Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)=[O:12])=[CH:9][CH:8]=[C:7]([CH2:22][OH:23])[N:6]=1)=[O:4].C(N(C(C)C)C(C)C)C.[CH3:33][Si:34]([CH3:41])([CH3:40])[CH2:35][CH2:36][O:37][CH2:38]Cl>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)=[O:12])=[CH:9][CH:8]=[C:7]([CH2:22][O:23][CH2:38][O:37][CH2:36][CH2:35][Si:34]([CH3:41])([CH3:40])[CH3:33])[N:6]=1)=[O:4]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1nc(CO)ccc1C(=O)c1ccc2c(c1)OCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1nc(COCOCC[Si](C)(C)C)ccc1C(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a dichloromethane(9 ml) solution of 6-hydroxymethyl-3-(3,4-methylenedioxyphenylcarbonyl)pyridine-2-carboxylic acid methyl ester(1.71 g,4.50 mmol) were added ethyldiisopropylamine(3.9 ml) and 2-trimethylsilylethoxymethyl chloride(2.4 ml) at room temperature. The mixture was stirred at room temperature for 17 h, partitioned between AcOEt and water, The organic layer was washed with a saturated aqueous solution of NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by MPLC(E. Merck lobar column Kieselgel 60/hexane:AcOEt=3:1 to 1:1) to give 6-(2-trimethylsilylethoxymethoxymethyl)-3-(3,4-methylenedioxyphenylcarbonyl)pyridine-carboxylic acid methyl ester(1.44 g).
Reaction SMILES: [SH:1][CH2:2][C:3]1[N:4]=[C:5]([CH3:10])[S:6][C:7]=1[CH:8]=O.C(O)(=O)C>C(O)C>[CH3:10][C:5]1[S:6][C:7]2[C:3](=[CH:2][S:1][CH:8]=2)[N:4]=1
Reactant: Cc1nc(CS)c(C=O)s1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nc2cscc2s1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
5 mmol of 4-(mercaptomethyl)-2-methyl-1,3-thiazole-5-carbaldehyde was dissolved in 50 ml of ethanol, then 50 mmol of acetic acid was added, and stirring was continued for 1 hour at a room temperature. Then the temperature was heated up to 80° C. to carry out the reaction for 4 hours. The reacted liquid was cooled down to a room temperature. The solvent was evaporated out and then purification was carried out using column separation with solvents of ethylacetate and hexane, obtaining 2-methylthieno[3,4-d][1,3]thiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:29]([F:28])[CH:30]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: O=C(Cl)c1cccc(F)c1
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4cccc(F)c4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VII as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16 above) with commercially available 3-fluorobenzoyl chloride gave the title compound. ES-MS m/e (%): 503.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][C:9]([CH2:11][OH:12])=[N:10][C:5]2=[CH:4][CH:3]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:15])[C:9]([CH2:11][OH:12])=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CI
Reactant: OCc1nc2ccc(Cl)nc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CO)nc2ccc(Cl)nc21

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that 3.00 g of 5-chloro-2-hydroxymethyl-3H-imidazo[5,4-b]pyridine (prepared as described in Preparation 43), 0.71 g of sodium hydride (as a 55 by weight dispersion in mineral oil), 1.1 ml of methyl iodide and 70 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 10:1 by volume as the eluent, to give 1.60 g of the title compound, melting at 204-210° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:28]I>C1COCC1.[H-].[Na+]>[C:1]([O:5][C:6](=[O:27])[N:7]([CH3:28])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
{2-[4-(3-Trifluoromethyl-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (333 mg, 0.873 mmol, 1 eq) was dissolved in dry THF (4.5 ml) and NaH, 60% (101 mg, 2.53 mmol, 2.9 eq) was added. After 30 min, the reaction mixture was treated with methyl iodide (545 μl, 8.73 mmol, 10 eq) and was stirred overnight. After overnight the excess NaH was quenched by a slow addition of water, diluted with brine (30 ml) and extracted with Et2O (3×20 ml). Combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give a product methyl-{2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (306 mg, yield=78%, purity=88%). [M+H]+=396.43 1H NMR (300 MHz; CDCl3) δ/ppm 1.43 (s, 9H), 2.74-2.93(m, 5H), 3.44 (t, J=8.53 Hz, 2H), 6.92-6.99 (m, 2H), 7.09-7.24 (m, 4H), 7.29-7.35 (m, 1H), 7.37-7.45 (m, 1H)
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2I)[CH:8]=1)#[N:2].[CH2:18]([C:20]1[N:24]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[N:23]=[C:22]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:21]=1)[CH3:19].O(C(C)(C)C)[Na]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:29]1[C:28]([NH2:31])=[CH:27][CH:26]=[C:25]([N:24]2[C:20]([CH2:18][CH3:19])=[CH:21][C:22]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[N:23]2)[CH:30]=1)#[N:2]
Reactant: N#CCCCOc1ccc2c(I)cccc2c1
Reactant: CCc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCc1cc(-c2cccnc2)nn1-c1ccc(N)c(-c2c(OCCCC#N)ccc3ccccc23)c1
Yield: 90.8 %

Procedure:
A mixture of 2-(3-cyanopropoxy)-5-iodonaphthalene (77.0 mg, 0.228 mmol), with 5-ethyl-3-(3-pyridyl)-1-(4′-aminophenyl)pyrazole (72.4 mg, 1.2 equiv.), NaO-t-Bu (40.8 mg, 1.86 equiv.), Pd2(dba)3 (5.2 mg, 2.5% equiv.) and (−)B1NAP (10.6 mg, 7.5% equiv.) in toluene (1 mL) was heated at 80° C. for 18 h. The mixture was diluted with ethyl acetate, filtered through diatomaceous earth and concentrated. Chromatography on silica gel gave the title compound (98.0 mg, 90.8%). 1H-NMR (CDCl3): 1.30 (t, J=7.4 Hz, 3H), 2.20-2.25 (m, 2H), 2.62-2.74 (m, 4H), 4.22 (t, J=5.4 Hz, 2H), 6.31 (bs, 1H), 6.59 (s, 1H), 6.99 (d, J=8.6 Hz, 2H), 7.17 (d, J=9.1 Hz, 1H), 7.20 (s, 1H), 7.29-7.34 (m, 4H), 7.43 (t, J=8.0 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.98 (d, J=9.2 Hz, 1H), 8.21 (d, J=7.9 Hz, 1H), 8.56 (d, J=4.2 Hz, 1H), 9.11 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:38][C:39]1[N:40]=[C:41]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[C:42]2[S:47][CH:46]=[CH:45][C:43]=2[N:44]=1.C(C1CCN(C(OC(C)(C)C)=O)CC1)=O>ClCCl>[Cl:38][C:39]1[N:40]=[C:41]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[C:42]2[S:47][C:46]([CH:2]([OH:1])[CH:3]3[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]3)=[CH:45][C:43]=2[N:44]=1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reaction time: 2 h
Yield: 21 %

Procedure:
Tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (1 g) in 20 mL of dichloromethane was combined with 2 g of Dess-Martin periodinane and stirred for 2 h, filtered through celite, extracted with saturated sodium bicarbonate, and evaporated. The crude product was placed on a column and 325 mg of the aldehyde, tert-butyl 4-formylpiperidine-1-carboxylate, was isolated. 260 mg 2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4 was reacted with 325 mg of tert-butyl 4-formylpiperidine-1-carboxylate following General Procedure D to give 100 mg of tert-butyl 4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(hydroxy)methyl)piperidine-1-carboxylate. The Boc group was removed from 100 mg of the alcohol using 0.125 mL of a 4.0 M HCl solution in dioxane in 10 mL of DCM with 0.5 mL of methanol. After several hours the DCM, methanol, and HCl was evaporated. The crude amine, (2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(piperidin-4-yl)methanol, was mesylated in 3 mL of DCM and 0.04 mL of triethylamine with 0.03 mL of methanesulfonyl chloride. The 4-N-methylsulfonylpiperidinyl compound was then coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 following General Procedure A to give 70 mg of 353 after reversed phase HPLC purification. MS (Q1) 530 (M)+
Reaction SMILES: C(O)(=O)C.N[CH:6]([OH:12])[CH2:7][C:8]([O:10][CH3:11])=[O:9].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:27]([O:34][C:35]1[C:36]([CH2:65][CH3:66])=[C:37]([CH2:55][CH2:56][NH:57][CH:58]([OH:64])CC(OC)=O)[C:38]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:40]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCCl>[CH2:27]([O:34][C:35]1[C:36]([CH2:65][CH3:66])=[C:37]([CH2:55][CH2:56][N:57]2[CH:7]([C:8]([O:10][CH3:11])=[O:9])[CH2:6][O:12][C:58]2=[O:64])[C:38]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:40]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCc1c(OCc2ccccc2)cc(OCc2ccccc2)c(-c2ccccc2)c1CCNC(O)CC(=O)OC
Reactant: COC(=O)CC(N)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCc1c(OCc2ccccc2)cc(OCc2ccccc2)c(-c2ccccc2)c1CCN1C(=O)OCC1C(=O)OC
Yield: 63 %

Procedure:
In the same manner as in the step 1 in Example 316, methyl 3-{2-[3,5-bis(benzyloxy)-2-ethyl-6-phenylphenyl]ethylamino}-3-hydroxypropionate was obtained from 2-[3,5-bis(benzyloxy)-2-ethyl-6-phenylphenyl]ethanal (280 mg, 0.64 mmol) obtained in the step 1 in Example 218, using acetic acid (0.6 mL), methyl 3-amino-3-hydroxypropionate (150 mg, 0.97 mmol), sodium triacetoxyborohydride (270 mg, 1.3 mmol) and 1,2-dichloroethane (6.0 mL). Then, in the same manner as in the step 2 in Example 315, methyl 3-{2-[3,5-bis(benzyloxy)-2-ethyl-6-phenylphenyl]ethyl}-2-oxo-1,3-oxazolidine-4-carboxylate (230 mg, 63%) was obtained from methyl 3-{2-[3,5-bis(benzyloxy)-2-ethyl-6-phenylphenyl]ethylamino}-3-hydroxypropionate obtained in the above.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:28][C:29]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:39](=[O:45])[CH2:40][C:41](=O)[CH2:42]C>>[F:28][C:29]1[C:34]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:39](=[O:45])/[CH:40]=[C:41](\[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])/[CH3:42]
Reactant: CCC(=O)CC(=O)c1cccc(C(F)(F)F)c1F
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Product: C/C(=C/C(=O)c1cccc(C(F)(F)F)c1F)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 12) from 190 mg (0.52 mmol) of Intermediate 45 and 120 mg (0.52 mmol) of Intermediate 37 to yield 102 mg (35% yield) of Example 26: 1H NMR (DMSO-d6, 400 MHz) δ11.36 (d, 1H, J=8.9), 7.9 (m, 3H), 7.77 (t, 1H, J=6.9), 7.46 (m, 3H), 7.42 (m, 1H), 7.11 (d, 2H, J=8.5), 6.81 (d, 2H, J=8.5), 5.22 (s, 1H), 4.14 (t, 2H, J=6.6), 4.1 (m, 1H), 3.13 (m, 1H), 2.87 (t, 2H, J=6.6), 2.78 (dd, 1H, J=13.7, 8.5), 2.31 (s, 3H), 1.68 (s, 3H); low resolution MS (ES+)m e 597.4(MH+).
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][NH:8][S:9]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH:16]=1)(=[O:11])=[O:10])(=[O:6])[O:4][CH3:5].[C:21](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:1][O:2][P:3]([CH2:7][N:8]([S:9]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH:16]=1)(=[O:10])=[O:11])[CH3:21])(=[O:6])[O:4][CH3:5]
Reactant: O=C([O-])[O-]
Reactant: COP(=O)(CNS(=O)(=O)c1cc2ccccc2s1)OC
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COP(=O)(CN(C)S(=O)(=O)c1cc2ccccc2s1)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
A reaction mixture consisting of 290 mg (0.83 mmol) of [(2-benzothiophenesulfonylamino)-methyl]-phosphonic acid dimethyl ester, 380 mg (1.16 mmol) of anhydrous cesium carbonate, 0.11 mL (1.16 mmol) of methyl iodide and 5 mL of anhydrous DMF stirred for 16 hours at room temperature. After the reaction was complete, DMF was evaporated in vacuum, and the residue was suspended in 15 mL of water and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, filtered and evaporated, providing an oily residue which was chromatographed on a silica gel column, eluent EtOAc/hexane (7:3), then dichloromethane/MeOH (20:1), to yield the title compound as a yellowish oil (190 mg, 63%): 1H NMR: (300 MHz, CDCl3) δH 3.00 (s, CH3), 3.48 (d, J=11.5 Hz, 2 H), 3.83 (d, J=10.9 Hz, 6 H, 2CH3), 7.45–7.50 (m, 2 H, Ar—H), 7.83–7.89 (m, 3 H, Ar—H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[OH:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:18][CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: OCc1cccnc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2cccnc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 3-(hydroxymethyl)pyridine and DBU in DME. EI-MS m/e (%): 293 (M+, 54), 276 ([M—NH3]+, 36), 92 (100), 65 (44), 39 (23).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[O:17][C:12]1([CH2:16][CH2:15][NH:14][CH2:13]1)[CH2:11][C:10]2=[O:21].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:27](C)=O.[Na+]>>[CH3:2][O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[O:17][C:12]1([CH2:16][CH2:15][N:14]([CH3:27])[CH2:13]1)[CH2:11][C:10]2=[O:21]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNC1)O2
Agent: C=O
Agent: Cl
Agent: [Na+]
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C)C1)O2

Procedure:
(±)-(E)-3-[1′-Methyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester was synthesized by treating Intermediate 1 (253 mg, 0.78 mmol), with aqueous 37% formaldehyde solution. (0.069 ml, 0.94 mmol), and NaBH(OAc)3 (252 mg, 1.17 mmol) according to the procedure for preparation of Example 2, Step A, to give the product as yellow solid (111 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25](O)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:29][NH:30][CH3:31].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:29][N:30]([CH3:31])[C:25]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[C:12]([C:14]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[O:24])[CH:11]=1)=[O:26]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (50 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) were added dimethylamine hydrochloride (60 mg, 0.74 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.87 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction solution was purified by preparative HPLC to afford the final product as a light brown solid.
Reaction SMILES: [C:1]1([CH:7]2[C:12](=[O:13])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].C(O)C.[Na+].[Cl-]>C1C=CC=CC=1>[C:1]1([C@H:7]2[C@H:12]([OH:13])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCNCC1c1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: O[C@@H]1CCNC[C@H]1c1ccccc1
Reaction time: 18 h

Procedure:
A mixture of 0.9 g of the free base, 3-phenyl-4-piperidone of Example 50c, above, 0.19 g of sodium borohydride and 15 ml of absolute ethanol is stirred at room temperature for 6 hours under a nitrogen atmosphere. The mixture is then treated with 25 ml of saturated aqueous NaCl solution and extracted with dichloromethane. The combined organic extracts are washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4 and concentrated in vacuo to a gum which TLC shows to be a mixture of cis and trans isomers, with the trans isomer predominant. Trituration of this material with benzene gives a well formed solid which is filtered off after allowing the mixture to stand 18 hours. The solid is washed with benzene and then hexane, and dried in vacuo to afford a solid, m.p. s 99°, 115°-127° C., with TLC showed contained only a small amount of the cis isomer. This material is taken up in 10 ml of boiling benzene, filtered, and boiled down to a volume of approximately 5 ml of solution to afford a solid of trans-3-phenyl-4-piperidinol, m.p. s 125.5°, 127°-128.5°, which TLC showed to be pure trans isomer.
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].[NH2:8][C:9]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([F:21])[C:10]=1[F:22].CO>C1COCC1>[CH3:2][O:14][C:13](=[O:15])[C:12]1[CH:16]=[C:17]([N+:18]([O-:20])=[O:19])[C:9]([NH2:8])=[C:10]([F:22])[C:11]=1[F:21]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1F
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A 2 M solution of TMS diazomethane in hexanes (6.88 mL, 13.75 mmol) is added to a suspension of 4-amino-2,3-difluoro-5-nitro-benzoic acid 3 (2.00 g, 9.17 mmol) in 25 mL of 4:1 THF:MeOH at 0° C. under nitrogen atmosphere. Upon completion of addition, reaction mixture is warmed to room temperature. After 0.5 hours, excess TMS diazomethane is destroyed by the careful addition of acetic acid. The reaction is then concentrated under reduced pressure and dried in vacuo to give 1.95 g (92%) of pure desired product: MS APCI (−) m/z 231 (M−1) detected.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17]N)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I.CS[C:22]1[NH:23][CH2:24][C:25](=[O:27])[N:26]=1.C(N(CC)CC)C>C(O)C>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][C:22]3[NH:23][CH2:24][C:25](=[O:27])[N:26]=3)[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NCCCOc1cc(CN2CCCCC2)ccn1
Reactant: CSC1=NC(=O)CN1
Agent: I
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1CNC(CCCOc2cc(CN3CCCCC3)ccn2)=N1

Procedure:
3-(4-Piperidinomethylpyrid-2-yloxy)propylamine (2.57 g), 2-methylthio-imidazolin-4-one hydroiodide (2.60 g) and triethylamine (2.18 g) were refluxed in ethanol (20 ml) for 5 hours. The mixture was refluxed for a further hour in the presence of additional 2-methylthio-imidazolin-4-one hydroiodide (2.60 g) to ensure completion.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:12]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]3=[N:11]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: c1ccc2[nH]nnc2c1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(-n2nc3ccccc3n2)cc1
Temperature: 130 °C
Yield: 28.9 %

Procedure:
A mixture of 4-chloronitrobenzene (55.0 g, 349 mmol), benzotriazole (50.0 g, 420 mmol), potassium carbonate (200 g, 500 mmol), and NMP (500 mL) was stirred and heated under argon at 130° C. for 5 hours. Progress of the reaction was monitored by thin layer chromatography. The reaction mixture was poured onto crushed ice (2 kg). After all ice melted, the solid was filtered off and washed with water (200 mL). The product was suspended in methanol (1.5 L) and stirred for 30 minutes. The crystals were filtered off and dried in a vacuum oven. Column chromatography of the obtained material using silica gel and hot solution of ethyl acetate (1%) in toluene as an eluent gave 2-(4-nitrophenyl)-2H-benzo[d][1,2,3]triazole (24.24 g, 30% yield). 1H NMR (400 MHz, CDCl3): δ 8.57 (d, J=9.2 Hz, 2H, 4-nitrophenyl), 8.44 (d, J=9.2 Hz, 2H, 4-nitrophenyl), 7.93 (m, 2H, benzotriazole), 7.47 (m, 2H, benzotriazole).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:2]2[O:3][C:4]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)=[CH:22][CH:21]=1
Reactant: Oc1ccc(S)cc1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1oc(Sc2ccc(O)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A mixture of methyl 3-(2-chloro-4-phenyl-5-oxazolyl)propionate (500 mg), 4-hydroxythiophenol (475 mg), potassium carbonate (520 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 3-[2-(4-hydroxyphenylthio)-4-phenyl-5-oxazolyl]propionate as colorless crystals (637 mg, yield 95%). The crystals were recrystallized from toluene-hexane. melting point: 157–158° C.