Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S(O[CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C@@H:10]1[CH2:23]OS(CCC)(=O)=O)(=O)=O)CC.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(O)C.CO.[OH-].[Na+]>[CH2:31]([N:38]1[CH2:23][C@@H:10]2[C@H:9]([CH2:14][CH2:13][C@H:12]([OH:15])[C@H:11]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:8]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCc1ccccc1
Reactant: CCCS(=O)(=O)OC[C@H]1CC[C@H](O)[C@@H](c2ccccc2C)[C@@H]1COS(=O)(=O)CCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: Cc1ccccc1[C@H]1[C@@H]2CN(Cc3ccccc3)C[C@H]2CC[C@@H]1O
Temperature: 140 °C

Procedure:
In a pressure tube was placed a solution of crude [(1S,2R,3R,4S)-4-hydroxy-3-(2-methylphenyl)cyclohexane-1,2-diyl]di(methylene) dipropanesulfonate (Step 1.85 g, 184 mmol) in ˜120 mL ethanol and benzylamine (70.2 mL, 643 mmol). The pressure tube was sealed and heated at 140° C. in an oil bath for 3 hr. The tube was cooled to RT and opened. LC-MS showed that the reaction was completed. The resulting mixture was diluted with 180 mL methanol and 100 mL 5 N aq. NaOH. The ethanol, some of water and benzylamine were removed under vacuum. The residue was dissolved in ethyl acetate and diluted with water. The organic layer was separated and the aqueous was extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and the solvent was evaporated under vacuum. The combined organics were concentrated, and the residue oil was purified by column chromatography (1:9 methanol:ethyl acetate. 1H-NMR (CDCl3): δ: 7.35-7.10 (9H, m), 3.81-3.62 (3H, m), 2.94 (1H, t, J=8.1 Hz), 2.83 (1H, t, J=10.0 Hz), 2.52 (2H, m), 2.40 (1H, t, J=10.0 Hz), 2.36 (3H, s), 2.20 (1H, m), 2.02-1.85 (3H, m), 1.60 (1H, m), 1.36 (1H, m). M++1: 322.19.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[Li]CCCC.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1>C1COCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([N:5]2[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]2=[O:9])=[O:24])=[CH:18][CH:17]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CC(C)[C@@H]1COC(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[C@@H]1COC(=O)N1C(=O)Cc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 106 %

Procedure:
To a solution of (4R)-4-isopropyl-1,3-oxazolidin-2-one (5.3 g, 41.1 mmol) in dry THF (100 mL) at −78° C. under argon, was added dropwise a 2.5M solution of n-BuLi in hexanes (17.0 mL, 42.5 mmol). After stirring at −78° C. for 15 min, (4-chlorophenyl)acetyl chloride (2.70 mL, 21.8 mmol) was added. The resulting reaction mixture was stirred at −78° C. for 30 min and 0° C. for 15 min, quenched with saturated NH4Cl (15 mL) and concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and washed with saturated Na2CO3 following by brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (10%–15% EtOAc/hexane) to give 6.48 g (23.1 mmol, 56%) of (4R)-3-[(4-chlorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one: 1H NMR (400 MHz, CDCl3) δ 7.31–7.22 (m, 4H), 4.45–4.41 (m, 1H), 4.35–4.16 (m, 4H), 2.39–2.29 (m, 1H), 0.89 d, 3H, J=7.2 Hz), 0.80 (d, 3 H, J=7.2 Hz); ESMS m/e: 282.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:38])[C@@H:19]([NH:27]C(=O)OCC2C=CC=CC=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6]1)[CH:2]=[CH2:3]>COCCOC.O>[CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:38])[C@@H:19]([NH2:27])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)c2cc(OC)ccc21
Solvent: O
Solvent: COCCOC
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2ccccc2)c2cc(OC)ccc21
Temperature: 110 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
Step V (2): A mixture of benzyl (2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate (700 mg, 1.36 mmol, from step N(1)), Ba(OH)2.H2O (1.46 g, 7.72 mmol), and DME/H2O (18 mL/12 mL) was heated at 110° C. in a sealed tube. After 16 h, cooled to rt, filtered of solid. Rinsed the vessel and filtercake with fresh DME and concentrated the filtrate in vacuo. The crude product was purified by silica-gel column chromatography (1-20% MeOH (containing 0.1% triethylamine)/chloroform, linear gradient) to provide 255 mg (49% yield) of the title compound. LC-MS (M+H)=383.0; HRMS (M+H)+=383.2332; [α]D +29.84 (c=6.43 mg/mL, methanol); 1H NMR (500 MHz, CDCl3) δ ppm 1.67 (d, 4H) 1.97 (d, J=13.43 Hz, 1H) 2.43-2.54 (m, 1H) 2.60-2.71 (m, 1H) 2.81 (dd, J=11.90, 8.55 Hz, 1H) 2.90-3.05 (m, 2H) 3.10-3.18 (m, 1H) 3.47 (s, 1H) 3.57 (s, 1H) 3.81 (s, 3H) 4.02-4.16 (m, 2H) 4.77 (dd, J=6.10, 3.97 Hz, 1H) 5.18 (dd, J=10.38, 1.53 Hz, 1H) 5.31 (dd, J=17.24, 1.68 Hz, 1H) 5.96 (dd, 1H) 6.85 (dd, J=8.24, 2.44 Hz, 1H) 6.95 (d, J=2.14 Hz, 1H) 7.15-7.35 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1=[CH:3][C:4]([O:6][C:7]1=[O:8])=O.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>C(O)(=O)C>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:16]2[C:4](=[O:6])[CH:3]=[C:2]([CH3:1])[C:7]2=[O:8])=[CH:13][CH:12]=1
Reactant: COc1ccc(CN)cc1
Reactant: CC1=CC(=O)OC1=O
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)C=C(C)C2=O)cc1

Procedure:
3-Methylmaleic anhydride (10 g, 89.2 mmol) and 4-methoxybenzylamine (11.6 mL, 89.2 mmol) were heated to 100° C. in 35 mL glacial acetic acid for 5 h. Solvent was evaporated. The residue was taken up in EtOAc and washed with sat'd aq NaHCO3, water, and brine. The organic phase was dried (MgSO4), filtered, and evaporated. The title compound was obtained as a solid and used without further purification (18.75 g, quant).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[C:19]2[NH:20][C:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)([C:24]([NH2:26])=[O:25])[CH2:22][O:23][C:18]=2[CH:17]=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[O:4]=[C:2]1[N:20]2[C:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)([C:24]([NH2:26])=[O:25])[CH2:22][O:23][C:18]3=[C:19]2[C:14](=[CH:15][CH:16]=[CH:17]3)[NH:13]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC(=O)C1(c2ccccn2)COc2cccc(N)c2N1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Reaction time: 1 h
Yield: 192.9 %

Procedure:
Triphosgene (20 mg, 0.07 mmol) was added to a solution of 5-amino-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide (40 mg, 0.2 mmol) in tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (60 μL, 0.3 mmol) at room temperature. The reaction was stirred for 1 h and then partitioned between ethyl acetate and water. The combined organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide (0.040 g. 80%). LCMS calculated for C15H13N4O3 (M+H)+: m/z=297.1. found: 297.1.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[F:21][C:22]1([F:41])[CH2:27][CH2:26][CH:25]([NH:28][C:29](=O)[O:30]C2C=CC([N+]([O-])=O)=CC=2)[CH2:24][CH2:23]1.CO>CC#N>[F:21][C:22]1([F:41])[CH2:23][CH2:24][CH:25]([NH:28][C:29]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:30])[CH2:26][CH2:27]1
Reactant: O=C(NC1CCC(F)(F)CC1)Oc1ccc([N+](=O)[O-])cc1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Solvent: CC#N
Solvent: CO
Product: O=C(NC1CCC(F)(F)CC1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (80 mg, 0.29 mmol) in MeCN (2 mL) was added 4-nitrophenyl 4,4-difluoro-cyclohexylcarbamate (217 mg, 0.72 mmol). The resulting mixture was then subjected to microwave irradiation at 120° C. for 15 min. Then, MeOH (0.5 mL) was added and the mixture was filtered. The filtrate was purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the title compound, which was dissolved in MeOH (1 mL). The solution was then passed through PL-HCO3 and the resin was washed with MeOH (2×0.3 mL). The combined filtrates were concentrated and dried in vacuo to give the title compound as a light-yellow solid. MS (ESI, positive ion) m/z: 439 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]([N:22]1[CH:26]=[C:25]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[N:24]=[N:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:39][C:40]1[N:41]=[C:42]([CH:45]=[CH:46][C:47]2[CH:52]=[CH:51][C:50]([S:53]([F:58])([F:57])([F:56])([F:55])[F:54])=[CH:49][CH:48]=2)[O:43][CH:44]=1.O>CN(C)C=O>[F:56][S:53]([F:54])([F:55])([F:57])([F:58])[C:50]1[CH:51]=[CH:52][C:47](/[CH:46]=[CH:45]/[C:42]2[O:43][CH:44]=[C:40]([CH2:39][O:37][C:34]3[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][CH2:28][CH2:27][C:25]4[N:24]=[N:23][N:22]([C:3]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=5)([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=5)[CH:26]=4)=[CH:36][CH:35]=3)[N:41]=2)=[CH:48][CH:49]=1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(CCCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FS(F)(F)(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nn4)cc3)co2)cc1
Reaction time: 0.25 h
Yield: 63.7 %

Procedure:
7.8 mg (0.20 mmol) 95% sodium hydride were given at 0° C. to a solution of 90 mg (0.20 mmol) 4-[4-(1-trityl-1H-[1,2,3]triazol-4-yl)-butyl]-phenol in 3.0 ml N,N-dimethylformamide and stirred for 15 min. 66 mg (0.20 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at 25° C. for 2 h. The reaction mixture was poured into water, the precipitate isolated by filtration und purified by LC-MS to yield 98 mg (65%) of the title compound
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13]([CH3:24])=[C:12]2[CH2:25][C:26]([NH2:28])=[O:27])C.[OH-].[Na+].O.Cl>CO>[NH2:28][C:26](=[O:27])[CH2:25][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:29])=[O:3])[CH:10]=2)[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13]=1[CH3:24]
Reactant: CCCCCCn1c(C)c(CC(N)=O)c2cc(OCCCC(=O)OCC)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCn1c(C)c(CC(N)=O)c2cc(OCCCC(=O)O)ccc21
Yield: 24 %

Procedure:
A mixture of 170 mg (0.42 mmol) of [4-[[3-(2-amino-2-oxoethyl)-1-hexyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid ethyl ester and 1 mL of 5N NaOH in 20 mL of MeOH was heated to maintain reflux for 2.5 hours, cooled, poured into water and made strongly acidic with 5N HCl. The mixture was extracted with ethyl acetate, dried (Na2SO4), concentrated at reduced pressure and the residue crystallized from MeOH. There was obtained 37 mg (24% yield) of [4-[[3-(2-amino-2-oxoethyl)-1-hexyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid. mp, 169-170° C.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:7]([NH:8]C(=O)OC(C)(C)C)[CH2:6][CH2:5][N:4]([CH2:16][CH2:17][N:18]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=3)[CH:21]=[CH:20][C:19]2=[O:30])[CH2:3]1.[ClH:31]>C(Cl)Cl.O1CCOCC1>[ClH:31].[ClH:31].[NH2:8][C@H:7]1[CH2:6][CH2:5][N:4]([CH2:16][CH2:17][N:18]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=3)[CH:21]=[CH:20][C:19]2=[O:30])[CH2:3][C@H:2]1[OH:1]
Reactant: COc1cnc2ccc(=O)n(CCN3CC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C3)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cnc2ccc(=O)n(CCN3CC[C@H](N)[C@H](O)C3)c2c1
Reaction time: 2 h

Procedure:
1,1-dimethylethyl ((3R,4S)-3-hydroxy-1-{2-[7-(methyloxy)-2-oxo-1,5-naphthyridin-1 (2H)-yl]ethyl}-4-piperidinyl)carbamate (258 mg, 0.6165 mmol) was dissolved in DCM (10 mL) and the solution was treated with 4M hydrogen chloride in 1,4-dioxane (2 ml). Effervescence and formation of a precipitate was observed. After 2 h, the solvents were removed under reduced pressure and the residue was dried under reduced pressure overnight, to give the title compound as a pale pink solid (223 mg).
Reaction SMILES: [NH2:1]N.C1COCC1.C[N:9](C)/[CH:10]=[C:11](\[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)/[C:12]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18])=O>>[N:25]1[CH:26]=[CH:27][C:22]([C:11]2[C:12]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[C:17]#[N:18])=[N:1][NH:9][CH:10]=2)=[CH:23][CH:24]=1
Reactant: CN(C)/C=C(/C(=O)c1cccc(C#N)c1)c1ccncc1
Reactant: NN
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2n[nH]cc2-c2ccncc2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A 1 M solution of hydrazine in THF (0.090 ml, 88.5 mmol) was added to 3-((E)-3-dimethylamino-2-pyridin-4-yl-acryloyl)benzonitrile (6.13 g, 22.1 mmol) and the mixture was stirred at 60° C. for 1 h. The product 3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzonitrile (4.89 g, 19.8 mmol, 90%) was isolated as a white solid by filtration from the reaction mixture.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:4]=[CH:5][C:6]([C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[CH3:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:41][CH:40]=2)=[CH:34][CH:33]=1>>[CH3:1][N:2]([CH3:23])[C:3]1[CH:11]=[C:7]2[C:6]([C:12]([C:13]3[CH:14]=[CH:15][C:16]([N:19]([CH3:20])[CH3:21])=[CH:17][CH:18]=3)([N:38]([C:39]3[CH:40]=[CH:41][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:43][CH:44]=3)[C:35]3[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])=[CH:37][CH:36]=3)[O:9][C:8]2=[O:10])=[CH:5][CH:4]=1
Reactant: CCCCCCCCc1ccc(Nc2ccc(CCCCCCCC)cc2)cc1
Reactant: CN(C)c1ccc(C(=O)c2ccc(N(C)C)cc2C(=O)O)cc1
Product: CCCCCCCCc1ccc(N(c2ccc(CCCCCCCC)cc2)C2(c3ccc(N(C)C)cc3)OC(=O)c3cc(N(C)C)ccc32)cc1
Yield: 87.6 %

Procedure:
Following a procedure similar to that described in Example 1 but employing 15.6 g of 5-(dimethylamino)-2-[4-(dimethylamino)benzoyl]benzoic acid and 19.6 g of 4,4'-dioctyldiphenylamine there was obtained 30.0 g of 6-(dimethylamino)-3-[4-(dimethylamino)phenyl]-3-[bis(4-octylphenyl)amino]phthalide, m.p. 208°-210° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed an orange-colored image which changed to green on the clay after fluoroescent light exposure.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[CH:14]=[C:13]([C:15]3[C:16]([NH:32][C:33]4[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)=[N:17][CH:18]=[C:19]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]4)[CH:20]=3)[N:12]=[C:11]([CH3:41])[N:10]=2)=CC=1.FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O>[CH3:40][O:39][C:36]1[N:35]=[CH:34][C:33]([NH:32][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:41])[N:10]=[C:9]([NH2:8])[CH:14]=3)=[CH:20][C:19]([CH2:21][N:22]3[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]3)=[CH:18][N:17]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(OC)nc3)nc(C)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(CN3CCN(S(C)(=O)=O)CC3)cc2-c2cc(N)nc(C)n2)cn1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
A solution of N,N-bis(4-methoxybenzyl)-6-(2-(6-methoxypyridin-3-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-2-methylpyrimidin-4-amine (137.7 mg, 0.190 mmol) and trifluoromethanesulfonic acid (50 μL, 0.563 mmol) in TFA (2.5 mL) was stirred at 80° C. for 2.5 h. The mixture was subsequently cooled to 25° C. and concentrated in vacuo. Sat. aq. NaHCO3 (25 mL) was carefully added to the residue (final pH about 8). The resulting suspension was sonicated for 2 min, and the precipitated solid was collected by vacuum filtration, washed with water (30 mL), and air-dried. The residue was taken up in MeOH, concentrated onto silica gel, and chromatographically purified (ISCO, 12 g, 0 to 10% MeOH/DCM) to yield 6-(2-(6-methoxypyridin-3-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-2-methylpyrimidin-4-amine (55.6 mg, 0.115 mmol, 60.4% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.80 (br. s., 1H); 8.37 (d, J=2.74 Hz, 1H); 8.14 (d, J=1.96 Hz, 1H); 8.10 (dd, J=8.90, 2.84 Hz, 1H); 7.86 (br. s., 1H); 6.76 (d, J=8.80 Hz, 1H); 6.70 (br. s., 1H); 4.95 (br. s., 2H); 3.93 (s, 3H); 3.43-3.56 (m, 2H); 3.26 (br. s., 4H); 2.78 (s, 3H); 2.63 (s, 3H); 2.58 (br. s., 4H). m/z (ESI, +ve ion) 485.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12].[F:29][CH2:30][CH:31](O)[CH2:32][F:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[F:29][CH2:30][CH:31]([CH2:32][F:33])[O:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12]
Reactant: OC(CF)CF
Reactant: O=C(c1cc([N+](=O)[O-])ccc1O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(c1cc([N+](=O)[O-])ccc1OC(CF)CF)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 113.6 %

Procedure:
A solution of (2-hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (50 mg), 1,3-difluoro-2-propanol [453-13-4] (27 mg), triphenylphosphine (76 mg) and diisopropylazodicarboxylate (48 mg) was refluxed overnight, concentrated in vacuo and purified by column chromatography (SiO2) to yield the title compound as a colorless solid (68 mg). MS (m/e): 474.1 (M+H+, 100%).
Reaction SMILES: [F:1][CH:2]([F:29])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([OH:27])[CH:20]=2)[O:17][CH:18]=1.[CH2:30](Br)[CH:31]([CH3:33])[CH3:32]>>[F:29][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:20]=2)[O:17][CH:18]=1
Reactant: CC(C)CBr
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3OCC(F)F)co2)cc1O
Product: COc1ccc(-c2nc(CCC(=O)c3ccccc3OCC(F)F)co2)cc1OCC(C)C

Procedure:
Using the compound obtained in Example 272 and isobutyl bromide, white powdery 1-[2-(2,2-difluoroethoxy)phenyl]-3-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-yl]-propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[NH:16][CH:15]=[N:14][C:13]=3[C:12](=[S:18])[N:11]3[CH2:19][CH2:20][N:21]=[C:10]23)=[CH:4][CH:3]=1.O.[OH-].[Na+].[CH3:25]I>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:13]([N:14]=[CH:15][N:16]=3)=[C:12]([S:18][CH3:25])[N:11]3[CH2:19][CH2:20][N:21]=[C:10]23)=[CH:4][CH:3]=1
Reactant: CI
Reactant: S=C1c2nc[nH]c2N(Cc2ccc(Cl)cc2)C2=NCCN12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSC1=C2N=CN=C2N(Cc2ccc(Cl)cc2)C2=NCCN21
Reaction time: 3 h

Procedure:
The product of Procedure 75, 6.65 g. (0.021 mole), was dissolved in a mixture of 100 ml. of water and 15 ml. of ethanol containing 1.0 g. (0.025 mole) of sodium hydroxide. Methyl iodide, 7.09 g. (0.05 mole) was then added whereupon a precipitate commenced to form and developed into a thick slurry within 3 hrs. The solid was collected, air dried, and recrystallized from DMF with charcoal treatment, m.p. 254.0°-256.0° dec.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[N:31]=[CH:30][N:29]=[C:28]([NH2:32])[C:27]=3[CH:33]([CH3:35])[CH3:34])[CH2:22][CH2:21]2)[CH2:4][CH2:3][CH2:2]1.[ClH:36].O1CCOCC1>CO>[Cl:36][CH2:4][CH2:3][CH2:2][NH:1][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=2)[N:9]=[C:8]1[CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[N:31]=[CH:30][N:29]=[C:28]([NH2:32])[C:27]=2[CH:33]([CH3:35])[CH3:34])[CH2:22][CH2:21]1
Reactant: Cl
Reactant: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4C(C)C)CC3)n2)ccc1F
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(-c2cn(CCNCCCCl)c(C3CCN(c4ncnc(N)c4C(C)C)CC3)n2)ccc1F
Temperature: 40 °C
Reaction time: 72 h

Procedure:
To a solution of 6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-isopropyl-pyrimidin-4-ylamine (70.0 mg; 0.15 mmol; 1.0 eq.) in methanol (0.5 ml), was added 4.0M HCl in dioxane (0.37 ml; 1.47 mmol; 10.0 eq.). The reaction mixture was stirred at 40° C. for 72 hr. After removal of the solvents, the crude was purified by prep HPLC to afford the title compound. LC-MS (M+H=515, obsd=515).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH2:12]([O:19][NH:20][CH3:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[CH2:12]([O:19][N:20]([CH3:21])[C:10]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=1)=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNOCc1ccccc1
Reactant: CSc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: CSc1cccc(NC(=O)N(C)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
3-(Methylthio)phenyl isocyanate (2.0 g, 12 mmol) was added dropwise to a solution of N-benzyloxy-N-methylamine (1.55 g, 11.3 mmol) in tetrahydrofuran (25 mL). The reaction mixture was stirred at ambient temperature for 2 hours then concentrated under vacuum. The residue was purified by flash chromatography (silica gel; ethyl acetate:hexanes) to provide 3.26 g of 1-benzyloxy-1-methyl-3-[3(methylthio)phenyl]urea as an oil.
Reaction SMILES: [CH:1]([N:4]1[C:30](=[O:31])[C:29]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:27][CH3:28])[C:18]([C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][C:20]=4[C:11]3=[C:10]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:9]=2[CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:37][C:38](OC(C)=O)=[O:39].O.[NH4+].[OH-]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:38]([N:7]1[CH2:8][C:9]2[C:10]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)=[C:11]3[C:20]4[CH:19]=[C:18]([C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)[C:17]([O:27][CH3:28])=[CH:16][C:15]=4[CH2:14][CH2:13][N:12]3[C:29]=2[C:30](=[O:31])[N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1)(=[O:39])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(cc1-c1cccnc1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCNC3
Agent: CN(C)c1ccncc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2c(cc1-c1cccnc1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(C)=O)C3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 32 mg of 10n in 200 μl of pyridine was treated with 30 μl of Ac2O and 1 mg of DMAP and was stirred at RT for 1 hr. Then, 2 ml of water was added and stirring was continued for 1 hr at RT. The mixture was made slightly alkaline by addition of conc. aq. NH4OH and was extracted with ethyl acetate. The organic layer was washed with a small amount of sat. NaCl, dried, concentrated and treated with diisopropyl ether, to give 30 mg of white crystalline 10p. Mp: 225-226° C.; Rf 0.40 (CH2Cl2/acetone 1/1). MS-ESI: [M+1] 541.12.