Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14](O)=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O.[N+:28](C1OC(C2C(C(Cl)=O)=CN(C3C=CC=CC=3)N=2)=CC=1)([O-])=O>ClC(Cl)C>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]([NH2:28])=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: O=C(O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: NC(=O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reaction time: 8 h

Procedure:
Heat 1 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid together with 0.56 g of phosphorus oxychloride and 10 ml of dichloroethane for 2 hours at 80° C. Add 10 ml of a 25% aqueous solution dropwise at 0° C to the thus-obtained solution of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic chloride. Allow the resulting mixture to stand overnight and then vacuum distil it to remove the organic solvent therefrom. Vacuum filter to separate formed precipitate and recrystallize the filter residue from dimethylformamide/methanol to obtain 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxamide [m.p. 236° to 238° C].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[NH:21][C:22]2[C:23]3[C:30]([CH3:31])=[C:29]([C:32](O)=[O:33])[S:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:35]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[NH:21][C:22]2[C:23]3[C:30]([CH3:31])=[C:29]([C:32]([NH2:35])=[O:33])[S:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCN(C(=O)OC(C)(C)C)C3)c12
Reactant: N
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCN(C(=O)OC(C)(C)C)C3)c12

Procedure:
Prepared analogously to example 1.4 from 4-[2-((S)-1-tert-butoxycarbonyl-pyrrolidin-3-yloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia in methanol.
Reaction SMILES: [C:1]([F:16])([O:5][C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])=[C:2]([F:4])[F:3].[Si]([F:21])(C)(C)C>>[C:6]([O:5][CH:1]([C:2]([F:21])([F:4])[F:3])[F:16])([C:7]([C:8]([F:10])([F:9])[F:11])([F:12])[F:13])([F:14])[F:15]
Reactant: FC(F)=C(F)OC(F)(F)C(F)(F)C(F)(F)F
Reactant: C[Si](C)(C)F
Product: FC(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Yield: 1 %

Procedure:
Example 8 was repeated using the same reactor and catalyst/support charge. CF3CF2CF2OCF(CF3)CO2SiMe3 (16.20 g, 40.3 mmol) was added dropwise over 1.5 hr. There was obtained 13.94 g of liquid product consisting of an equimolar mixture of PPVE and TMSF. Less than 0.2% starting TMS ester remained, and less than 1% C3F7OCHFCF3 was produced.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:35])[CH:32]([CH3:34])[CH3:33]>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:12][CH:11]([C:26]3[O:28][N:35]=[C:31]([CH:32]([CH3:34])[CH3:33])[N:30]=3)[CH2:10]2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CC(C)C(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CC(C)c1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
200 mg (0.50 mmol) of the compound from Example 44A and 76 mg (0.75 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 2. Yield: 144 mg (58% of theory)
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:39][CH2:38][C:37]2[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reactant: NCc1ccc(F)cc1
Solvent: CCO
Solvent: O
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NCc4ccc(F)cc4)ncnc32)[C@]1(C)F
Yield: 54.8 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.2 g, 0.43 mmol) in ethanol (about 5 ml) was added 4-fluorobenzylamine (about 0.39 ml, 3.46 mmol) and refluxed for about 2 hours. Completion of the reaction monitored by thin-layer chromatography and water added to the reaction mixture. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compound (0.13 g) as a colorless gummy mass. Yield: 56%; 1H NMR (300 MHz, CDCl3): δ 8.74 (s, 1H), 8.38 (d, 1H, J=3.9 Hz), 8.06-8.03 (m, 2H), 7.58-7.56 (m, 1H), 7.47-7.42 (m, 2H), 6.46 (d, 1H, J=20.1 Hz), 4.94-4.72 (m, 2H), 4.66-4.59 (m, 1H), 2.11 (s, 3H), 1.79 (s, 3H), 1.41 (m, 3H); Mass: [M+Na]+: 485 (40%), [M+1]+ 463 (45%).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.Cl[S:32]([N:35]1[CH2:39][CH2:38][CH2:37][C@H:36]1[C:40]([O:42][CH3:43])=[O:41])(=[O:34])=[O:33].C(N(CC)CC)C>C(#N)C>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:32]([N:35]3[CH2:39][CH2:38][CH2:37][C@H:36]3[C:40]([O:42][CH3:43])=[O:41])(=[O:33])=[O:34])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: COC(=O)[C@@H]1CCCN1S(=O)(=O)Cl
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Temperature: 60 °C
Reaction time: 20 h
Yield: 16.1 %

Procedure:
The product of Example 205 (0.030 g, 0.0703 mmol) in acetonitrile (2 ml) was treated with the product of Example 461A (0.018 g, 0.077 mmol) and triethylamine (0.011 ml, 0.077 mmol), stirred at 60° C. for 20 hours and cooled to about 25° C. The solvent was evaporated under reduced pressure, and the residue was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/10 mM ammonium acetate in water over 8 minutes (10 minutes run time) at a flow rate of 40 mL/min give the title compound (7 mg, 16%). 1H NMR (300 MHz, DMSO-d6) δ 0.99 (d, J=6.25 Hz, 6 H) 1.59 (m, 2 H) 1.67 (m, 2 H) 1.87 (m, 4 H) 2.09 (d, J=8.46 Hz, 1 H) 3.60 (s, 3 H) 4.26 (dd, J=8.64, 3.86 Hz, 1 H) 4.50 (m, 2 H) 7.55 (m, 4 H) 7.73 (d, J=8.82 Hz, 1 H) 8.57 (dd, J=8.09, 1.84 Hz, 1 H) 8.90 (dd, J=4.78, 1.84 Hz, 1 H) 10.53 (s, 1 H) 14.07 (s, 1 H). MS (ESI−) m/z 617 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C)=[C:4]([CH:12]2[CH2:14][CH2:13]2)[CH:3]=1.Cl>CCOC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH:12]2[CH2:14][CH2:13]2)[CH:3]=1
Reactant: CC(=O)Nc1ccc(Cl)cc1C1CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(Cl)cc1C1CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A suspension of N-(4-chloro-2-cyclopropylphenyl)acetamide (689 mg, 3.29 mmol) in 2M HCl (aq) (25 ml, 823 mmol) was stirred at 100° C. for 3 hrs and then 90° C. for 16 hrs. The resulting mixture was cooled to RT, diluted with EtOAc and water and the layers separated. The organic layer was extracted with 0.1 M HCl (aq) and the organic portion was discarded. To the combined aqueous portions was added 2M NaOH (aq) until basic and resulting mixture was extracted with EtOAc (2×). The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under vacuum to give the title compound as a dark yellow oil.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:47]1([CH3:56])[CH:52]=[CH:51][CH:50]=[C:49]([CH2:53][CH2:54][NH2:55])[CH:48]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:55][CH2:54][CH2:53][C:49]4[CH:48]=[C:47]([CH3:56])[CH:52]=[CH:51][CH:50]=4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cccc(CCN)c1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCCc2cccc(C)c2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with N-(2-m-tolyl-ethyl)-amine (Oakwood) to give the title compound. LC-MS (ES+) 782 [(M+H)+].
Reaction SMILES: [CH2:1]([N:4]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C:5]1[C:10](=[O:11])[N:9]2[C@@H:12]([C:24](O)=[O:25])[CH2:13][C@:14]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:15])[C:8]2=[N:7][CH:6]=1)[CH:2]=[CH2:3].[CH2:37]([O:44][C:45](=[O:57])[NH:46][C:47]([C:49]1[CH:54]=[CH:53][C:52]([CH2:55][NH2:56])=[CH:51][CH:50]=1)=[NH:48])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:20]([O:19][C:17](=[O:18])[CH2:16][C@@:14]1([CH3:15])[C:8]2=[N:7][CH:6]=[C:5]([N:4]([CH2:1][CH:2]=[CH2:3])[C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[C:10](=[O:11])[N:9]2[C@@H:12]([C:24](=[O:25])[NH:56][CH2:55][C:52]2[CH:51]=[CH:50][C:49]([C:47]([NH:46][C:45]([O:44][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:57])=[NH:48])=[CH:54][CH:53]=2)[CH2:13]1)([CH3:21])([CH3:23])[CH3:22]
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)O)C[C@@]2(C)CC(=O)OC(C)(C)C
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)CC(=O)OC(C)(C)C
Yield: 63.7 %

Procedure:
Following a procedure similar to that for the preparation of 18 g, intermediate 38c (268.9 mg, 0.54 mmol) was coupled with [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid benzyl ester (223.9 mg, 0.70 mmol) to provide 262.3 mg (64%) of intermediate 38d. MS (ESI) 763.5 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]3[N:30]=[CH:29][C:28]4=[CH:31][CH:32]=[C:33]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[N:40]([S:42]([CH3:45])(=[O:44])=[O:43])[CH3:41])[N:27]4[N:26]=3)=[C:20]([O:46][CH3:47])[CH:19]=2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]3[N:30]=[CH:29][C:28]4=[CH:31][CH:32]=[C:33]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[N:40]([CH3:41])[S:42]([CH3:45])(=[O:44])=[O:43])[N:27]4[N:26]=3)=[C:20]([O:46][CH3:47])[CH:19]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: COc1cc(CN2CCN(C(=O)CNC(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(CN2CCN(C(=O)CN)CC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 25 °C

Procedure:
Into an 8 dram vial, {2-[4-(4-{7-[2-(Methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-3-methoxy-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (78 mg, 0.11 mmol), Methylene chloride (2.00 mL), and Trifluoroacetic Acid (1.00 mL, 13.0 mmol) were added. The reaction was stirred at room temperature over the weekend. The reaction was partitioned with saturated NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give a yellow solid The solid was partitioned with saturated NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The collected fractions afforded N-[2-(2-{4-[4-(2-Amino-acetyl)-piperazin-1-ylmethyl]-2-methoxy-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide as a yellow solid. LCMS (E/I+) 579.09 (M+H). NMR 1H (DMSO-d6)-8.96 (s, 1H), 7.93-7.99 (m, 1H), 7.90 (d, 1H, J=8.05 Hz), 7.72 (s, 1H), 7.63-7.73 (m, 1H), 7.52-7.58 (m, 2H), 7.00 (d, 1H, J=4.66 Hz), 6.93-6.98 (m, 2H), 6.74 (d, 1H, J=7.94 Hz), 3.84 (s, 3H), 3.35-3.46 (m, 8H), 3.05 (s, 3H), 2.88 (s, 3H), 2.32 (bs, 4H).
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])(=O)=O.N1C(C)=CC=CC=1C.[Br:24][C:25]1[CH:26]=[C:27]([CH2:31]O)[CH:28]=[N:29][CH:30]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:24][C:25]1[CH:30]=[N:29][CH:28]=[C:27]([CH2:31][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH:26]=1
Reactant: OCc1cncc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OCc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Tert-butyldimethylsilyl trifluoromethanesulfonate (1.174 ml, 5.11 mmol) was added to 2,6-lutidine (0.743 ml, 6.38 mmol) and (5-bromopyridin-3-yl)methanol (800 mg, 4.25 mmol) stirred in CH2Cl2 (10 ml) cooled to 0° C. and the mixture was stirred at 0° C. for 1 h. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The combined organic fractions were dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography to provide 3-bromo-5-({[tertbutyl(dimethyl)silyl]oxy}methyl)pyridine: MS: cal'd 325 (MNa+), exp 325 (MNa+).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:19][NH2:20]>C1(C)C=CC=CC=1>[O:11]([C@@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:19][NH2:20])=[O:2])[CH2:6][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: COC(=O)[C@H]1CC[C@@H](Oc2ccccc2)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: NNC(=O)[C@H]1CC[C@@H](Oc2ccccc2)CC1
Temperature: 120 °C

Procedure:
A mixture of cis-4-phenoxy-cyclohexanecarboxylic acid methyl ester (0.55 g, 2.3 mmol) and hydrazine hydrate (0.11 g, 2.3 mmol) was heated at 120° C. for 24 h. After cooling to room temperature the reaction mixture was suspended in toluene (70 ml). After evaporation of the solvent, the residue was suspended in toluene (70 ml) again. The solvent was evaporated and the residue was dried in high vacuo (1-2 mbar) to give the crude title compound (0.50 g, 92%) as light yellow foam, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[NH:4][C:5]([C:22](F)([F:24])[F:23])=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]([CH2:14][CH2:15][CH3:16])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C1CCN2C(=NCCC2)CC1>C1COCC1>[F:24][CH:22]([F:23])[C:5]1[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([CH2:14][CH2:15][CH3:16])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:3]([C:2]([F:27])([F:1])[F:26])[N:4]=1
Reactant: CCCC1C(C(=O)OCC)=C(C(F)(F)F)NC(C(F)(F)F)=C1C(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCc1c(C(=O)OCC)c(C(F)F)nc(C(F)(F)F)c1C(=O)OCC
Temperature: 0 °C
Yield: 64.7 %

Procedure:
A mixture of 20.0 g (0.05 mole) of diethyl 2,6-bis(trifluoromethyl)-l,4-dihydro-4-n-propyl-3,5-pyridinedicarboxylate, 7.62 g (0.05 mole) of DBU, and 200 ml of THF is held at reflux for 9 hours, cooled an poured into 500 ml of ice water. The mixture is extracted with ether (2×200 ml). The ether extract is washed with diluted hydrochloric acid, dried (MgSO4), and concentrated to give 12.4 g (64.5%) of the desired product, nD25 1.4436.
Reaction SMILES: [CH:1]1([C:10]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[C:15]([O:23][CH3:24])[CH:14]=2)=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.O.O[Li].O>C1COCC1>[CH:1]1([C:10]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:23][CH3:24])[CH:14]=2)=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(=O)C2CCc3ccccc32)cc1OC
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC(=O)C2CCc3ccccc32)ccc1C(=O)O
Temperature: 45 °C

Procedure:
To a stirred solution of methyl 4-(1-indanoyloxy)-2-methoxy-benzoate (125 mg, 0.43 mmol) in THF:H2O (1 mL: 0.2 mL) was added LiOH.H2O (35.2 mg, 0.84 mmol). The reaction was heated to 45° C. over 12 h and then cooled to ambient temperature. The solvent was removed under reduced pressure. The crude solid was passed through a small plug of silca gel packed in 80:20 hexanes:EtOAc and eluted with 50:50 hexanes:EtOAc. The solvent was removed under reduced pressure to afford 4-(1-indanoyloxy)-2-methoxy-benzoic acid as a foam.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([O:27]CC)=[O:26])=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)[O:11][CH:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)[O:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(-c3nc(-c4ccc(C)cc4)co3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2coc(-c3ccc(-c4ccc(C(=O)O)cc4)cc3)n2)cc1
Reaction time: 18 h

Procedure:
A solution of Example 186C (130 mg, 0.34 mmol) in THF (15.0 mL) and methanol (5.0 mL) at room temperature was treated with 2N sodium hydroxide (3.0 mL), stirred for 18 hours, concentrated, treated with water (2.0 mL), and adjusted to pH<7 with 2N HCl. The precipitate was filtered and dried under vacuum to provide the desired product. MS (DCI) m/e 356 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ8.72 (s, 1H), 8.18-8.15 (m, 2H), 8.08-8.04 (m, 4H), 7.97-7.86 (m, 4H), 7.31-7.28 (m, 2H), 2.35 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>C(Cl)Cl.O.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[N:19]([CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)=[O:18])=[N+:20]=[N-:21]
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: [N-]=[N+]=NCC(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 4 h
Yield: 94.5 %

Procedure:
To a mixture of 1-(4-benzyloxy-phenyl)-2-bromo-ethanone (28.55 g; 93.6 mmol) in CH2Cl2 (300 mL) and water (30 mL) was added nBu4NBr (1.51 g; 4.7 mmol) and NaN3 (6.69 g; 102.9 mmol) in one portion. After 4 h at RT, the layers were separated. The organic layer was washed water, dried (Na2SO4), filtered and concentrated in vacuo to afford 2-azido-1-(4-benzyloxy-phenyl)-ethanone (23.64 g).
Reaction SMILES: [O:1]1[C@@H:3]2[CH2:4][C:5]3[C:10]([C@H:2]12)=[CH:9][CH:8]=[CH:7][CH:6]=3.C(#[N:13])C.S(=O)(=O)(O)O>O>[NH2:13][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:1]
Reactant: CC#N
Reactant: c1ccc2c(c1)C[C@H]1O[C@@H]21
Agent: O=S(=O)(O)O
Solvent: O
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: -16 °C
Reaction time: 1.5 h
Yield: 49.8 %

Procedure:
Into a 300 ml four-neck flask, 10.0 g (75.8 mmol) of cis-(±)-1,2-epoxyindan (VI) and 40 ml of acetonitrile were introduced. This mixture was cooled to -16° C. in an ice/salt bath. To this mixture, 10.62 g (113.6 mmol) of fuming sulfuric acid (containing 25% of sulfuric anhydride) was dropwise added at -13° to -17° C. in a period of 1.5 hour. The mixture was left for 1.5 hour to return to room temperature. An HPLC analysis of the contents revealed that 21.2% of cis-oxazoline derivative (IV: R=CH3) had been generated while no trans-amide derivative (III': R=CH3, Y=OH) was detected. Then, 72 ml of water was added thereto. The resulting mixture was treated in the same manner as Example 8 to yield 5.62 g (yield: 49.8%) of cis-(±)-1-aminoindan-2-ol (V) as a white crystal. Its purity determined by an HPLC was 98.7%.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[C:13]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]([O:37]CC2C=CC(OC)=CC=2)[CH:22]([CH2:30][CH2:31]OS(C)(=O)=O)[C:23]([O:25]C(C)(C)C)=[O:24])=[CH:15][CH:14]=1>CN(C)C=O>[C:13]1([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH:21]([OH:37])[CH:22]([CH2:30][CH2:31][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[C:23]([OH:25])=[O:24])=[CH:17][CH:18]=1
Reactant: COc1ccc(COC(CCc2ccc(-c3ccccc3)cc2)C(CCOS(C)(=O)=O)C(=O)OC(C)(C)C)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(O)C(CCN1C(=O)c2ccccc2C1=O)C(O)CCc1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
Potassium phthalimide (8.8 mg, 60 μmol) was added in one portion to a stirred solution of 1,1-dimethylethyl 5-(4-biphenylyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)-2-{2-[(methylsulfonyl) oxy]ethyl}pentanoate (28.4 mg, 50 μmol) in dimethylformamide (0.5 mL) under nitrogen at room temperature. The resulting solution was heated at 80° C. for 1 h 45 min then cooled to room temperature. The volatiles were evaporated and the residue taken up in dichloromethane (0.5 mL). Trifloroacetic acid (0.5 mL) was added in one portion and the resulting solution stirred for 1 h at room temperature. The volatiles were evaporated and the residue purified by mass directed auto-preparative HPLC to give the title compound as a white solid (6.0 mg, 27%). LC/MS: 3.43 min; z/e 444, calcd (M+1) 444. 1H NMR (400 MHz: CDCl3): 7.85 (2H), 7.70 (2H), 7.55 (1H), 7.50 (1H), 7.45 (2H), 7.30 (1H), 7.25 (4H), 3.85 (3H), 2.95 (1H), 2.75 (1H), 2.60 (1H), 2.20 (1H), 2.05 (1H), 1.90 (2H).