert-butoxycarbonyl)amino)-3-hydroxybutanoic acid (453 mg, 2.07 mmol) in DMF (10 mL) at 0° C. was added HATU (865 mg, 2.28 mmol). The mixture was stirred for 5 min to dissolve the solids at which time (S)-2-amino-3-(4-methoxyphenyl)-N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)propanamide TFA salt (2.07 mmol assumed) and DIEA (1.71 mL, 10.35 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated to provide crude tert-butyl ((2S,3S)-3-hydroxy-1-(((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)carbamate as a yellow oil that was carried forward without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:13]=[C:12]([C:21]([OH:23])=O)[CH:11]=1)=[O:8].[CH:26]1([NH2:29])[CH2:28][CH2:27]1.N1C=CC=CC=1.CCCP(O)(O)=O.C(=O)([O-])[O-].[K+].[K+]>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:13]=[C:12]([C:21]([NH:29][CH:26]2[CH2:28][CH2:27]2)=[O:23])[CH:11]=1)=[O:8]
Reactant: O=C(O)c1cc(NC(=O)c2cc(Br)ccc2Cl)n(-c2ccccc2)n1
Reactant: NC1CC1
Agent: CCCP(=O)(O)O
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Product: O=C(NC1CC1)c1cc(NC(=O)c2cc(Br)ccc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 131.4 %

Procedure:
To 5-(5-bromo-2-chlorobenzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Preparation 12, 200 mg, 0.48 mmol), cyclopropylamine (137 mg, 2.40 mmol) and pyridine (114 mg, 1.44 mmol) in methyl THF (5 mL) was added 1-propylphosphonic acid cyclic anhydride (50% solution in EtOAc, 0.48 mL, 0.82 mmol) at room temperature. The reaction was stirred at room temperature for 17 hours. A 2M aqueous solution of potassium carbonate was added until the pH became basic and the solution was extracted with EtOAc (3×15 mL). The combined organic layers were concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with EtOAc to afford the title compound (290 mg, 88%).
Reaction SMILES: O1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:22]2[CH:5]=[N:4][N:3]=[C:2]2[C:6]2[CH:14]=[CH:13][C:9]3[NH:10][CH:11]=[N:12][C:8]=3[CH:7]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(CN)cc1
Reactant: c1nc2ccc(-c3nnco3)cc2[nH]1
Product: COc1ccc(Cn2cnnc2-c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from 5-(1,3,4-oxadiazol-2-yl)benzimidazole (186 mg, 1 mmol) and 4-methoxybenzylamine (0.5 ml) as described above; yield: 0.083 g (27.2%); MS m/z: 306.4 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.66 (s, 3H); 5.29 (s, 2H); 6.80-6.83 (m, 2H); 6.95-6.97 (m, 2H); 7.61 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 7.82 (d, 1H, 3J=8.7 Hz); 7.91 (d, 1H, 4J=1.7 Hz); 8.73 (s, 1H); 8.96 (s, 1H); HPLC (METHOD [A]): it 8.18 min (99.6%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH:22]([F:32])[C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29](=[O:30])[C:26]3[CH:25]=[CH:24][C:23]([CH:22]([F:32])[F:21])=[CH:28][N:27]=3)[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1ccc(C(F)F)cn1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(C(F)F)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 5-(difluoromethyl)picolinic acid [J. D. Scott et al. WO2011044181 (2011)] following General Procedure G yielded the title compound as a colorless amorphous solid. MS: m/z=447.5 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[C:15]([CH3:17])=[CH2:16])([CH3:4])([CH3:3])[CH3:2]>CCO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[CH:15]([CH3:17])[CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc(C(=O)OC)ccc1C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(C)(C)C)c(C(C)C)c1
Reaction time: 192 h
Yield: 85.9 %

Procedure:
To the ester 26.2 (167 mg, 0.72 mmol) in EtOH/EtOAc (1/1, v/v, 3.00 mL), was added Pd(OH)2/C (10 mg). The mixture was placed under an atmosphere of hydrogen and stirred for 8 days. The resulting mixture was filtered through Celite and concentrated in vacuo to give a clear oil (145 mg, 86%). The crude product (26.3) was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([CH3:11])[CH:3]=1.I[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=[C:13]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][C:4]=3[CH3:11])[C:21]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: Cc1cc(O)ccc1B(O)O
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: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1cc(O)ccc1-c1nn(C(C)C)c2ncnc(N)c12
Temperature: 80 °C
Yield: 44.9 %

Procedure:
A solution of 4-hydroxy-2-methylphenylboronic acid (110 mg, 0.66 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.33 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by silica gel column chromatography [MeOH—CH2Cl2, 2:98] to yield BA60 (42 mg, 22% yield). ESI-MS (M+H)+ m/z calcd 284, found 284.