Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([N:32]=[C:33]=[O:34])[CH:12]=[C:13]([Cl:31])[C:14]=1[O:15][C:16]([F:30])([F:29])[CH:17]([O:19][C:20]([F:28])([F:27])[C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[F:18].[CH3:35][N:36]1[C:43](=[O:44])[CH2:42][C:40](=[O:41])[N:39]([CH3:45])[C:37]1=[O:38].C(Cl)Cl>C1(C)C=CC=CC=1>[CH3:45][N:39]1[C:40](=[O:41])[CH:42]([C:33](=[O:34])[NH:32][C:11]2[CH:10]=[C:9]([Cl:8])[C:14]([O:15][C:16]([F:29])([F:30])[CH:17]([O:19][C:20]([F:28])([F:27])[C:21]([F:25])([F:26])[CH:22]([F:23])[F:24])[F:18])=[C:13]([Cl:31])[CH:12]=2)[C:43](=[O:44])[N:36]([CH3:35])[C:37]1=[O:38]
Reactant: O=C=Nc1cc(Cl)c(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)F)c(Cl)c1
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)C(C(=O)Nc2cc(Cl)c(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)F)c(Cl)c2)C(=O)N(C)C1=O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
1.04 g (10.3 mmol) of triethylamine and then 9.25 g (20.5 mmol) of 3,5-dichloro-(4-(2-(1,1,2,2,3,3-hexafluoropropoxy)-1,1,2-trifluoroethoxy))-phenyl isocyanate were added to 3.20 g (20.5 mmol) of 1,3-dimethylbarbituric acid in 40 ml of toluene at room temperature. The mixture was subsequently stirred at 40° C. for 2 hours, 200 ml of methylene chloride were added and the mixture was washed with 100 ml of 2N aqueous hydrochloric acid and several times with water. After drying over magnesium sulfate, the mixture was concentrated.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH:16]1[C:25]([OH:27])=[O:26])=[O:14]>CO.O.C(O)C.O>[NH2:3][CH2:12][C:13]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH:16]1[C:25]([OH:27])=[O:26])=[O:14]
Reactant: O=C(O)C1CCc2ccccc2N1C(=O)CN1C(=O)c2ccccc2C1=O
Solvent: CO
Solvent: CCO
Solvent: O
Product: NCC(=O)N1c2ccccc2CCC1C(=O)O
Reaction time: 0.25 h
Yield: 38.3 %

Procedure:
To a stirred mixture of the compound of Example I (75.2 g, 0.206 mole) and methanol (400 ml) was added 85% N2H4.H2O (12.7 ml, 0.220 mole) dissolved in methanol (30 ml) dropwise over 0.5 hours. After stirring under ambient conditions for 15 minutes, the solution was heated to reflux. Reflux was maintained for 6.0 hours, then allowed to cool overnight at 0°. The crystalline solid was collected, washed with methanol (50 ml) and air dried to give 68.0 g. This solid (68.0 g) was stirred in H2O (175 ml) for 2.0 hours, then filtered. The insoluble solid was washed with H2O (2×5 ml). The filtrate and washing were combined and concentrated under high vacuum to 1/3 its volume. This was diluted with abs. ethanol (150 ml) and concentrated under reduced pressure to a solid residue. This residue was triturated in abs. ethanol (100 ml), collected by filtration and air dried to give 25.2 g. This crude solid was stirred in ethanol/H2O (9:1, 300 ml) for 2.0 hours, filtered and air dried to give 18.6 g (0.079 mole, 38% yield) of title product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](Cl)=[N:13][CH:12]=1.[CH2:19]([NH2:24])[CH2:20][CH2:21][CH2:22][NH2:23]>>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([NH:23][CH2:22][CH2:21][CH2:20][CH2:19][NH2:24])=[N:13][CH:12]=1
Reactant: Nc1cc(F)ccc1NC(=O)c1ccc(Cl)nc1
Reactant: NCCCCN
Product: NCCCCNc1ccc(C(=O)Nc2ccc(F)cc2N)cn1
Yield: 47 %

Procedure:
N-(2-Amino-4-fluorophenyl)-6-chloronicotinamide (266 mg, 1 mmol) and 7 ml of 1,4-butanediamine were heated to 80° C. for 3 hours. The excess 1,4-butanediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (149 mg, 47% yield) as a brown solid. LC-MS (m/z) 318 (M+1).
Reaction SMILES: BrC1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)(O[C@@H](CCN4C=C(B5OC(C)(C)C(C)(C)O5)C=N4)C)OCC)=CC=3OC)N=2)=CC=1.[Br:57][C:58]1[N:63]=[C:62]([C:64](=[O:67])[NH:65][CH3:66])[C:61]([NH:68][C:69]2[C:74]([C:75]([F:78])([F:77])[F:76])=[CH:73][N:72]=[C:71]([NH:79][C:80]3[CH:93]=[CH:92][C:83]([CH2:84][P:85](=[O:91])([OH:90])[O:86][CH:87]([CH3:89])[CH3:88])=[CH:82][C:81]=3[O:94][CH3:95])[N:70]=2)=[CH:60][CH:59]=1.[CH3:96][C:97]([CH3:115])([CH2:100][N:101]1[CH:105]=[C:104]([B:106]2[O:110][C:109]([CH3:112])([CH3:111])[C:108]([CH3:114])([CH3:113])[O:107]2)[CH:103]=[N:102]1)[CH2:98]O>>[Br:57][C:58]1[N:63]=[C:62]([C:64](=[O:67])[NH:65][CH3:66])[C:61]([NH:68][C:69]2[C:74]([C:75]([F:78])([F:76])[F:77])=[CH:73][N:72]=[C:71]([NH:79][C:80]3[CH:93]=[CH:92][C:83]([CH2:84][P:85](=[O:90])([O:86][CH:87]([CH3:88])[CH3:89])[O:91][CH2:96][C:97]([CH3:115])([CH3:98])[CH2:100][N:101]4[CH:105]=[C:104]([B:106]5[O:110][C:109]([CH3:112])([CH3:111])[C:108]([CH3:114])([CH3:113])[O:107]5)[CH:103]=[N:102]4)=[CH:82][C:81]=3[O:94][CH3:95])[N:70]=2)=[CH:60][CH:59]=1
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CP(=O)(O)OC(C)C)cc2OC)ncc1C(F)(F)F
Reactant: CC(C)(CO)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)O[C@H](C)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CP(=O)(OCC(C)(C)Cn3cc(B4OC(C)(C)C(C)(C)O4)cn3)OC(C)C)cc2OC)ncc1C(F)(F)F
Yield: 39.8 %

Procedure:
Racemic Compound 73A was prepared analogously to Compound 69A by using propan-2-yl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 72B, 265 mg, 0.418 mmol) and 2,2-dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 47B, 117 mg, 0.418 mmol) to afford 149 mg of the title compound (40%). MS (ESI): m/z=895.81/897.83 [M+H]+. UPLC: tR=1.77 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[CH3:18].Cl>CN(C)C=O>[CH2:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[OH:1])[CH3:18]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C=O)cc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3,4-Dihydroxybenzaldehyde (101.6 g) and potassium carbonate (101.7 g) were suspended in N,N-dimethylformamide (500 mL). To the mixture was added dropwise ethyl iodide (58.8 mL) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added dropwise 2 mol/L hydrochloric acid (500 mL), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/1) to give the title compound (74.3 g).
Reaction SMILES: C[O:2][CH:3]=[CH:4][C@H:5]([N:7]1[C:12](=[O:13])[C:11]([C:14]2[N:18]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[N:17]=[CH:16][CH:15]=2)=[C:10]([CH3:27])[N:9]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[C:8]1=[O:38])[CH3:6].Cl.O.C(OCC)(=O)C>O1CCCC1>[CH3:27][C:10]1[N:9]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[C:8](=[O:38])[N:7]([C@@H:5]([CH2:4][CH:3]=[O:2])[CH3:6])[C:12](=[O:13])[C:11]=1[C:14]1[N:18]([C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)[N:17]=[CH:16][CH:15]=1
Reactant: COC=C[C@@H](C)n1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n([C@H](C)CC=O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 105.8 %

Procedure:
To a solution of (R)-4-(5-(3-(4-methoxy-3-buten-2-yl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 397) (300 mg) in tetrahydrofuran (3.0 ml) was added 1N hydrochloric acid (10 ml) and the resulting mixture was stirred at 50° C. for two hours. To the reaction mixture was added water (10 ml) followed by an addition of ethyl acetate (20 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-4-(5-(6-methyl-2,4-dioxo-3-(4-oxobutane-2-yl)-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (309 mg). UPLC/MS 508 (M+H)/1.06 min (measurement condition 9)
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH:3]([N:6]2[C:12](=[O:13])[NH:11][C:9](=[O:10])[C:8]([F:14])=[CH:7]2)[CH2:2]1.N.C([N+](CCC)(CCC)CCC)CC.[N+]([O-])([O-])=O.[Pd+2:33].[N+]([O-])([O-])=O>O>[Pd:33].[CH2:1]1[CH2:5][O:4][CH:3]([N:6]2[C:12](=[O:13])[NH:11][C:9](=[O:10])[C:8]([F:14])=[CH:7]2)[CH2:2]1
Reactant: [Pd+2]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: N
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: [Pd]
Reaction time: 0.5 h

Procedure:
The wet cake from Step A is charged to a mixing tank containing de-ionized water under sustained agitation to completely disperse the TS-1 crystals. This takes approximately 20 to 60 minutes. The pH is measured and adjusted with aqueous ammonia to a value of 9.5. The typical pH of TS-1 wet cake with tetrapropylammonium template in water is approximately 9. Aqueous tetraammine palladium nitrate is added to the mixing tank and the contents are agitated for 30 minutes while monitoring the pH. Sufficient tetraammine palladium nitrate is used to provide 0.1 wt % Pd on the TS-1. The TS-1 crystal slurry is transferred to Step C.
Reaction SMILES: [NH2:1][C@@:2]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)([CH3:28])[C@@:3]([NH:12][C:13](=O)[C:14]1[C:19]([O:20][CH2:21][CH3:22])=[CH:18][C:17]([C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16][CH:15]=1)([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[CH3:4].P(Cl)(Cl)(Cl)=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C@@:2]2([CH3:28])[C@:3]([C:5]3[CH:6]=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=3)([CH3:4])[NH:12][C:13]([C:14]3[C:19]([O:20][CH2:21][CH3:22])=[CH:18][C:17]([C:23]([CH3:25])([CH3:24])[CH3:26])=[N:16][CH:15]=3)=[N:1]2)=[CH:30][CH:31]=1
Reactant: CCOc1cc(C(C)(C)C)ncc1C(=O)N[C@@](C)(c1ccc(Cl)cc1)[C@](C)(N)c1ccc(Cl)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1
Temperature: 25 °C

Procedure:
rac-N-[(1S*,2R*)-2-Amino-1,2-bis-(4-chloro-phenyl)-1-methyl-propyl]-6-tert-butyl-4-ethoxy-nicotinamide (200 mg, 0.4 mmol) was dissolved in toluene (8 mL) and phosphorus oxychloride (0.2 mL, 0.83 mmol) was added. The reaction mixture was refluxed under nitrogen overnight. It was allowed to cool to room temperature and poured into ice water, basified with saturated solution of sodium sulfate (10 mL). Reaction mixture was extracted with ethyl acetate (2×20 ml) and methylene chloride (2×10 mL). The combined organic layers were washed with brine and water, dried with magnesium sulfate, filtered and evaporated. Purification was by chromatography (silica gel, eluting with 0-30% ethyl acetate/methylene chloride, then 5% methanol/methylene chloride) to give rac-5-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-2-tert-butyl-4-ethoxy-pyridine as a solid. (20 mg). LR-MS: 496 [(M+H)+]
Reaction SMILES: [F:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1.[Li+].CC([N-]C(C)C)C.[Cl:22][C:23]1[CH:24]=[C:25]([O:36][S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])[CH:26]=[C:27]([Cl:35])[C:28]=1[CH2:29]OS(C)(=O)=O>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([O:36][S:37]([C:40]([F:42])([F:43])[F:41])(=[O:39])=[O:38])[CH:26]=[C:27]([Cl:35])[C:28]=1[CH2:29][CH:10]1[CH2:11][CH2:12][N:8]([C@H:5]2[CH2:6][CH2:7][C@H:2]([F:1])[CH2:3][CH2:4]2)[C:9]1=[O:13]
Reactant: O=C1CCCN1[C@H]1CC[C@H](F)CC1
Reactant: CS(=O)(=O)OCc1c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1[C@H]1CC[C@H](F)CC1
Reaction time: 8 h

Procedure:
To a solution of trans-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one (252 mg, 1.36 mmol) in 13 mL dry THF, add 1.09 mL of 2M LDA (1.2 eq.) in THF dropwise at −78° C. Then, add 821 mg of trifluoro-methanesulfonic acid 3,5-dichloro-4-methanesulfonyloxymethyl-phenyl ester (1.5 eq) at −78° C. Allow the resulting solution to stand at room temp for overnight. Quench the mixture with saturated aqueous NH4Cl and extract with CH2Cl2. Wash the organic layer with water, then brine, and dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford the title compound: mass spectrum (m/z): 358 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].F[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1.O>CN(C=O)C.CCCCCC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.3 %

Procedure:
4-Benzyloxy-phenol (500 mg, 2.50 mmol) was dissolved in 7 mL of DMF. K2CO3 (414 mg 3.00 mmol) was added and the resulting mixture was stirred at room temperature for 10 mins. 4-Fluorobenzaldehyde (371 mg, 3.00 mmol) was added and the resulting mixture was stirred at 50° C. for 2 hours. The reaction mixture was then heated to 80° C. for 3 hours. Water was then added and the product was extracted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 710 mg of crude product. Purification by column chromatography (using silica gel of mesh size of 60-120 and 3/97 EtOAc:Hexane as the eluent) afforded 550 mg (72% yield) of 4-(4-Benzyloxy-phenoxy)-benzaldehyde. LC-MS purity: 99.5%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.[C:41]1([N:47]=[C:48]=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([NH:29][C:48]([NH:47][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:49])=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=[CH:39][CH:40]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(N)nc3)n2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(NC(=O)Nc4ccccc4)nc3)n2)cc1
Yield: 38.5 %

Procedure:
A solution of N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-yl)pyridine-2,5-diamine (0.150 g, 0.281 mmol) and phenyl isocyanate (Fluka) (0.077 mL, 0.70 mmol) in THF (3 mL) was stirred at rt for 5 h. The resulting solid was collected by filtration to give 1-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-ylamino)pyridin-2-yl)-3-phenylurea (0.0707 g) as a yellow solid. The filtrate and wash were concentrated and purified by silica gel chromatography (25 g, eluent: EtOAc in hexanes 0%-30%) to give a second batch of the product (0.0924 g). The total yield was 0.1631 g, 89%. 1H NMR (300 MHz, CDCl3) δ 11.83 (s, 1H); 11.66 (br. s., 1H); 8.80-8.89 (m, 1H); 8.41 (br. s., 1H); 8.27-8.36 (m, 1H); 7.88-7.99 (m, 1H); 7.62 (d, J=8.18 Hz, 2H); 7.31-7.41 (m, 3H); 7.15-7.24 (m, 4H); 7.03-7.12 (m, 1H); 6.75-6.93 (m, 5H); 6.64-6.73 (m, 1H); 4.85 (br. s., 4H); 3.79 (d, J=10.96 Hz, 6H); 2.61 (s, 3H). m/z (ESI, +ve ion) 654.0 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[C:13]([F:32])=[CH:14][C:15]([C:26]4[CH2:27][CH2:28][O:29][CH2:30][CH:31]=4)=[CH:16][C:17]=3[C:18]32[CH2:24][O:23][C:22]([NH2:25])=[N:21]3)=[CH:9][CH:8]=1)(=O)=O.[N:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>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.CN(C=O)C>[O:29]1[CH2:30][CH:31]=[C:26]([C:15]2[CH:14]=[C:13]([F:32])[C:12]3[O:11][C:10]4[C:19](=[CH:20][C:7]([C:39]5[CH:40]=[N:35][CH:36]=[N:37][CH:38]=5)=[CH:8][CH:9]=4)[C@:18]4([CH2:24][O:23][C:22]([NH2:25])=[N:21]4)[C:17]=3[CH:16]=2)[CH2:27][CH2:28]1
Reactant: OB(O)c1cncnc1
Reactant: NC1=NC2(CO1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
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: CN(C)C=O
Product: NC1=N[C@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
Temperature: 75 °C

Procedure:
A vial was charged with 2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (150 mg, 0.300 mmol), pyrimidin-5-ylboronic acid (111 mg, 0.899 mmol), and Pd(PPh3)4 (34.6 mg, 0.030 mmol). The vial was purged with Ar (g), then DMF (2 mL) and potassium carbonate (0.749 mL, 1.499 mmol) (as a 2.0 M aq. solution) were added in sequence. The vial was capped and heated in a Biotage Initiator microwave reactor for 1.5 h at 75° C. The product was purified via Gilson HPLC (gradient elution 20-90% MeCN/H2O, 0.1% TFA) to afford (R)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an off white solid. Found MS: MH+=431.
Reaction SMILES: [Br:1][C:2]1[C:3]([Br:30])=[CH:4][C:5]2[N:11]([C:12](=[O:23])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]3)[C:10]3[N:24]=[CH:25][CH:26]=[CH:27][C:9]=3[C:8](=S)[NH:7][C:6]=2[CH:29]=1.[C:31](OCC)(=[O:34])[NH:32][NH2:33]>>[Br:1][C:2]1[C:3]([Br:30])=[CH:4][C:5]2[N:11]([C:12](=[O:23])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]3)[C:10]3[N:24]=[CH:25][CH:26]=[CH:27][C:9]=3[C:8]3[N:7]([C:31](=[O:34])[NH:32][N:33]=3)[C:6]=2[CH:29]=1
Reactant: CCOC(=O)NN
Reactant: O=C(CN1CCN(CCO)CC1)N1c2cc(Br)c(Br)cc2NC(=S)c2cccnc21
Product: O=C(CN1CCN(CCO)CC1)N1c2cc(Br)c(Br)cc2-n2c(n[nH]c2=O)-c2cccnc21

Procedure:
In the manner given in Example 13, 8,9-dibromo-6,11-dihydro-11-[[4-(2-hydroxyethyl)piperazino]acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione is heated to about 200° C. with ethyl carbazate to give 6,7-dibromo-2,9-dihydro-9-[[4-(2-hydroxyethyl)piperazino]acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:15][C:16]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:17]=1[C:18]([NH:20][CH2:21][CH:22]([O:25]C)OC)=O>CS(O)(=O)=O>[Cl:15][C:16]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:17]=1[C:18]1[O:25][CH:22]=[CH:21][N:20]=1
Reactant: COC(CNC(=O)c1cc([N+](=O)[O-])ccc1Cl)OC
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=[N+]([O-])c1ccc(Cl)c(-c2ncco2)c1
Temperature: 142.5 °C
Yield: 94.2 %

Procedure:
Under nitrogen, phosphorus pentoxide (0.98 g, 6.90 mmol) was added portionwise to a slurry of 2-chloro-N-(2,2-dimethoxy-ethyl)-5-nitro-benzamide (0.5 g, 1.73 mmol) in methanesulfonic acid (5 mL) at r.t. The mixture was heated to 140-145° C. for 6 h. After cooling to r.t., the mixture was poured onto ice-water and extracted with ethyl acetate. The combined organic phases were washed with water then brine, dried over sodium sulfate, filtered and concentrated in vacuo. Further drying under high vacuum gave 2-(2-chloro-5-nitrophenyl)-oxazole (0.366 g, 94%) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[O:14][N:13]=[C:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[CH:11]=3)=[N:7][C:6]=2[CH:27]=1.[CH2:28](I)[CH3:29]>>[CH2:28]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[O:14][N:13]=[C:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH3:18])[CH:11]=3)=[N:7][C:6]=2[CH:27]=1)[CH3:29]
Reactant: C[C@@H](COc1cc(-c2nc3cc(O)ccc3o2)on1)NC(=O)OC(C)(C)C
Reactant: CCI
Product: CCOc1ccc2oc(-c3cc(OC[C@H](C)NC(=O)OC(C)(C)C)no3)nc2c1

Procedure:
Using tert-butyl [(1S)-2-{[5-(5-hydroxy-1,3-benzoxazol-2-yl)isoxazol-3-yl]oxy}-1-methylethyl]carbamate and ethyl iodide, and in the same manner as in Example 2, step E, the title compound was obtained.
Reaction SMILES: C(OC(=O)N[CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:40])[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][N:37]=[N+:38]=[N-:39])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(C)(C)C.C(Cl)Cl.[C:45]([OH:51])(C(F)(F)F)=[O:46]>>[N:37]([CH2:36][CH2:35][CH2:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][C:45]([OH:51])=[O:46])=[CH:25][CH:24]=2)=[O:40])=[CH:28][CH:29]=1)=[N+:38]=[N-:39]
Reactant: CC(C)(C)OC(=O)NCCOCCOCCOCCNc1ccc(C(=O)c2ccc(OCCCN=[N+]=[N-])cc2)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=NCCCOc1ccc(C(=O)c2ccc(NCCOCCOCCOCCC(=O)O)cc2)cc1
Reaction time: 1 h
Yield: 97 %

Procedure:
tert-butyl-(2-(2-(2-(2-((4-(4-(3-azidopropoxy)benzoyl)phenyl)-amino)ethoxy)ethoxy)ethoxy)ethyl)-carbamate (1.75 g, 2.91 mmol) was dissolved in a solution of DCM:TFA (2:1, 12 ml) and left to stir for ca. 1 h. Upon completion, reaction was then concentrated under reduced pressure, co-evaporated with toluene, and left on oil pump for 5 hs to yield 1.52 g (97.0% yield) of (2-(2-(2-(2-((4-(4-(3-azidopropoxy)benzoyl)phenyl)-amino)ethoxy)ethoxy)ethoxy)ethyl)carboxylic acid as colorless oil.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]([OH:19])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CC[N:22]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl-].[NH4+]>CN(C=O)C.O>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]([NH2:22])=[O:19])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(C(=O)O)c1-c1ccc(F)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(C(N)=O)c1-c1ccc(F)cc1
Yield: 87.5 %

Procedure:
A solution of the compound (16.87 g, 64.32 mmol) obtained in step 2, WSC (16.03 g, 83.62 mmol), HOBt (11.30 g, 83.62 mmol), TEA (11.65 mL, 83.62 mmol) and ammonium chloride (4.47 g, 83.62 mmol) in DMF (200 mL) was stirred at room temperature for 2 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→85% ethyl acetate/hexane) to give 1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (14.72 g, 56.3 mmol, 88%) as a white powder.