Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH:19](Br)[C:18]2=[O:24])[C:13]([I:25])=[C:12]([C:26]([NH:28][CH2:29][CH:30]([O:36][C:37](=[O:39])[CH3:38])[CH2:31][O:32][C:33](=[O:35])[CH3:34])=[O:27])[C:11]=1[I:40])=[O:9])(=[O:3])[CH3:2]>C(O)(=O)C.C(OCC)(=O)C.C([O-])(=O)C.[Ag+]>[C:1]([O:4][CH:19]1[CH2:20][CH2:21][CH2:22][N:17]([C:14]2[C:13]([I:25])=[C:12]([C:26]([NH:28][CH2:29][CH:30]([O:36][C:37](=[O:39])[CH3:38])[CH2:31][O:32][C:33](=[O:35])[CH3:34])=[O:27])[C:11]([I:40])=[C:10]([C:8]([NH:7][CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:41][O:42][C:43](=[O:45])[CH3:44])=[O:9])[C:15]=2[I:16])[C:18]1=[O:24])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2CCCC(Br)C2=O)c1I)OC(C)=O
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2CCCC(OC(C)=O)C2=O)c1I)OC(C)=O
Temperature: 25 °C

Procedure:
To a solution of N,N'-bis[2,3-bis(acetyloxy)propyl]-5-(3-bromo-2-oxo-1-piperidinyl)-2,4,6-triiodo-1,3-benzenedicarboxamide of example 8b (13.7 g, 13.3 mmol) in glacial acetic acid (400 ml), was added silver acetate (5.6 g, 33.5 mmol) and the mixture was refluxed for 21 hours. After cooling to room temperature, the mixture was filtered, and the filtrate concentrated in vacuo. The residue thus obtained, was redissolved in ethyl acetate (500 ml) and washed successively with water (50 ml), saturated aqueous sodium bicarbonate (3×50 ml) and saturated aqueous sodium chloride (50 ml). After drying over magnesium sulfate, the solvent was evaporated in vacuo and the crude product, that resulted, was purified by column chromatography over silica gel to obtain 5-[3-(acetyloxy)-2-oxo-1-piperidinyl]-N,N'bis[2,3-bis(acetyloxy)propyl]-2,4,6-triiodo-1,3-benzenedicarboxamide as a white fluffy solid (10.3 g, 83% yield).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#N)[CH3:12].C(O)(=[O:23])C.O>C1(C)C=CC=CC=1>[CH2:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:23])[CH3:12]
Reactant: CCc1cccc(C#N)c1
Reactant: CC(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cccc(C=O)c1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Add a 1 M solution of diisobutylaluminum hydride in toluene (76 mmol) dropwise to a solution of m-ethylbenzonitrile (38 mmol) in toluene (50 mL) under nitrogen in a dry ice-acetone bath. Stir for 30 minutes then add acetic acid (20 mL) dropwise followed by water (100 mL). Stir the reaction for 2 hours. Separate the layers and extract the aqueous with toluene. Dry the combined organic layers over sodium sulfate, and evaporate to give the title compound (4.5 g, 88% yield). 1HNMR (400.43 MHz, CDCl3): δ 9.97 (s, 1H), 7.69-7.66 (m, 2H), 7.46-7.40 (m, 2H), 2.71 (q, J=7.6 Hz, 2H), 1.25 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[C:5]([F:10])[C:6](=[N:8][NH2:9])[N:7]=1.[CH:19]1([CH2:24][C@H:25]([CH2:29][N:30]([CH:38]=[O:39])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:26](=[O:27])[C@H:25]([CH2:24][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:29][N:30]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH:38]=[O:39])[C:5]([F:10])=[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[N:3]=1
Reactant: NN=c1nc(Cl)[nH]c(NCCc2ccsc2)c1F
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NCCc2ccsc2)c1F)OC1CCCCO1
Reaction time: 8 h
Yield: 60.5 %

Procedure:
2-Chloro-5-fluoro-6-{[2-(3-thienyl)ethyl]amino}-4(1H)-pyrimidinone hydrazone as a brown sticky solid (0.1401 g) and (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (0.253 g, 0.586 mmol) were dissolved in DMF (7 mL). NMM (0.27 mL, 2.90 mmol) was added, followed by HOAt (0.080 g, 0.588 mmol) and EDC (0.112 g, 0.584 mmol). After stirring overnight, the reaction mixture was purified by RP-HPLC to provide [(2R)-3-[2-(2-chloro-5-fluoro-6-{[2-(3-thienyl)ethyl]amino}-4-pyrimidinyl)hydrazino]-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide as an orange solid (0.1677 g). LCMS: (M+H)+=569.3.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:8]2=[O:25])=[C:4]([F:28])[CH:3]=1.[CH3:29][S:30]([O-:32])=[O:31].[Na+].[C@@H]1(N)CCCC[C@H]1N>CS(C)=O>[F:28][C:4]1[CH:3]=[C:2]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:27]=[CH:26][C:5]=1[O:6][C@H:7]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:8]1=[O:25]
Reactant: CS(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Oc3ccc(Br)cc3F)C2=O)CC1
Agent: N[C@@H]1CCCC[C@H]1N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Oc3ccc(S(C)(=O)=O)cc3F)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
(S)-tert-Butyl 4-(3-(4-bromo-2-fluorophenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (1.8 g, 3.9 mmol) was dissolved in DMSO (30 mL) and purged with nitrogen. Sodium methanesulfinate (0.60 g, 5.9 mmol) and trans-cyclohexane-1,2-diamine (0.19 mL, 1.6 mmol) were added followed by Cu(I) triflate benzene complex (0.20 g, 0.39 mmol). The reaction was plunged into a 110° C. oil bath under nitrogen and stirred overnight. The reaction was cooled to ambient temperature, partitioned between water and EtOAc, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (100% EtOAc) to afford (S)-tert-butyl 4-(3-(2-fluoro-4-(methylsulfonyl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (1.6 g, 3.5 mmol, 89% yield) as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:10]1[CH:11]=[C:12]([NH:16][C:17]([NH:19][C@@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@H:23]([O:30][C:31]3[CH:32]=[CH:33][C:34]4[N:35]([C:37]([N:40]5[CH2:45][CH2:44][CH:43]([CH2:46][OH:47])[CH2:42][CH2:41]5)=[N:38][N:39]=4)[CH:36]=3)[CH2:22][CH2:21]2)=[O:18])[N:13]([CH3:15])[N:14]=1)([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:6]([C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:18])[NH:19][C@@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@H:23]([O:30][C:31]3[CH:32]=[CH:33][C:34]4[N:35]([C:37]([N:40]5[CH2:45][CH2:44][CH:43]([CH2:46][O:47][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:42][CH2:41]5)=[N:38][N:39]=4)[CH:36]=3)[CH2:22][CH2:21]2)[N:13]([CH3:15])[N:14]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCC(CO)CC4)n3c2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCC(COS(C)(=O)=O)CC4)n3c2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.5 %

Procedure:
Methanesulfonyl chloride (8.8 μL, 0.13 mmol) was added to a solution of Intermediate 14g (50 mg, 0.08 mmol) and DIPEA (46 μL, 0.26 mmol) in DCM (1.5 mL) and the reaction mixture was stirred at RT for 1 h. The mixture was diluted with DCM (5 mL) and washed with water (3×5 mL). The organic layer was passed through a phase separator and concentrated in vacuo to afford the title compound (57 mg, 100%). LCMS (Method 3): Rt: 3.21 min, m/z 651 [MH+].
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]2[NH:23][N:24]=[N:25][C:21]=2[CH:20]=1>>[N:23]1[C:22]2[CH:26]=[CH:27][C:19]([NH:18][CH:4]=[C:5]3[C:16]4[C:8](=[CH:9][CH:10]=[C:11]5[C:15]=4[S:14][CH:13]=[N:12]5)[NH:7][C:6]3=[O:17])=[CH:20][C:21]=2[NH:25][N:24]=1
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc2nn[nH]c2c1
Yield: 54 %

Procedure:
The title compound was prepared in 54% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 5-aminobenzotriazole according to Procedure J: 1H NMR (DMSO-d6): δ 11.18 (d,1H), 10.9 (s, 1H), 9.23 (s, 1H), 8.12 (d, 1H), 7.96 (s, 1H), 7.78 (d, 1H), 7.48 (s, 1H), 7.1 (d, 1H); APCI−MS m/z 333 (M−H)−.
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][C:5](=[NH:9])OCC.Cl.[C:11]([NH2:14])(=[NH:13])[CH3:12].O.NN.[N:18]([O-])=O.[Na+].Cl>O>[CH3:12][C:11]1[N:14]=[N:9][C:5]([CH2:4][CH2:3][OH:2])=[N:18][N:13]=1
Reactant: CCOC(=N)CCO
Reactant: CC(=N)N
Reactant: O=N[O-]
Agent: Cl
Agent: NN
Agent: [Na+]
Solvent: O
Product: Cc1nnc(CCO)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
To a mixture of ethyl 3-hydroxypropanimidate hydrochloride (2 mmol, 307 mg) and acetamidine hydrochloride (10 mmol, 945 mg) was added hydrazine hydrate (2 mL) under an atmosphere of argon. After stirring at room temperature for 2 hours, the mixture was diluted with water (25 mL) and sodium nitrite (25 mmol, 1.72 g) was added. To this solution was added 2% aqueous HCl dropwise on an ice bath until the now pink solution reached a pH of 3. The aqueous solution was extracted with methylene chloride (5×50 mL), dried with magnesium sulfate, the solvent was removed by rotary evaporation, and then dried under vacuum to afford the product, 2-(6-methyl-1,2,4,5-tetrazin-3-yl)ethanol (140 mg, 37%), as a pink oil. LRMS-ESI [M+H]+ calcd. for C5H9N4O+: 141.08, found: 140.7.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([C:40](O)=[O:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:43][CH3:44])=[O:5])[CH3:2].Cl.C[O:47][C:48](=[O:52])[CH2:49][CH2:50][NH2:51].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:27]=3)[C:22]([C:40](=[O:41])[NH:51][CH2:50][CH2:49][C:48]([OH:52])=[O:47])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:43][CH3:44])=[O:5])[CH3:2]
Reactant: COC(=O)CCN
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C(=O)NCCC(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reaction time: 21 h
Yield: 85.3 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-carboxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (200 mg) is dissolved in N,N-dimethylformamide (2 ml), and thereto are added triethylamine (53 μl), 3-aminopropionic acid methyl ester hydrochloride (67 mg), 1-hydroxybenzotriazole hydrate (65 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (92 mg) under ice-cooling. The mixture is stirred for 21 hours. The reaction solution is concentrated under reduced pressure, then the residue is partitioned by adding a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the organic layer is concentrated under reduced pressure. The resulting residue is dissolved in methanol (2 ml), and thereto is added 5N aqueous NaOH solution (1 ml), and the mixture is stirred at room temperature for 2 hours. To the reaction solution is added 6N HCl (0.85 ml), and then the mixture is extracted with ethyl acetate and the organic layer is concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=1:0→19: 1) to give (2R,4S)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[(2-carboxyethyl)carbamoyl]pyrimidin-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (190 mg). MS (m/z): 699 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([CH3:13])[CH3:12])=[O:10])=[CH:4][CH:3]=1.CC1C=CC(S(O[CH2:25][CH2:26][CH2:27][NH:28][C:29]2[C:30](=[O:46])[N:31]([C:42]([CH3:45])([CH3:44])[CH3:43])[S:32](=[O:41])(=[O:40])[C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=O)=O)=CC=1>>[C:42]([N:31]1[C:30](=[O:46])[C:29]([NH:28][CH2:27][CH2:26][CH2:25][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:11]([CH3:12])[CH3:13])=[O:10])=[CH:6][CH:7]=2)=[C:33]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[S:32]1(=[O:40])=[O:41])([CH3:43])([CH3:44])[CH3:45]
Reactant: CN(C)C(=O)Cc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Product: CN(C)C(=O)Cc1ccc(OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Yield: 59 %

Procedure:
The title compound was prepared as described for Example 12 from 2-(4-hydroxyphenyl)-N,N-dimethylacetamide and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate. The reaction mixture was evaporated, purified twice by silica gel column chromatography (Horizons Biotage) using 75-85% EtOAc in petroleum ether 40-60° C. and then 50% DCM in EtOAc as eluent to give the title compound (0.072 g, 59%). 1H NMR (500 MHz CDCl3): δ 7.54-7.49 (m, 2H), 7.46-7.42 (m, 3H), 7.18 (d, 2H), 6.82 (d, 2H), 5.76 (t, 1H), 3.87 (t, 2H), 3.66 (s, 2H), 3.08 (m, 2H), 3.01 (s, 3H), 2.98 (s, 3H), 1.83 (m, 2H), 1.74 (s, 9H); 13C NMR (CDCl3): δ 171.5, 159.8, 157.4, 135.3, 131.8, 130.1, 129.7, 128.8, 127.8, 125.3, 114.8, 107.1, 66.1, 61.7, 42.5, 40.3, 37.9, 35.9, 28.9, 27.8; Mass Spectrum M+H+ 500.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH3:20])[CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]3[O:37][C:38]4[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:39]=4[N:40]=3)=[CH:31][CH:30]=2)[O:23]1.NC1N=CN=C2N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=C(C3C=CC(NC4OC5C=CC=CC=5N=4)=C(F)C=3)C=12>>[C:18]([OH:19])(=[O:23])[CH3:17].[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH3:20])[CH2:13]3)[N:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:32]([NH:35][C:36]4[O:37][C:38]5[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:39]=5[N:40]=4)=[CH:33][CH:34]=3)[C:10]=12
Reactant: CC1(C)OB(c2ccc(Nc3nc4cc(Cl)ccc4o3)cc2)OC1(C)C
Reactant: COCCN1CCC(n2nc(I)c3c(N)ncnc32)C1
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Product: CC(=O)O
Product: COCCN1CCC(n2nc(-c3ccc(Nc4nc5cc(Cl)ccc5o4)cc3)c3c(N)ncnc32)C1

Procedure:
rac-N2-(4-{4-Amino-1-[1-(2-methoxyethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-chloro-1,3-benzoxazol-2-amine monoacetate was prepared from rac-3-iodo-1-[1-(2-methoxyethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.319 mmol) and N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-chloro-1,3-benzoxazol-2-amine (0.148 g, 0.399 mmol) in a manner similar to that used for the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as an off-white solid (0.080 g, 50%). 1H NMR (DMSO-d6, 400 MHz) 1.91 (s, 3H), 2.33 (m, 2H), 2.66 (m, 2H), 2.75-2.85 (m, 3H), 3.17 (t, 1H), 3.24 (s, 3H), 3.45 (t, 2H), 5.37 (m, 1H), 7.18 (d, 1H), 7.55 (d, 2H), 7.68 (d, 2H), 7.92 (d, 2H), 8.24 (s, 1H), 9.80 (s, 1H); RP-HPLC Rt 11.337 min, 97% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 505 (MH+).
Reaction SMILES: [C:1]1([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](O)(=O)C.C=O>CO>[C:1]1([NH:7][C:8]2[S:9][C:10]3[CH2:16][NH:15][CH2:14][CH2:13][C:11]=3[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: NCCc1csc(Nc2ccccc2)n1
Agent: C=O
Solvent: CO
Product: c1ccc(Nc2nc3c(s2)CNCC3)cc1
Reaction time: 0.33 h
Yield: 382.9 %

Procedure:
A solution of 2-phenylamino-4-(2-aminoethyl)thiazole (0.30 g, 1.37 mmol) in methanol (15 ml) was treated with acetic acid (0.02 ml, 0.35 mmol) and formaldehyde (0.11 ml of a 37% aqueous solution, 1.37 mmol). After 20 minutes, the reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated in vacuo to provide a glassy solid (0.31 g, 1.34 mmol, 98% yield) which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:30])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:29]=[CH:28][C:22](C(N=[N+]=[N-])=O)=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].C1(C)C=CC=CC=1.[N-:38]=[C:39]=[O:40]>ClCCl>[N:38]([C:22]1[CH:28]=[CH:29][C:19]([C:16]2[N:17]=[CH:18][N:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:2]([F:30])([F:1])[C:3]([F:4])([F:5])[F:6])=[CH:9][CH:10]=3)[N:15]=2)=[CH:20][CH:21]=1)=[C:39]=[O:40]
Reactant: [N-]=C=O
Reactant: [N-]=[N+]=NC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C=Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A 250 mL, three-neck flask, fitted with magnetic stirring, air condenser, temperature probe and nitrogen inlet, was charged with 4-(1-(4-(perfluoroethoxy)-phenyl)-1H-1,2,4-triazol-3-yl)benzoyl azide (5.00 g, 11.2 mmol) and toluene (100 mL). The brown solution was heated to 100° C. slowly and allowed to stir for 1 hour. Analysis of crude reaction mixture by LCMS shows the desired isocyanate. The reaction was cooled to 25° C. and the solvent removed by rotary evaporation to give a solid. The solid was dissolved in dichloromethane and the solution filtered to remove a small amount of a black insoluble material. The light-brown filtrate was rotary evaporated to yield 4.6 g of a tan solid. The solid was taken up in 30 mL of methyl tert-butyl ether, heated to effect a slightly turbid solution and filtered hot. The filtrate was re-heated to effect solution again and heptane (about 10-15 mL) was slowly added. The solution was placed on a rotary evaporator and the solvent was slowly removed under reduced pressure. When the first sign of solid was noted, the vacuum was broken and the mixture was allowed to slowly rotate at 40° C. to effect precipitation of solid. The solid was collected by vacuum filtration to give 3.4 g (77% yield) of a light tan solid, mp=119-121° C. 1H NMR (600 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.10-8.05 (m, 4H), 7.60 (d, J=8.7 Hz, 2H), 7.38 (dd, J=8.3, 1.6 Hz, 2H). 13C NMR (151 MHz, DMSO) δ 161.77, 146.66, 144.37, 136.23, 134.45, 128.26, 127.78, 125.91, 124.93, 123.57, 121.59.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[OH-:12].[Na+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=1.Cl>C(O)C>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:4]([C:2]([OH:12])=[O:3])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:1]=2)=[CH:17][CH:16]=1
Reactant: [OH-]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1cc(-c2ccc(F)cc2)nc2ccccc12

Procedure:
To a suspension of 36.78 g (0.25 mol) of isatin in 500 ml of ethanol was added 75 ml of 10N sodium hydroxide. After a few minutes of stirring a solid precipitated. To this mixture was added 35 ml (0.286 mol) of p-fluoroacetophenone, and it was stirred and heated under reflux for 1.5 hr. It was then allowed to cool slightly, and acidified with 250 ml of 3N hydrochloric acid. The precipitated solid was collected, washed with water and with ether, and dried to give 50.6 g of crude product, mp 205-215. Recrystallization from ethanol gave 38.8 g of the above-named acid, mp 210°-213° dec.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][CH2:32][N:33]1[CH:37]=[C:36]([C:38](=[O:40])[NH2:39])[N:35]=[CH:34]1)=[O:6])[CH:2]=[CH2:3].F[C:42](F)(F)S(OC)(=O)=O.[Cl:50]CCl>>[Cl-:50].[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][CH2:32][N+:33]1[CH:37]=[C:36]([C:38](=[O:40])[NH2:39])[N:35]([CH3:42])[CH:34]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CCn3cnc(C(N)=O)c3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: ClCCl
Reactant: COS(=O)(=O)C(F)(F)F
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC[n+]3cc(C(N)=O)n(C)c3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [Cl-]
Reaction time: 0.5 h

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-{2-(4-carbamoylimidazol-1-yl)ethyl}-pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (2.07 g) in dichloromethane (20 ml) was added methyl trifluoromethanesulfonate (1.16 ml) at 0° C. and the solution was stirred for 30 minutes. To the mixture was added a suspension of ion exchange resin, Amberlist A-26 (Cl- type, Trademark, made by Rohm and Haas Co., Ltd.) (10 ml) in dichloromethane (10 ml) and the whole was stirred for 5 minutes. The resin was removed by filtration and washed with a mixture of dichloromethane and methanol (4/1, 50 ml). The filtrate was concentrated in vacuo to give allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-{2-(4-carbamoyl-3-methyl-1-imidazolio)ethyl}pyrrolidin-4yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1azabicyclo[3.2.0]hept-2-ene-2-carboxylate chloride (2.75 g) as a pale yellow solid. This compound was immediately used as the starting compound for the next step.
Reaction SMILES: [CH2:1]([NH:19][C:20](OCC(=C)COC(=O)CCCCC[Br:33])=O)[CH2:2][CH2:3][CH2:4]CCCCCCCCCCCCCC.[CH2:36]([NH:54][C:55]([O:57][CH2:58][C:59](=[CH:70][CH3:71])[CH2:60][O:61][C:62](=[O:69])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]Br)=[O:56])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]>>[Br-:33].[CH2:36]([NH:54][C:55]([O:57][CH2:58][C:59](=[CH:70][CH3:71])[CH2:60][O:61][C:62](=[O:69])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][N+:19]1[CH:1]=[CH:2][CH:3]=[CH:4][CH:20]=1)=[O:56])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CC=C(COC(=O)CCCCCBr)COC(=O)NCCCCCCCCCCCCCCCCCC
Reactant: C=C(COC(=O)CCCCCBr)COC(=O)NCCCCCCCCCCCCCCCCCC
Product: CC=C(COC(=O)CCCCC[n+]1ccccc1)COC(=O)NCCCCCCCCCCCCCCCCCC
Product: [Br-]

Procedure:
Following the procedure described in Example 6, but replacing 1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane with an approx. 1:1 mixture of E- and Z-isomers of 1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-ethylidenepropane (from Preparation 29), an approx. 1:1 mixture of E- and Z-isomers of the desired compound is obtained.