Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][OH:4].[CH3:5][CH2:6][CH2:7][C:8](Cl)=[O:9]>C(N(CC)CC)C>[C:8]([O:1][CH2:2][CH2:3][OH:4])(=[O:9])[CH2:7][CH2:6][CH3:5]
Reactant: CCCC(=O)Cl
Reactant: OCCO
Solvent: CCN(CC)CC
Product: CCCC(=O)OCCO

Procedure:
As a nonlimiting example using method B in FIG. 2 to obtain the (5-oxo-1,3-oxathiolan-2-yl)methyl butanoate or its 5-acetyloxy derivative is to react 1,2-dihydroxy ethane with n-butyryl chloride in triethylamine. This reaction produces 2-hydroxyethyl butanoate, which is further reacted P2O5 in dry DCM, followed by DMSO and triethylamine to produce 2-oxyethyl butanoate. The 2-oxyethyl butanoate can be converted to the 5-acetyloxy derivative of (5-oxo-1,3-oxathiolan-2-yl)methyl butanoate by the process described above, or it can be converted into (5-oxo-1,3-oxathiolan-2-yl)methyl butanoate by reacting with mercaptoacetic acid and CSA in dry DCM.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][NH:4][C:3]=1/[CH:15]=[C:16]1\[C:17](=[O:35])[NH:18][C:19]2[C:24]\1=[C:23]([C:25]1[CH:26]=[C:27]([CH2:31][C:32](O)=[O:33])[CH:28]=[CH:29][CH:30]=1)[CH:22]=[CH:21][CH:20]=2.[CH3:36][C@H:37]1[CH2:42][NH:41][CH2:40][C@@H:39]([CH3:43])[NH:38]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[CH3:36][C@H:37]1[NH:38][C@@H:39]([CH3:43])[CH2:40][N:41]([C:32](=[O:33])[CH2:31][C:27]2[CH:26]=[C:25]([C:23]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:24]=3/[C:16](=[CH:15]/[C:3]3[NH:4][CH:5]=[C:6]([C:7]([N:9]5[CH2:10][CH2:11][O:12][CH2:13][CH2:14]5)=[O:8])[C:2]=3[CH3:1])/[C:17](=[O:35])[NH:18]4)[CH:30]=[CH:29][CH:28]=2)[CH2:42]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Cc1c(C(=O)N2CCOCC2)c[nH]c1/C=C1\C(=O)Nc2cccc(-c3cccc(CC(=O)O)c3)c21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1c(C(=O)N2CCOCC2)c[nH]c1/C=C1\C(=O)Nc2cccc(-c3cccc(CC(=O)N4C[C@@H](C)N[C@@H](C)C4)c3)c21

Procedure:
(3-{3-[1-[3-Methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4-yl}-phenyl)-acetic acid was coupled with (2S,6R)-2,6-dimethyl-piperazine (3 eq.), EDC (1.5 eq.) and HOBt (1 eq.) in THF using the general amidation procedure to give the titled compound.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH2:12][CH:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]2)=[C:2]=S.C(OC1CC2C(CC=1)=CC=CC=2N=C=S)C.[N:35]([CH2:38][C:39]([C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)=[O:40])=[N+]=[N-].N(CC(C1C=CC(C(F)(F)F)=CC=1)=O)=[N+]=[N-]>>[CH3:47][C:44]1[CH:43]=[CH:42][C:41]([C:39]2[O:40][C:2]([NH:1][C:4]3[CH:5]=[CH:6][CH:7]=[C:8]4[C:13]=3[CH2:12][CH:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]4)=[N:35][CH:38]=2)=[CH:46][CH:45]=1
Reactant: CS(=O)(=O)NC1CCc2cccc(N=C=S)c2C1
Reactant: Cc1ccc(C(=O)CN=[N+]=[N-])cc1
Agent: CCOC1=CCc2cccc(N=C=S)c2C1
Agent: [N-]=[N+]=NCC(=O)c1ccc(C(F)(F)F)cc1
Product: Cc1ccc(-c2cnc(Nc3cccc4c3CC(NS(C)(=O)=O)CC4)o2)cc1
Yield: 64.4 %

Procedure:
The title compound was prepared using the procedure as described in Example 1H, substituting the product of Example 23C (128 mg, 0.453 mmol) for the product of Example 1F and the product of Example 9A (95 mg, 0.544 mmol) for the product of Example 1G. The crude product was purified by flash chromatography eluting with 2% to 5% CH3OH/CH2Cl2 followed by 100% EtOAc which gave 116 mg (64%) of the title compound as a tan solid. 1H NMR (DMSO-d6) δ 9.13 (s, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.30 (s, 1H), 7.23 (m, 3H), 7.11 (t, J=7.8 Hz, 1H), 6.85 (d, J=7.5 Hz, 1H), 3.58 (m, 1H), 3.11 (m, 1H), 2.99 (s, 3H), 2.87 (m, 2H), 2.56 (m, 1H), 2.31 (s, 3H), 2.01 (m, 1H), 1.66 (m, 1H); MS (ESI+) m/z 398 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:5]([Cl:20])[CH:4]=1)#[N:2].[NH2:21][OH:22]>C(O)C>[Cl:20][C:5]1[CH:4]=[C:3]([C:1](=[N:21][OH:22])[NH2:2])[CH:19]=[CH:18][C:6]=1[CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1Cl
Reactant: NO
Solvent: CCO
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)cc1Cl
Yield: 76 %

Procedure:
A solution of tert-butyl 2-((4-cyano-2-chlorobenzyl)(methyl)amino)acetate (1.25 g, 4.25 mmol) and 50% aqueous hydroxylamine (1.30 mL) in ethanol (10 mL) was heated at 80° C. for 5 hours. The solvent was evaporated under vacuum. The residue was partitioned between DCM and water. The organic phase was passed through a hydrophobic frit and concentrated under vacuum to afford the title compound (1.34 g, 76%). 1H NMR (CDCl3, 400 MHz) δ 7.63 (1H, d, J=1.8 Hz), 7.59 (1H, d, J=8.0 Hz), 7.50 (1H, dd, J=8.0, 1.8 Hz), 4.84 (2H, s), 3.83 (2H, s), 3.25 (2H, s), 2.42 (3H, s), 1.48 (9H, s).
Reaction SMILES: [CH3:1][C@:2]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[N:14][C:15]([NH:18][NH2:19])=[CH:16][CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1.[CH3:28][O:29][CH2:30][CH2:31][O:32][C:33]1[CH:42]=[C:41]2[C:36]([CH:37]=[CH:38][C:39]([CH:43]=O)=[N:40]2)=[CH:35][CH:34]=1.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O>CCO>[CH3:1][C@:2]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:17]=[CH:16][C:15]3[N:14]([C:43]([C:39]4[CH:38]=[CH:37][C:36]5[C:41](=[CH:42][C:33]([O:32][CH2:31][CH2:30][O:29][CH3:28])=[CH:34][CH:35]=5)[N:40]=4)=[N:19][N:18]=3)[CH:13]=2)[C:8]([F:9])([F:10])[F:11])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CCN([C@@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: COCCOc1ccc2ccc(C=O)nc2c1
Agent: O=Ic1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: COCCOc1ccc2ccc(-c3nnc4ccc([C@H](N5CC[C@](C)(NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A mixture of tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (53 mg, 0.14 mmol), 7-(2-methoxyethoxy)quinoline-2-carbaldehyde (30 mg, 0.13 mmol) and EtOH (1.4 mL) was stirred at ambient temperature overnight. The solvent was removed under reduced pressure. The residue was dissolved in DCM (1.4 mL) and iodosobenzene diacetate (54 mg, 0.17 mmol) was added. The reaction mixture was stirred at ambient temperature overnight and then loaded to a silica gel column eluting with 1:2 to 3:1 EtOAc/hexanes to give tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(3-(7-(2-methoxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (72 mg, 92%).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:28][C:29]1[N:34]=[C:33]([N:35]2[C:43](=[O:44])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]2=[O:45])[CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>CC#N>[O:45]=[C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43](=[O:44])[N:35]1[C:33]1[N:34]=[C:29]([CH2:28][N:11]([CH:9]2[C:10]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7][CH2:8]2)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:30]=[CH:31][CH:32]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCCN(Cc1cccc(N2C(=O)c3ccccc3C2=O)n1)C1CCCc2cccnc21

Procedure:
Using General Procedure A: Reaction of 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione, 2-(6-bromomethyl-pyridin-2-yl)-isoindole-1,3-dione (Goswami, S. et al. J. Am. Chem. Soc. 1989, 111, 3425-6), and DIPEA in CH3CN gave 2-{4-[[6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pyridin-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione as a tan solid. Deprotection with hydrazine following General Procedure E gave the free base. Conversion to the HBr salt using General Procedure D gave COMPOUND 355 as a white solid. 1H NMR (D2O) δ 1.51-1.55 (m, 4H), 1.71-1.85 (m, 1H), 1.91-2.03 (m, 1H), 2.13-2.18 (m, 1H), 2.32-2.36 (m, 1H), 2.46-2.54 (m, 1H), 2.67-2.74 (m, 1H), 2.90-2.99 (m, 4H), 3.98 (s, 2H), 4.38 (dd, 1H, J=5.7, 10.8 Hz), 6.90-6.96 (m, 2H), 7.80-7.86 (m, 2H), 8.30 (br d, 1H, J=8.1 Hz), 8.58 (br d, 1H, J=5.7 Hz); 13C NMR (D2O) δ 20.00, 20.43, 25.14, 25.26, 27.63, 39.57, 51.24, 52.88, 59.64, 113.08, 113.21, 125.70, 139.29, 140.38, 145.05, 146.08, 147.71, 151.86, 154.94; ES-MS m/z 326 (M+H). Anal. Calcd. for C19H27N5.3.4HBr.1.8H2O: C, 36.05; H, 5.41; N, 11.06; Br, 42.92. Found: C, 35.93; H, 5.24; N, 10.91; Br, 43.14.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[CH:5][N:4]=1.Cl.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][N:13]=1>Cl.C(Cl)Cl.CO>[OH:9][C:7]1[C:6]([CH:18]([C:15]2[CH:14]=[N:13][C:12]([CH3:11])=[CH:17][CH:16]=2)[OH:19])=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: Cc1ccc(C=O)cn1
Reactant: CSc1nccc(O)n1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CSc1ncc(C(O)c2ccc(C)nc2)c(O)n1

Procedure:
A mixture of 10.0 g (0.07 mol) of 2-methylthio-4-hydroxypyrimidine and 12.4 g (0.079 mol) of 2-methyl-5-formylpyridine hydrochloride in 75 ml of concentrated hydrochloric acid was heated at reflux for 1 hour. After working up as in Example 1 an oil is obtained which is taken up in methylene chloride-methanol then recrystallized from ethyl acetate to give 4-hydroxy-5-[(6-methyl-3-pyridinyl)hydroxymethyl]-2-methylthiopyrimidine; 9.3 g (50%), m.p. 140°.
Reaction SMILES: [OH:1][CH:2]([C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1)[CH3:3].[CH3:24]C(C)([O-])C.[K+].CI>>[CH3:24][C:12]1[C:13](=[O:23])[CH2:14][CH2:15][C@@:16]2([CH3:17])[C:11]=1[CH2:10][CH2:9][C@@H:8]1[C@@H:18]2[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@H:7]1[CH2:6][CH2:5][C@@H:4]2[CH:2]([OH:1])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: CC(O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Solvent: CI
Product: CC1=C2CC[C@H]3[C@@H]4CC[C@H](C(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O

Procedure:
With reference to Scheme 4, alkylation of 1a, such as 20-hydroxy-4-pregnen-3-one, using potassium t-butoxide and methyl iodide yields 4-methyl-20-hydroxy-4-pregnen-3-one 1b. Allylic bromination of N-bromosuccinimide in carbon tetrachloride yields the 6β-bromo derivative. Protection of the C-20 alcohol as its t-butyldimethyl silyl derivative yields 3. Lithium aluminum hydride reduction of the ketone in 3 with concomitant double bond migration and loss of bromide should yield 4. Protection of the C-3 alcohol as a tetrahydropyranyl ether, followed by deprotection and oxidation of the C-17 alcohol should yield the C-17 ketone 7. Removal of the C-3 tetrahydropyranyl ether yields 4α-methyl-5-pregnen-20-one.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11](=O)[CH3:12])[CH:8]=[CH:7][N:6]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH3:16][C:17]([S@:20]([NH:22][CH:11]([C:9]1[CH:8]=[CH:7][N:6]=[C:5]([O:4][CH2:3][C:2]([F:15])([F:14])[F:1])[CH:10]=1)[CH3:12])=[O:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccnc(OCC(F)(F)F)c1
Product: CC(N[S@](=O)C(C)(C)C)c1ccnc(OCC(F)(F)F)c1
Yield: 75 %

Procedure:
The title compound is prepared in 75% yield (0.52 g, a white solid) from 1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethanone (0.47 g, 2.14 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[C:17]([O:21][C:22]([N:24]1[CH2:31][CH:30]2[O:32][CH:26]([CH2:27][NH:28][CH2:29]2)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:5]=[C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH2:3][CH2:2][N:28]1[CH2:27][CH:26]2[O:32][CH:30]([CH2:31][N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH2:25]2)[CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: N#Cc1ccc2c(c1)CCN2C(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(CCC(=O)N3CCc4cc(C#N)ccc43)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1-(3-Chloropropionyl)-2,3-dihydro-1H-indole-5-carbonitrile (3.07 g, 0.031 mol; see step (v) above), 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (3 g, 0.031 mol; see WO 01/28992) and potassium carbonate (6.43 g, 0.0465 mol) were taken in dry acetonitrile (30 mL) and stirred at 60° C. overnight under a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to provide a crude product. This product was then purified by column chromatography using methanol in DCM as eluent to yield the sub-title compound as pale yellow solid. Yield: 5 g.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1.Br[C:27]1[N:35]2[C:30]([CH:31]=[N:32][C:33]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([N:43]4[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]4)=[CH:39][C:38]=3[O:50][CH3:51])=[N:34]2)=[CH:29][CH:28]=1.[CH3:52][O:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1B(O)O.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+].O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:51][O:50][C:38]1[CH:39]=[C:40]([N:43]2[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]2)[CH:41]=[CH:42][C:37]=1[NH:36][C:33]1[N:32]=[CH:31][C:30]2=[CH:29][CH:28]=[C:27]([C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=3[O:53][CH3:52])[N:35]2[N:34]=1
Reactant: COc1ccccc1B(O)O
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(Br)n2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
Into a 30 mL vial, Palladium Acetate (0.010 g, 0.000046 mol) and Triphenylphosphine (0.030 g, 0.00011 mol) were added and purged under an atmosphere of Nitrogen for 5 minutes 1,4-Dioxane (1.00 mL, 0.0128 mol) was added and stirred for 10 minutes. (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine (0.0952 g, 0.000228 mol), 2-methoxybenzeneboronic acid (0.0694 g, 0.000456 mol), N,N-Dimethylformamide (2.20 mL, 0.0284 mol) and 1.50 M of Sodium carbonate in Water (1.00 mL, 0.00150 mol) were added, respectively. The reaction mixture was heated at 80° C. overnight. The solvent was removed under vacuum. The solid was washed with DCM. The organic was removed under vacuum. The reaction was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 10% methanol). The collected fraction afforded a solid. The solid was washed with 10% Et2O/hexane to give [2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine a yellow solid (38 mg, 37%). LCMS (E/I+) 445.19 (M+H). NMR 1H (DSMO-d6)-8.88 (s, 1H), 7.83 (t, 2H, J=8.76 Hz), 7.48 (s, 1H), 7.43 (t, 1H, J=7.16 Hz), 7.19 (d, 1H, J=8.36 Hz), 7.08 (t, 1H, J=7.52 Hz), 6.94 (d, 1H, J=4.68 Hz), 6.90 (d, 1H, J=4.60 Hz), 6.63 (s, 1H), 6.35 (d, 1H, J=9.04 Hz), 3.84 (s, 3H), 3.78 (s, 3H), 3.05-3.16 (bm, 4H), 2.46 (bs, 4H), 2.23 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28](OB(O)O)[CH:29]=[CH:30][CH:31]=1)=[O:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:30]4[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=4)[C:24]([O:23][CH3:22])=[O:25])[CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1COC1CCCNC1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Product: COC(=O)c1cccc(N2CCCC(OCc3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 71.8 %

Procedure:
Using 3-[[2-(4-chlorophenyl)-4-methylthiazol-5-yl]methoxy]piperidine (60.2 mg, 0.186 mmol) and 3-(methoxycarbonyl)phenylboric acid (66.9 mg, 0.372 mmol), the same procedure was followed as in Example 2 to give 61.0 mg (72%) of the desired compound as a colorless oil.
Reaction SMILES: CC(=CC)C.P([O-])(O)(O)=O.[Na+].Cl([O-])=[O:13].[Na+].[F:16][C:17]1[CH:18]=[C:19]([C@:23]2([CH2:28][O:29][C:30]3[C:35](=[O:36])[N:34]([CH2:37][O:38][CH3:39])[C:33]([CH3:40])=[N:32][C:31]=3[CH3:41])[CH2:25][C@H:24]2[CH:26]=[O:27])[CH:20]=[CH:21][CH:22]=1>C(Cl)(Cl)Cl.O.CC(C)=O.O>[F:16][C:17]1[CH:18]=[C:19]([C@:23]2([CH2:28][O:29][C:30]3[C:35](=[O:36])[N:34]([CH2:37][O:38][CH3:39])[C:33]([CH3:40])=[N:32][C:31]=3[CH3:41])[CH2:25][C@H:24]2[C:26]([OH:13])=[O:27])[CH:20]=[CH:21][CH:22]=1
Reactant: COCn1c(C)nc(C)c(OC[C@@]2(c3cccc(F)c3)C[C@H]2C=O)c1=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COCn1c(C)nc(C)c(OC[C@@]2(c3cccc(F)c3)C[C@H]2C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
2-methyl 2-butene (1.14 ml), sodium dihydrogen phosphate (389 mg) and sodium chlorite (305 mg) were added to an acetone-water mixed solvent (8 ml-2 ml) of the compound 326-8 (779 mg). The obtained mixture was stirred at room temperature for 1 hour. Thereafter, water was added to the reaction solution, and chloroform was added to the reaction solution to carry out liquid separation and extraction. A small amount of 1 N hydrochloric acid was added to the obtained extract, and chloroform was further added to the reaction solution to carry out liquid separation and extraction. The obtained organic layer was dried over magnesium sulfate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, so as to obtain a crude product of the title carboxylic acid (814 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])=[N:7]2.[CH:22]([Sn](CCCC)(CCCC)CCCC)=[CH2:23]>C1(C)C=CC=CC=1.C(#N)C>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH:22]=[CH2:23])[N:7]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccccc1CNc1ccc2c(Br)cccc2n1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C=Cc1cccc2nc(NCc3ccccc3OC)ccc12

Procedure:
(5-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (prepared from 5-bromo-2-chloroquinoline and 2-methoxy-benzylamine as described in example 3, step A, 1 g, 2.9 mmol) was dissolved in 30 mL toluene. Vinyltributyltin (952 mg, 3.0 mmol) and tetrakis(triphenylphosphin)palladium (67 mg, 0.058 mmol) was added. The reaction mixture was refluxed overnight. The mixture was diluted with 100 mL acetonitrile and extracted three times with heptane (100 mL each). The acetonitrile phase was dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->80:20 gradient). The title compound was obtained as a yellow oil (544 mg, 64%), MS: m/e=291.3 (M+H+).
Reaction SMILES: [NH2:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1.[C:16](=O)(O)[O-:17].[Na+]>C(O)=O>[CH:16]([NH:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1)=[O:17]
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(N)S1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: Cn1c([N+](=O)[O-])cnc1C1=CNN(NC=O)S1

Procedure:
The above compound is prepared by refluxing 8 gm. of 2-(2-amino-5-thiadiazolyl)-1-methyl-5-nitroimidazole in 30 ml. of 98% formic acid for 10 hours, cooling, and adding the mixture to saturated sodium bicarbonate solution, and the solid collected. The compound melts at 225° to 227° C.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:24][C:25]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([N:28]2[CH2:29][CH2:30][C:25]([OH:24])([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:26][CH2:27]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC1(c2ccccc2)CCNCC1
Product: O=C(CC(c1ccccc1)(c1ccccc1)c1ccccc1)N1CCC(O)(c2ccccc2)CC1

Procedure:
Following the procedures set out in Example 1, 1 part of 3,3,3-triphenylpropionyl chloride and 2 parts of 4-hydroxy-4-phenylpiperidine are reacted to provide 1-(3,3,3-triphenylpropionyl)-4-hydroxy-4-phenylpiperidine. 0.23 Parts of this amide is reacted with 0.05 parts of lithium aluminum hydride in 3.0 parts by volume of ethyl ether to provide 1-(3,3,3-triphenylpropyl)-4-hydroxy-4-phenylpiperidine. This compound has the following structural formula ##STR31##
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:13][O:14]C1C(OC)=CC(C(O)=O)=C([N+]([O-])=O)C=1>>[NH2:1][C:2]1[CH:10]=[C:9]([O:14][CH3:13])[C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC
Reactant: COc1ccc(N)c(C(N)=O)c1
Product: COc1cc(N)c(C(N)=O)cc1OC

Procedure:
According to the preparation of 10, 4,5-dimethoxy-2-nitrobenzoic acid (5) (1.0 g, 4.4 mmol) was used to afford 11 (0.8 g) as brown powder; MS m/z 196 (M+).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:22](=[O:29])([O:26]CC)[O:23]CC)[P:14](=[O:21])([O:18]CC)[O:15]CC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Cl>[C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:22](=[O:23])([OH:26])[OH:29])[P:14](=[O:15])([OH:18])[OH:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOP(=O)(OCC)C(NCCCCSc1ccccc1)P(=O)(OCC)OCC
Agent: Cl
Product: O=P(O)(O)C(NCCCCSc1ccccc1)P(=O)(O)O
Yield: 58.6 %

Procedure:
Tetraethyl 4-(phenylthio)butylaminomethylenebisphosphonate (11.1 g) was dissolved in concentrated hydrochloric acid (150 ml) and the mixture was refluxed for 2.5 hours. After the reaction mixture was concentrated under reduced pressure, water was poured and separated crystals were collected by filtration to obtain 4-(phenylthio)butylaminomethylenebisphosphonic acid (4.94 g) as a white powder. Sodium methylate (28% methanol solution, 13.3 g) was added to the suspension of this powder (4.08 g) in methanol (50 ml), and the resultant was stirred at room temperature for one hour and then concentrated under reduced pressure. Methanol was added to the residue, the separated white crystals were collected by filtration and recrystallized from water-methanol to obtain tetrasodium 4-(phenylthio)butylaminomethylenebisphosphonate as a white powder (3.90 g, 43% ).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19](=[O:47])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38]CC)=[O:37])[CH:31]=2)=[O:29])[CH:25]=[CH:24][C:23]=1[O:41][CH2:42][CH2:43][CH2:44][CH2:45]Br)C>CCCCCC.C(OCC)(=O)C>[C:36]([C:32]1[CH:31]=[C:30]([C:28]([C:26]2[CH:25]=[CH:24][C:23]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][O:1][C:2]3[CH:12]=[CH:11][C:5]4[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=4[C:3]=3[CH2:13][CH2:14][CH3:15])=[C:22]([CH2:21][CH2:20][C:19]([OH:47])=[O:18])[CH:27]=2)=[O:29])[CH:35]=[CH:34][CH:33]=1)([OH:38])=[O:37]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCBr
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCOc2ccc(C(=O)c3cccc(C(=O)O)c3)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 50.9 %

Procedure:
Starting with 0.144 g (0.70 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, and 0.35 g (0.69 mmol) of 2-(4-bromobutoxy)-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, the title compound (0.202 g; 63.4% overall yield) was obtained as a white solid, mp 177°-180° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 22.