Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.[CH3:20][C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=1[CH3:27].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:26]=1[CH3:27])[O:28][CH2:15][CH2:14][CH2:13][O:12][C:8]1[CH:7]=[C:6]([CH2:5][CH:4]([O:17][CH3:18])[C:3]([OH:2])=[O:19])[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Reactant: Cc1ccc(O)cc1C
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCCOc2ccc(C)c(C)c2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 323, Step 1) and 3,4-dimethylphenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. 1H-NMR (CDCl3, 200.15 MHz): 7.18 (d, 1H, J=7.5), 7.02 (d, 1H, J=8.3), 6.84–6.62 (m, 5H), 4.14 (t, 2H, J=6.4), 4.12 (t, 2H, J=5.9), 4.02 (dd, 1H, J=7.3, 4.0), 3.39 (s, 3H), 3.13 (dd, 1H, J=14.2, 4.6), 2.97 (dd, 1H, J=14.0, 7.5), 2.23 (q, 1H, J=6.2.1), 2.22 (s, 3H), 2.18 (s, 3H). MS (ES) for C21H26O5 [M+Na]+: 381.2.
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH:14]=[CH:13]N=[CH:11]1)(N1C=CN=C1)=[O:4].[NH2:15][C:16]1[C:24]([Cl:25])=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=1.[OH2:28]>C1COCC1.C(#N)C>[NH2:15][C:16]1[C:24]([Cl:25])=[CH:23][C:19]([C:20]([O:22][CH2:17][CH:16]2[CH2:24][CH2:11][N:10]([C:3]([O:4][C:19]([CH3:23])([CH3:20])[CH3:18])=[O:28])[CH2:14][CH2:13]2)=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1cc(N)c(Cl)cc1C(=O)OCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 42 %

Procedure:
Sodium hydride (5.8 g) was added to a solution of 1,1-dimethylethyl 1-piperidine-4-methanolcarboxylate (25 g) in THF (800 ml). The mixture was stirred and refluxed for 3 hours (H2 gas evolution), then cooled (solution I). 1,1′-Carbonylbis-1H-imidazole (19.5 g) was added to a suspension of 4-amino-5-chloro-2-methoxybenzoic acid (24 g) in ACN (800 ml), stirred at room temperature. This mixture was stirred for 2 hours at room temperature (solution II). At room temperature, solution (II) was poured out into solution (I) and the reaction mixture was stirred for 20 hours at room temperature. Water (±10 ml) was added. The organic solvent was evaporated. The residue was partitioned between DCM and H2O. The insoluble solid was filtered off. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was crystallized from ACN (0° C.). The precipitate was filtered off and dried, filtered and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered off and dried (vacuum; 50° C.), yielding 20 g (42%) 1,1-dimethylethyl 4-[[(4-amino-5-chloro-2-methoxy-benzoyl)oxy]methyl]-1-piperidine-carboxylate (intermediate 10).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][N:13]2C(OC(C)(C)C)=O)=[CH:9][CH:8]=1)=[O:5].[C:27]([C:31]1[CH:32]=[C:33]2[C:38](=O)[O:37][C:35](=[O:36])[C:34]2=[CH:40][CH:41]=1)([CH3:30])([CH3:29])[CH3:28]>C1COCC1.C(OCC)C>[NH:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[N:1]3[C:38](=[O:37])[C:33]4[C:34](=[CH:40][CH:41]=[C:31]([C:27]([CH3:29])([CH3:28])[CH3:30])[CH:32]=4)[C:35]3=[O:36])[CH:15]=2)[CH:11]=[N:12]1
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(NC(=O)c3ccccc3N)cc21
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)OC2=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(c1)C(=O)N(c1ccccc1C(=O)Nc1ccc3cn[nH]c3c1)C2=O
Reaction time: 72 h
Yield: 16.3 %

Procedure:
To a stirring solution of 2-amino-N-(1-Boc-6-indazolyl)benzamide (1 g, 2.8 mmol) in THF (30 mL) was added 4-t-butylphthalic anhydride (1.2 g, 5.9 mmol) and the solution was heated to reflux. After 72 h, the vessel was cooled and the volume was reduced to about 10 mL in vacuo. The mixture was diluted with diethyl ether (20 mL) and after sonication, a white solid was collected. This solid was processed by methods substatially equivalent to those described in Example 2-F to give 200 mg of N-(6-indazolyl)-2-(5-t-butyl-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)benzamide.
Reaction SMILES: [Mg].[CH2:2](Br)[CH3:3].[Cl:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1.[Cl-].[NH4+]>CCOCC>[Cl:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([CH2:2][CH3:3])([OH:11])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: CCN(CC)CCCOc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCN(CC)CCCOc1ccc(C(O)(CC)c2ccc(Cl)cc2)cc1
Temperature: -30 °C

Procedure:
To a Grignard reactant prepared from 7.2 g. of magnesium turnings and 32.6 g. of ethyl bromide in 120 ml. of dry ether a solution of 25.6 g. of 4-chloro-4'-[3-(diethylamino)-propoxy]-benzophenone in 300 ml. of dry ether is added dropwise, with stirring at -30° C. The reaction mixture is refluxed for 30 minutes. After cooling, it is poured onto a solution of ammonium chloride in ice water. The aqueous phase is extracted with ether, the ethereal phase is washed to neutral with water, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. Distillation of the residue in vacuo yields 15.3 g. of the title compound, boiling at 212° to 214° C./13.3 Pa.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]([NH2:32])[C:27]([O:30][CH3:31])=[N:28][CH:29]=4)[CH:21]=[C:20]4[C:16]=3[CH:17]=[N:18][N:19]4S(C3C=CC(C)=CC=3)(=O)=O)=[N:12][N:11]=2)[CH2:3]1.[CH3:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[S:51](Cl)(=[O:53])=[O:52].N1C=CC=CC=1.[OH-].[Na+].Cl>C(Cl)(Cl)Cl.O1CCOCC1>[CH3:8][C@H:6]1[O:7][C@@H:2]([CH3:1])[CH2:3][N:4]([CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]([NH:32][S:51]([C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=5[O:44][CH3:43])(=[O:53])=[O:52])[C:27]([O:30][CH3:31])=[N:28][CH:29]=4)[CH:21]=[C:20]4[C:16]=3[CH:17]=[N:18][NH:19]4)=[N:12][N:11]=2)[CH2:5]1
Reactant: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(S(=O)(=O)c4ccc(C)cc4)c3c2)cc1N
Reactant: COc1ccccc1S(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccccc1S(=O)(=O)Nc1cc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cn[nH]c3c2)cnc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 39 %

Procedure:
5-{4-(5-{[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-[(4-methylphenyl)sulfonyl]-1H-indazol-6-yl}-2-(methyloxy)-3-pyridinamine (150 mg, 0.254 mmol) was dissolved in chloroform (3 ml) then 2-(methyloxy)benzenesulfonyl chloride (79 mg, 0.382 mmol) was added. Pyridine (0.082 ml, 1.018 mmol) was added to the reaction mixture and it was stirred at room temperature for 5 h. The compound was dissolved in 1,4-dioxane (2 ml) and 2M sodium hydroxide (2 ml) and stirred at room temperature for 3 h. The reaction mixture was neutralized to pH 7 with 2M HCl, then the solvent was removed under a stream of nitrogen. The solid was dissolved in DMSO then filtered through a filter tube and purified by Mass Directed Automated Preparative HPLC. The solvent was removed under nitrogen to give the title compound as a white solid (60 mg).
Reaction SMILES: Cl.Cl.Cl.Cl.Cl.[Cl:6][C:7]1[N:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[C:14]2([CH3:22])[CH3:21])[C:10]([F:23])=[C:9]([NH:24][NH2:25])[N:8]=1.[CH:26]1([CH2:31][C@H:32]([CH2:36][N:37]([CH:46]=[O:47])[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:33](O)=[O:34])[CH2:30][CH2:29][CH2:28][CH2:27]1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C>[Cl:6][C:7]1[N:8]=[C:9]([NH:24][NH:25][C:33](=[O:34])[C@H:32]([CH2:31][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:36][N:37]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:46]=[O:47])[C:10]([F:23])=[C:11]([N:13]2[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[C:14]2([CH3:21])[CH3:22])[N:12]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: CN(C)C1CCN(c2nc(Cl)nc(NN)c2F)C1(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(C)C1CCN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OCc3ccccc3)c2F)C1(C)C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a solution of racemic 1-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-N,N,2,2-tetramethyl-3-pyrrolidinamine pentahydrochloride (0.3649 g, 0.752 mmol) in DMF (5 mL) was added (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.2140 g, 0.701 mmol), N-methylmorpholine (0.770 mL, 7.00 mmol), 1-hydroxy-7-azabenzotriazole (114 mg, 0.838 mmol), and EDC (161 mg, 0.840 mmol). The solution was stirred overnight and purified directly by Gilson RPLC to provide [(2R)-3-(2-{2-chloro-6-[3-(dimethylamino)-2,2-dimethyl-1-pyrrolidinyl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.1755 g, 42% yield, mixture of diastereomers) as a brown oil. LCMS: (M+H)+: 590.4.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28].Cl.O>O1CCCC1.N1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([O:26][C:23]1[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([N+:27]([O-:29])=[O:28])[CH:22]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(C(=O)Oc2ccc(Cl)c([N+](=O)[O-])c2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 22 h
Yield: 106.1 %

Procedure:
3,5-Di-t-butyl-4-hydroxybenzoyl chloride (56.2 g; 0.209 mole) in tetrahydrofuran (70 ml) was added with stirring to a solution of 4-chloro-3-nitrophenol (36.3 g; 0.209 mole) in pyridine (170 ml) at 0° C. over 20 minutes. The reaction mixture was stirred at room temperature for 22 hours and poured into an ice cold solution of 10M-hydrochloric acid (350 ml) and water (1400 ml). The mixture was extracted into ether (500 ml) and the ethereal extract washed successively with 2M-hydrochloric acid (150 ml), 2% sodium carbonate solution (4×150 ml) and water (2×100 ml). The extract was dried and the ether removed to give a dark orange oil (90 g). This material was chromatographed (silica) eluting with 4:1 hexane:ethyl acetate, to give the product (60.6 g; 72%) as a yellow viscous oil.
Reaction SMILES: [CH:1]1([CH:7]([C:13]([O:15]CC)=O)[C:8]([O:10]CC)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C(C(OCC)=O)[C:23](OCC)=[O:24])C(C)C.[CH3:33][C:34](C)([CH3:43])[CH2:35][C:36]([CH2:41][OH:42])([CH2:39][OH:40])[CH2:37][OH:38]>>[CH:1]1([C:7]([CH2:8][OH:10])([CH2:13][OH:15])[CH2:23][OH:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[CH2:35]([C:36]([CH2:37][OH:38])([CH2:39][OH:40])[CH2:41][OH:42])[CH:34]([CH3:43])[CH3:33]
Reactant: CC(C)(C)CC(CO)(CO)CO
Reactant: CCOC(=O)C(C(=O)OCC)C1CCCCC1
Reactant: CCOC(=O)C(CC(C)C)C(=O)OCC
Product: CC(C)CC(CO)(CO)CO
Product: OCC(CO)(CO)C1CCCCC1

Procedure:
2-Cyclohexyl-2-hydroxymethylpropan-1,3-diol and 2-isobutyl-2-hydroxymethylpropan-1,3-diol were prepared from diethyl cyclohexylmalonate and diethyl i-butylmalonate respectively in a manner analogous to the synthesis of 2-(2,2-dimethylpropyl)-2-hydroxymethylpropane-1,3-diol (example 5).
Reaction SMILES: [NH:1]=[C:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:6]=1[NH:15][C:16]([NH:18][C:19]([O:21][CH3:22])=[O:20])=[S:17])[CH2:3][CH3:4].[OH-].[Na+].[CH3:25]I>CC(C)=O.O>[NH:1]=[C:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:6]=1[NH:15][C:16](=[N:18][C:19]([O:21][CH3:22])=[O:20])[S:17][CH3:25])[CH2:3][CH3:4]
Reactant: CI
Reactant: CCCSc1ccc(C(=N)CC)c(NC(=S)NC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCSc1ccc(C(=N)CC)c(NC(=NC(=O)OC)SC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a suspension of 1-iminopropyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (1 g.; 0.00295 mole) in acetone (30 ml.) and water (15 ml.) there is added 50.8% aqueous sodium hydroxide (0.23 g.; 0.00295 mole). The solution that forms is stirred at room temperature for one hour and to it there is added methyl iodide (0.42 g.; 0.00295 mole). The turbid solution formed is stirred at room temperature for 30 minutes and is poured into water (500 ml.). The suspension formed is stirred at room temperature for one hour and is vacuum filtered. The filter cake is dried to afford 1-iminopropyl-2-(3-carbomethoxy-S-methylisothioureido)-4-propylthiobenzene (0.85 g.; 81.5%), m.p. 85°-90° C. (dec.).
Reaction SMILES: [C:1](=O)(OC(Cl)(Cl)Cl)[O:2]C(Cl)(Cl)Cl.[CH:13]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)([CH3:15])[CH3:14].[CH3:23][O:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[CH:32]([NH:34][C:35]1[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([NH2:45])[CH:41]=3)[N:36]=1)[CH2:31][CH2:30]2>>[CH:13]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:1]([NH:45][C:40]2[CH:41]=[C:42]3[C:37](=[CH:38][CH:39]=2)[N:36]=[C:35]([NH:34][CH:32]2[C:33]4[C:29](=[CH:28][CH:27]=[CH:26][C:25]=4[O:24][CH3:23])[CH2:30][CH2:31]2)[CH:44]=[CH:43]3)=[O:2])[CH2:18][CH2:17]1)([CH3:15])[CH3:14]
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)NC4CCN(C(C)C)CC4)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-isopropyl-piperidin-4-ylamine (CAS no. 127285-08-9) and rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example 172); MS: m/e=474.7 (M+H+).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]3[CH:34]=[CH:33][NH:32][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH2:24][C:25]([O:27]CCCC)=[O:26])[CH3:23])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].CC(O)=O.O>CO>[CH:1]1([NH:5][C:6]2[C:7]3[CH:34]=[CH:33][NH:32][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH2:24][C:25]([OH:27])=[O:26])[CH3:23])(=[O:20])=[O:21])=[CH:15][CH:14]=3)[N:11]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCCCOC(=O)CN(C)S(=O)(=O)c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CN(CC(=O)O)S(=O)(=O)c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.5 %

Procedure:
To a solution of butyl 2-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylphenylsulfonamido)acetate (15 mg, 0.031 mmol) in MeOH (2 mL), aqueous 1N NaOH (1.00 mL, 1.00 mmol) was added. The mixture was stirred at room temperature for 3 h. Glacial HOAc (0.20 mL) was added to neutralize NaOH. When water was added, precipitate came out, which was collected by filtration to give the titled compound (3 mg). MS 431.0 (M+H); UV 206.1, 312.7 nm.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[CH2:8]1[O:10][CH2:9]1.[CH2:11]([OH:13])[CH3:12]>>[OH:13][CH2:11][CH2:12][S:1][C:2]1[S:3][C:4]([S:7][CH2:9][CH2:8][OH:10])=[N:5][N:6]=1
Reactant: Sc1nnc(S)s1
Reactant: C1CO1
Reactant: CCO
Product: OCCSc1nnc(SCCO)s1

Procedure:
2,5-Dimercapto-1,3,4-thiadiazole(80.6 grams, 0.54 moles) and ethanol (150 ml) were charged into reaction flask and stirred. The flask was flushed with nitrogen and then ethylene oxide (54 grams, 1.3 moles) was added slowly via a gas inlet directly above the surface of the solution. The reaction mixture was refluxed with stirring for 15 minutes. The solvent was stripped off by using a rotary evaporator at approximately 20 mm Hg and 100° C. The product was a white solid and characterized by infrared absorption bands at 3350, 2900, 1675, 1385, 1285, 1050, 750, and 710 cm-1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:17](O)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C:14]([C:17](=[O:18])[N:31]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:30])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCc1ccccc1
Reactant: O=C(OCc1ccccc1)N1CCC(C(=O)O)(c2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CN(Cc1ccccc1)C(=O)C1(c2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 4-phenyl-piperidine-1,4-dicarboxylic acid monobenzyl ester (3.39 g, 10 mmol) and SOCl2 (7 mL, 100 mmol) in CHCl3 (150 mL) is heated at reflux for 3 h. The solvent and excess SOCl2 are evaporated into a cold trap and the residue is redissolved in CHCl3 (50 mL). The solution is added to a solution of methylbenzylamine (1.45 g, 12 mmol) and DIPEA (2 mL, 12 mmol) in cold (0° C.) CHCl3 (100 mL). The mixture is stirred for 15 h at r.t. and then quenched with sat. aq. Na2CO3 (50 mL). The phases are separated and the aq. phase is extracted with CH2Cl2 (2×50 mL). The combined organic extracts are washed with 1N aq. HCl (50 mL) and sat. aq. NaCl (50 mL), dried (Na2SO4), filtered and evaporated. The residue is purified by FC (SiO2, heptane-EtOAc) to provide the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[CH:33][CH:32]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][O:29][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[CH:33][CH:32]=3)=[CH:26][CH:27]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: OCc1ccc(CN(CCc2ccccc2)c2nc(-c3ccccc3)cs2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.5 %

Procedure:
To a solution of [4-[[(2-phenylethyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl]phenyl]methanol (409 mg, 0.98 mmol), methyl 3-(4-hydroxyphenyl)propanoate (195 mg, 1.18 mmol) and tributylphosphine (297 mg, 1.47 mmol) in tetrahydrofuran (20 mL) was added 1,1′-(azodicarbonyl)dipiperidine (371 mg, 1.47 mmol), and the mixture was stirred at room temperature for 16 hr. The insoluble materials were filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (273 mg, yield 50%) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:18](=[N:19][C:20]([NH:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[N:21][CH:22]=3)[N:17](COCC[Si](C)(C)C)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1(CCNC2N=C3N(COCC[Si](C)(C)C)N=C(C4C=CC=CC=4)C3=CN=2)CCOCC1.C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:18](=[N:19][C:20]([NH:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)=[N:21][CH:22]=3)[NH:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3ccccc3)c2)c2cnc(NCCN3CCOCC3)nc21
Agent: C[Si](C)(C)CCOCn1nc(-c2ccccc2)c2cnc(NCCN3CCOCC3)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(CNc2cccc(-c3n[nH]c4nc(NCCN5CCOCC5)ncc34)c2)cc1
Reaction time: 3 h

Procedure:
To a stirred solution of a mixture of [3-(3-benzylamino-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine and (2-morpholin-4-yl-ethyl)-[3-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-amine (210 mg, crude) in dichloromethane (5 mL) was added TFA (5 mL) at room temperature. The resulting mixture was stirred for another three hours at this temperature. The solvent was evaporated under reduced pressure and the residue was treated with saturated aqueous NaHCO3 (3 mL) and extracted with EtOAc (10 mL). The organic phase was washed with brine (5 mL) and dried to give crude product. It was purified by prep-HPLC to give [3-(3-benzylamino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine as yellow solid. (Yield 24 mg, 14.9%).
Reaction SMILES: FS([O-])(=O)=O.[C:6]([C@@H:9]1[CH2:13][C@H:12]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[CH2:11][N+:10]1([CH2:25][CH2:26][OH:27])[CH3:24])(=[O:8])[NH2:7].O[C@@H]([C@H]1[C:52](=[O:53])[N:33]2[CH:34]([C:39]([O:41]C([N+]([O-])=O)C3C=CC=CC=3)=[O:40])C(=O)[C@H](C)[C@H]12)C>>[C:6]([C@@H:9]1[CH2:13][C@H:12]([S:14][C:15]2[C@H:16]([CH3:17])[C@@H:21]3[C@@H:20]([C@H:19]([OH:22])[CH3:18])[C:52](=[O:53])[N:33]3[C:34]=2[C:39]([O-:41])=[O:40])[CH2:11][N+:10]1([CH2:25][CH2:26][OH:27])[CH3:24])(=[O:8])[NH2:7]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OC(c3ccccc3)[N+](=O)[O-])C(=O)[C@H](C)[C@H]12
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)[N+](C)(CCO)C2)cc1
Agent: O=S(=O)([O-])F
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@H]3C[C@@H](C(N)=O)[N+](C)(CCO)C3)[C@H](C)[C@H]12

Procedure:
Following a procedure similar to that described in Example 7, but using 0.37 g of (2S, 4S)-2-carbamoyl-1-(2-hydroxyethyl)-4-(4-methoxybenzylthio)-1-methylpyrrolidinium fluorosulfonate (prepared as described in preparation 16) [in step (1)] and 260 mg of -nitrobenzyl (1R, 5R, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate [in step (2)], 17 mg of the title compound were obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[N:22]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:31][OH:32].C1COCC1>C(#N)C.O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4](/[C:1](=[N:31]/[OH:32])/[CH3:2])=[CH:9][CH:8]=2)(=[O:12])=[O:11])=[C:15]([N:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[N:22]2)[CH:16]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Reactant: NO
Agent: [Ti+4]
Agent: CC[O-]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: C/C(=N\O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Temperature: 60 °C

Procedure:
A 4 mL vial was charged with 4-acetyl-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-benzenesulfonamide (synthesized according to general procedures F and G, 100 mg, 0.23 mmol), hydroxylamine hydrochloride (49 mg, 0.70 mmol), and 2 mL THF. The resultant slurry was mixed well, then titanium ethoxide (98 μL, 47 mmol) was added and the mixture heated to 60° C. overnight. The reaction mixture was subsequently diluted with ˜2 mL of acetonitrile/H2O and purified by reversed phase HPLC to afford N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-4-{1-[(E)-hydroxyimino]-ethyl}benzenesulfonamide: MS (ES) M+H expected 443.0, found 443.0.