Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=[CH:8][CH:7]=1)([OH:3])=[O:2].B(C1C=CC([C:53]2C=C(C(O)=O)[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[N:54]=2)=CC=1)(O)O.B(O)O>>[C:37]([C@:21]12[CH2:33][CH2:32][C@@H:31]([C:34]([CH3:36])=[CH2:35])[C@@H:22]1[C@@H:23]1[C@@:18]([CH3:40])([CH2:19][CH2:20]2)[C@@:17]2([CH3:41])[C@@H:26]([C@:27]3([CH3:30])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:43])([CH3:42])[C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:5]4[CH:53]=[N:54][C:55]5[C:60]([C:4]=4[C:1]([OH:3])=[O:2])=[CH:59][CH:58]=[CH:57][CH:56]=5)=[CH:7][CH:8]=2)=[CH:29][CH2:28]3)[CH2:25][CH2:24]1)([OH:39])=[O:38]
Reactant: O=C(O)c1cc(-c2ccc(B(O)O)cc2)nc2ccccc12
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: OBO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(-c7cnc8ccccc8c7C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for compound (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(2-carboxyethyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (example 4a) using 2-(4-boronophenyl)quinoline-4-carboxylic acid as the reactant boronic acid. The product was isolated as a white solid (4.7 mg, 27%). LCMS: m/e 684.65 (M−H)−, 5.11 min (method 3). 1H NMR (400 MHz, <DMSOmix>) δ ppm 0.95-1.00 (m, 9H), 1.01 (s, 6H), 1.05-1.77 (m, 17H), 1.69 (s, 3H), 1.80-1.94 (m, 2H), 2.07-2.23 (m, 2H), 2.31-2.38 (m, 1H), 2.94-3.06 (m, 1H), 4.59 (s, 1H), 4.72 (s, 1H), 5.33 (d, J=6.15 Hz, 1H), 7.30 (d, J=7.32 Hz, 2H), 7.59-7.67 (m, 1H), 7.74-7.84 (m, 1H), 8.08-8.14 (m, 1H), 8.18 (d, J=8.79 Hz, 2H), 8.32-8.42 (m, 1H), 8.72 (d, J=6.15 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([C:26]([OH:28])=O)[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.[Cl-].[F:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][NH3+:53])=[C:48]([C:54]([NH:56][CH3:57])=[O:55])[CH:47]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([N:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:10]([C:26]([NH:53][CH2:52][C:49]2[CH:50]=[CH:51][C:46]([F:45])=[CH:47][C:48]=2[C:54]([NH:56][CH3:57])=[O:55])=[O:28])[C:9]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1c(OCc2ccccc2)c2ncccc2n(Cc2ccccc2)c1=O
Reactant: CNC(=O)c1cc(F)ccc1C[NH3+]
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1c(OCc2ccccc2)c2ncccc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyl-4-(benzyloxy)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylic acid (0.15 g, 0.39 mmol) in DMF (4 mL) was added HOAT (0.26 g, 1.94 mmol) and EDC (0.07 g, 0.47 mmol). The solution was stirred for 10 minutes at which time EDC (0.036 g, 0.23 mmol), {4-fluoro-2-[(methylamino)carbonyl]phenyl}methanaminium chloride (0.108 g, 0.47 mmol), and DIEA (0.10 g, 0.78 mmol) were added. The reaction was then stirred at room temperature overnight at which time the solution was purified by preparative reverse phase HPLC eluting with a gradient of 5-95% acetonitrile/water (0.1% TFA). The fractions that contained the desired product were concentrated. Note that during the prep des-O-benzyl product was also obtained. The mixture was taken on to the next step.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([NH:22][CH:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)=[N:19][N:18]=4)=[C:13]([NH:36][CH:37]([CH3:39])[CH3:38])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl>C(Cl)Cl.CCOCC>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:12]=[C:13]([NH:36][CH:37]([CH3:39])[CH3:38])[C:14]([C:17]4[O:21][C:20]([NH:22][CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)=[N:19][N:18]=4)=[CH:15][N:16]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(NC2CCN(C(=O)OC(C)(C)C)CC2)o1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(NC2CCNCC2)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of tert-butyl 4-((5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)piperidine-1-carboxylate (Example 111) (250 mg, 0.3 mmol) in DCM (10 mL), Ether.HCl (10 mL) was added at −10° C. Stirred the reaction mixture at 0° C. for 30 min. Reaction temperature was slowly brought to room temperature. The reaction mass was concentrated under reduced pressure to dryness. The material obtained was purified by prep. HPLC to afford the title compound, N2-(benzo[d]thiazol-6-yl)-N4-isopropyl-5-(5-(piperidin-4-ylamino)-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine 1H NMR: 400 MHz, CD3OD: δ 1.37 (d, J=6.40 Hz, 6H), 1.90-2.00 (m, 2H), 2.33-2.37 (m, 2H), 3.20-3.29 (m, 2H), 3.50-3.53 (m, 2H), 3.87-3.93 (m, 2H), 6.28 (s, 1H), 7.63 (dd, J=1.20, 8.40 Hz, 1H), 8.21-8.27 (m, 3H), 9.54 (bs, 1H). LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.277 min; LCMS (ES-API), m/z 451.2 (M−H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 30 min (36 min run time); Flow rate: 1.0 μL/min; Retention time: 8.965 min; Purity: 98.1%.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Na].Br[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>CO.O>[CH:2]([C:1]([O:8][CH3:9])=[O:7])([C:3]([O:5][CH3:6])=[O:4])[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CCC/C=C\CBr
Reactant: COC(=O)CC(=O)OC
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)CCC/C=C\CC(C(=O)OC)C(=O)OC
Reaction time: 0.25 h

Procedure:
Dimethyl malonate (39.6 g) is added slowly with cooling and stirring to a solution of 6.9 g of sodium dissolved in 100 ml of absolute methanol and the mixture stirred for 15 min. The bromoester of formula 9, methyl cis-7-bromo-5-heptenoate (65.7 g) is added dropwise. The mixture is heated at reflux for 1 hr., cooled and diluted with water. The mixture is extracted with ether. The ether extracts are dried (Na2SO4) and concentrated. The residue is distilled under reduced pressure to give the title compound, b.p. 140° - 150° C/0.7 mm.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:6]=2[N:7]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[O:15]1[CH2:16][CH2:17][N:12]([C:8]2[C:6]3[N:7]=[C:2]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[N:3]=[C:4]([N:18]4[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]4)[C:5]=3[N:11]=[CH:10][N:9]=2)[CH2:13][CH2:14]1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc(Cl)nc3c(N4CCOCC4)ncnc23)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(N4CCOCC4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-8-morpholino-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 232°-233° C.) and piperazine.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])=[N:7][C:6]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=O)[O:26]C4C=CC=CC=4)=[CH:20][CH:19]=3)=[N:5][C:4]=2[CH2:3]1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38]>>[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH:38][C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([C:6]2[N:7]=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])[C:9]3[CH2:10][N:2]([CH3:1])[CH2:3][C:4]=3[N:5]=2)=[CH:19][CH:20]=1)=[O:26]
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc2c1CN(C)C2
Reactant: CN(C)CCN
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCN(C)C)cc2)nc2c1CN(C)C2

Procedure:
Method as described for example 51 using intermediate 10 and N1,N1-dimethylethane-1,2-diamine as starting materials. Purified by prep. LCMS (high pH).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.S([O-])([O-])=[O:16].[Na+].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][N+:3]=1[O-:16]
Reactant: Cc1ccc(Oc2ccccc2)cn1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(Oc2ccccc2)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2-methyl-5-phenoxy-pyridine (3.6 g, 19 mmol) described in Manufacturing Example 121-1-1,3-chloroperoxybenzoic acid (5.6 g, 33 mmol), and methylene chloride (80 mL) was stirred at room temperature for 45 minutes. Aqueous sodium sulfite was added to the reaction solution, and the organic layer was separated and was washed with 5 N aqueous sodium hydroxide (7 mL). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain 2-methyl-5-phenoxy-pyridine 1-oxide (3.3 g). 2-methyl-5-phenoxy-pyridine 1-oxide (3.3 g, 16 mmol) and acetic anhydride (20 mL) were stirred for 40 minutes at 115° C. Acetic anhydride was evaporated under a reduced pressure, aqueous sodium bicarbonate and ethyl acetate were added to the residue, and the organic layer was separated. The ethyl acetate solution was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate=2:1) to obtain an acetic acid 5-phenoxy-pyridin-2-ylmethyl ester (3.0 g). Acetic acid 5-phenoxy-pyridin-2-ylmethyl ester (3.0 g, 12 mmol), 5 N aqueous sodium hydroxide (8.0 mL), and methanol (20 mL) were stirred for 20 minutes at 60° C. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain the title compound (2.6 g, 65%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[BrH:22]>O>[Br:22][C:2]1[CH:3]=[C:4]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Br
Reactant: Nc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: OC(c1cccc(Br)c1)(C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of 2-(3-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (3.1 g, 12 mmol) in HBr (48%, 24 mL) and H2O (4.8 mL) was added NaNO2 (990 mg, 14 mmol) in H2O (3 mL) dropwise at 0° C. The mixture was stirred at 0° C. for 30 minutes and was then added to a solution of CuBr (6.9 g, 48 mmol) in HBr (48%, 24 mL) and H2O (4.8 mL) at 0° C. The mixture was stirred at 0° C. for 30 min. The mixture was partitioned between ethyl acetate and H2O. The aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine and dried over MgSO4. Solvent was removed and the residue was purified by column chromatography (0-20% ethyl acetate-hexane) to yield 2-(3-bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (3.1 g, 79%). 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.57 (t, J=0.8 Hz, 1H), 7.55 (t, J=0.9 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H), 3.62 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][N:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH2:33][C:34]2[CH:39]=[CH:38][C:37](Br)=[CH:36][CH:35]=2)[NH:23][S:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])[N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[F:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[Cl-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:1]([O:5][C:6](=[O:41])[CH2:7][N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:46]3[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=3)=[CH:36][CH:35]=2)[NH:23][S:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])[N:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(Br)cc2)NS(=O)(=O)c2cccnc2)n1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(-c3ccc(F)cc3)cc2)NS(=O)(=O)c2cccnc2)n1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 94.2 %

Procedure:
To a solution of tert-butyl({6-[(4-bromobenzyl)(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-yl}tert-butoxycarbonylamino)acetate (185 mg, 0.285 mmol) obtained in Example 9-(a) in toluene (2 ml) were added 4-fluorophenylboronic acid (61.3 mg, 0.438 mmol), palladium acetate (4.9 mg, 0.044 mmol), tripotassium phosphate (202 mg, 0.953 mmol) and water (0.2 ml), followed by being subjected to argon atmosphere. Then a solution of tricyclohexylphosphine in 20% toluene (130 μl, 0.088 mmol) was added to the mixture, and it was stirred at 100° C. for 2.5 hours under argon atmosphere. After completion of the reaction, a saturated aqueous sodium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=9:1→7:3 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (178 mg) as a white foam. (Yield: 94%)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([F:20])=[C:18](Cl)[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C([Li])CCC.[I:27]I>O1CCCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([F:20])=[C:18]([I:27])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Fc1c(-c2ccc3c(c2)OCO3)nc2ccccc2c1Cl
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Fc1c(-c2ccc3c(c2)OCO3)nc2ccccc2c1I
Reaction time: 3 h
Yield: 48.8 %

Procedure:
To a −78° C. solution of 2-benzo[1,3]dioxol-5-yl-4-chloro-3-fluoro-quinoline (from step A, 0.073 g, 0.24 mmol) in tetrahydrofuran (2 mL) was added butyl lithium (0.36 mL, 2.5 M in hexane, 0.6 mmol). The resulting reaction mixture was stirred for 3 h., after which a solution of iodine (0.06 g, 0.24 mmol) in 0.8 mL of THF was added. The reaction mixture was stirred for an additional 2 h. and diluted with water (20 mL). The aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic layers were dried over sodium sulfate, concentrated and purified via silica gel column chromatography to give the title compound (0.046 g, 48%). MS (ES) 393.8 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:21])[NH:10][N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:28]([O:34][C@@H:35]1[C@@H:40]([O:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[C@H:39]([O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:38]([CH2:55][O:56][C:57](=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59])[O:37][C@@H:36]1Br)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].O>C(#N)C>[CH2:1]([C:8]1[C:9]([O:21][C@@H:36]2[O:37][C@H:38]([CH2:55][O:56][C:57](=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59])[C@@H:39]([O:48][C:49](=[O:54])[C:50]([CH3:51])([CH3:52])[CH3:53])[C@H:40]([O:41][C:42](=[O:47])[C:43]([CH3:44])([CH3:45])[CH3:46])[C@H:35]2[O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:30])[CH3:31])=[N:10][N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)n1[nH]c(=O)c(Cc2ccccc2)c1C(C)C
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(Cc2ccccc2)c1C(C)C
Temperature: 25 °C
Yield: 55 %

Procedure:
To a solution of 4-benzyl-1-ethoxycarbonyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (0.100 g) in acetonitrile (3 mL) were added potassium carbonate (0.0575 g) and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (0.211 g) successively under stirring at room temperature. In addition, the mixture was stirred at 50° C. for 2.5 hours. The mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/8 to 1/5 to 1/4) to give 4-benzyl-1-ethoxycarbonyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.15 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:5])[CH2:4][NH:3]1.[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1>N1C=CC=CC=1.CCOCC>[CH3:1][C:2]1([CH3:5])[CH2:4][N:3]1[S:12]([C:9]1[CH:10]=[CH:11][C:6]([CH3:16])=[CH:7][CH:8]=1)(=[O:14])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)CN1
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N2CC2(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.2 %

Procedure:
To a solution of 2,2-dimethylaziridine (5.42 g; 0.076 mole; sold by Polysciences, Inc., Warrington, Pa.) in pyridine (100 mL) cooled in an ice bath, is added p-toluenesulfonyl chloride (21.81 g; 0.114 mole) in one portion. The reaction is stirred at 0° C. for 2 hours; diluted with ether (400 mL); washed with cold 10% H3PO4 (2×150 mL), with a saturated NaHCO3 solution (3×150 mL) and brine (1×150 mL); and dried over MgSO4. Rotary evaporation of the solution affords a yellowish solid which is crystallized from ethyl acetate to yield the product 2,2-dimethylN-p-toluenesulfonyl-aziridine (4.48 g). 1H NMR (CDCl3): 1.53 (6H, s), 2.45 (5H, m), 7.2-8.0 ppm (4H, m, aromatics).
Reaction SMILES: [CH3:1][C@H:2]([CH:30]=[CH2:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C@@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19]C=C)[CH:13]=1)=[O:4].CC1C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:1][C@H:2]1[C:3](=[O:4])[NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH:13]=2)[C@@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19][CH:31]=[CH:30]1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccccc2NC(=O)[C@H](C)C=C)ccn1
Agent: C[C@@H]1/C=C/C[C@H](NC(=O)OC(C)(C)C)c2cc(ccn2)-c2ccccc2NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: C[C@@H]1C=CC[C@H](NC(=O)OC(C)(C)C)c2cc(ccn2)-c2ccccc2NC1=O
Temperature: 40 °C
Reaction time: 4.5 h

Procedure:
To a round bottom flask was added 45E (1.34 g, 3.18 mmol), pTsOH (0.665 g, 3.50 mmol), and dichloromethane (265 ml). The clear yellow solution was degassed with argon for 30 min. The reaction was then warmed to 40° C. for 1 h. Then a solution of GrubbsII (0.486 g, 0.572 mmol) in DCM (4 mL) was added dropwise to the reaction mixture. After 4.5 h, the reaction was cooled to rt, washed with sat. NaHCO3, brine, dried over MgSO4, filtered, and concentrated to give brown solid. The residue was purified by silica gel chromatography to give the desired product (0.97 g, 78%) as light brownish foam. 1H NMR (500 MHz, METHANOL-d4) δ 8.57-8.52 (m, 1H), 7.51-7.41 (m, 3H), 7.34-7.30 (m, 1H), 7.28 (dd, J=5.2, 1.7 Hz, 1H), 6.92 (s, 1H), 5.71 (ddd, J=15.3, 10.5, 4.7 Hz, 1H), 4.61 (dd, J=11.4, 3.4 Hz, 1H), 4.39 (dd, J=15.1, 9.4 Hz, 1H), 3.14-3.07 (m, 1H), 2.72 (ddd, J=8.6, 7.2, 3.7 Hz, 1H), 2.05-1.95 (m, 1H), 1.44 (s, 9H), 1.04 (d, J=6.9 Hz, 3H). MS (ESI) m/z: 394.1 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[O:9][N:8]=[CH:7][CH:6]=1.O.[NH2:12][NH2:13]>C(O)CCC>[O:9]1[C:5]([CH2:4][C:3]([NH:12][NH2:13])=[O:2])=[CH:6][CH:7]=[N:8]1
Reactant: NN
Reactant: COC(=O)Cc1ccno1
Solvent: O
Solvent: CCCCO
Product: NNC(=O)Cc1ccno1
Yield: 41 %

Procedure:
As described for example 112a, isoxazol-5-yl-acetic acid methyl ester in butanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture was heated under reflux for 4 h. Evaporation of all volatiles and chromatography (SiO2, dichloromethane:methanol:aq.ammonia (25%)=100:0:0 to 90:10:1) afforded the title compound as a white solid (yield: 41%). 1H-NMR (300 MHz, DMSO): δ=3.65 (s, 2H), 4.31 (s, 2H), 6.32 (s, 1H), 8.46 (s, 1H), 9.32 (s, 1H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.Br[C:27]1[C:28]([F:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[F:34][C:28]1[C:27]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH2:12]3)=[CH:32][CH:31]=[C:30]([CH3:33])[N:29]=1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: Cc1ccc(Br)c(F)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)c(F)n1

Procedure:
To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (250 mg, 0.68 mmol) in dry 1,4 dioxane (5 ml), polymer supported Pd(PPh3)4 (14 mg, 0.5 mmol/g, 0.007 mmol) was added along with 3-bromo-2-fluoro-6-methylpyridine (194 mg, 1.02 mmol) and 680 μl of a 2M Na2CO3 solution in water. The resulting mixture was heated at 90° degrees for 3 hours. Then after cooling the resin was removed by filtration and then the solvent was removed under reduced pressure. The residue was taken up with DCM, washed with water and loaded on a 25M+ silica cartridge eluating with a cyclohexane/AcOEt 75/25 mixture. 175 mg of title compound were recovered as white solid (74%). Due to the use of chiral Intermediate 7, the final compound is believed to be N-[(2S)-5-(2-fluoro-6-methyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N:4][N:3]=1
Reactant: CCCCCC(=O)Nc1nnc(C)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCNc1nnc(C)s1

Procedure:
N-(5-Methyl-1,3,4-thiadiazol-2-yl)-hexanamide (16 g, 0.075 mole) was added portionwise to stirred tetrahydrofuran (THF) (120 ml) containing lithium aluminium hydride (2.9 g, 0.076 mole) at a temperature below 15° C. The mixture was stirred and refluxed for 2 hours. The mixture was cooled in ice and treated with water (2.9 ml) in THF (29 ml) followed by a 2 N solution of sodium hydroxide (2.9 ml) and water (5.8 ml). The mixture was then treated with `Supercel` and filtered. The filtrate was evaporated to give the title product which was recrystallised from 50% aqueous methanol (9.5 g) m.p. 101°-105° C.