Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:13]=[CH:12][C:11]2[N:10]3[C:14](=[O:22])[O:15][C@@H:16]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[C@@H:9]3[CH2:8][C:7]=2[CH:6]=1)=[O:4].[N-:23]=[N+:24]=[N-:25].[Na+].CC(C)=O>O1CCCC1.C(Cl)Cl.CO.CO.C(OCC)(=O)C>[N:23]([CH2:2][C:3]([C:5]1[CH:13]=[CH:12][C:11]2[N:10]3[C:14](=[O:22])[O:15][C@@H:16]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[C@@H:9]3[CH2:8][C:7]=2[CH:6]=1)=[O:4])=[N+:24]=[N-:25]
Reactant: CC(=O)NC[C@@H]1OC(=O)N2c3ccc(C(=O)CCl)cc3C[C@@H]12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(=O)NC[C@@H]1OC(=O)N2c3ccc(C(=O)CN=[N+]=[N-])cc3C[C@@H]12

Procedure:
A mixture of (1S,9aS)N-[(7-chloroacetyl-9,9a-dihydro-3-oxo-1H,3H-oxazolo[3,4-a]indol-1-yl)methyl]acetamide (EXAMPLE 48, 43 mg) and sodium azide (82 mg) are stirred in aqueous tetrahydrofuran (66%) for 3 days. Acetone (1ml) is added and the mixture was heated in an oil bath (38°-50°) for 8 hours then concentrated to an aqueous layer and extracted with ethylacetate (6×2 ml). The combined organic layers are dried over magnesium sulfate and concentrated to provide the product as as an oil. The oil is taken up in methylene chloride/methanol and then placed on a 1000 μ silica preparative plate and developed in methanol/ethylacetate (10/90, 2×) to give the title compound. ##STR3##
Reaction SMILES: [CH2:1]([NH:7][C:8]([NH:10][CH2:11][CH2:12][Cl:13])=[O:9])[CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4].C(O)C.[N:17]([O-])=[O:18].[Na+]>Cl.O>[CH2:1]([NH:7][C:8]([N:10]([CH2:11][CH2:12][Cl:13])[N:17]=[O:18])=[O:9])[CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)CCNC(=O)NCCCl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)CCNC(=O)N(CCCl)N=O
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
A 2.07 g (10 mmol) quantity of 1-neohexyl-3-(2-chloroethyl) urea was dissolved in 15 ml of concentrated HCl:ethanol, 2:1, at 10° C., and 690 mg (10 mmol) sodium nitrite dissolved in 3 ml of water was added. Stirring at 5° C. continued for 1.5 hrs. and the precipitate was washed with four 25 ml portions of distilled water. After drying in vacuo overnight, 1.7 g (74%) of the product was obtained which melted at 43.0°-43.5° C. (decomposes). IR analysis showed peaks at 1705/cm (C=O) and 1525/cm (C--N=O). NMR: singlet (9H) at 0.9 ppm, multiplet (2H) at 1.3 ppm, symmetrical multiplet (6H) at 3.8 ppm. No evidence of isomeric material was detected.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([O-:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Na+].[NH:22]1[CH:26]=[CH:25][N:24]=[C:23]1[CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1I)[OH:28]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH:27]([C:23]2[NH:24][CH:25]=[CH:26][N:22]=2)[OH:28])(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: OC(c1ncc[nH]1)c1ccccc1I
Agent: [Na+]
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1ccccc1C(O)c1ncc[nH]1
Yield: 51.7 %

Procedure:
The title compound was prepared from sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (193 mg, 0.62 mmol) and 1H-imidazol-2-yl(2-iodophenyl)methanol (171 mg, 0.57 mmol) according to the method of Example 6 Step 4. Purification by flash column chromatography eluting with ethyl acetate gave solid (2-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}phenyl)(1H-imidazol-2-yl)methanol (135 mg, 51%). 1H NMR (500 MHz, d6-DMSO) δ 11.94 (1H, s), 8.54 (1H, s), 8.30 (1H, s), 8.19 (1H, d, J=8.6 Hz), 8.11 (1H, d, J=7.9 Hz), 8.07 (1H, d, J=8.7 Hz), 8.02-7.97 (1H, m), 7.94-7.86 (2H, m), 7.84 (1H, d, J=7.7 Hz), 7.78-7.67 (2H, m), 7.61-7.53 (1H, m), 7.41-7.32 (2H, m), 6.88 (1H, s), 6.84 (1H, d, J=5.2 Hz), 6.52 (1H, s), 6.12 (1H, d, J=5.2 Hz); m/z (ES+) 459 [MH+].
Reaction SMILES: [OH:1][CH2:2][CH2:3]CCCC1CCCC1=O.OCCCCCC1CCCC1=O.[C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39])(=[O:27])[CH3:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC(=O)C)(=O)C>>[C:2]([O:39][C:35]1[CH2:36][CH2:37][CH2:38][C:34]=1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:25](=[O:27])[CH3:26])(=[O:1])[CH3:3]
Reactant: CC(=O)OCCCCCC1CCCC1=O
Reactant: O=C1CCCC1CCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCCCCCC1=C(OC(C)=O)CCC1

Procedure:
A solution of 400 g. (2.04 moles) of a mixture of 2-(5-hydroxypentyl)cyclopentanone and 2-(5-acetoxypentyl)cyclopentanone (Example 70) and 4.0 g. of p-toluenesulfonic acid monohydrate in 1 l. of acetic anhydride is refluxed at a rate to maintain a steady distillation of acetic acid from the reaction through a helix-packed fractionation column. The reaction is continued with the addition of acetic anhydride to maintain a constant volume until complete conversion of starting materials to product is evident. The mixture is cooled and partitioned between 2 l. of hexane and 3 l. of cold water containing solid sodium bicarbonate to maintain a neutral pH. The organic phase is washed with saturated brine, dried (MgSO4), and evaporated to yield 452 g. of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[CH3:37][O:38][C:39](=[O:43])[CH2:40][CH2:41][NH2:42]>>[CH3:37][O:38][C:39](=[O:43])[CH2:40][CH2:41][NH:42][C:23](=[O:24])[CH:22]([N:8]1[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[CH:7]1[CH2:6][C:5]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)CCN
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: COC(=O)CCNC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 3-amino-propionic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH:12]([OH:17])[CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2>O1CCCC1.C([BH-](CC)CC)C.[Li+]>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]([OH:16])[CH2:13][CH:12]([OH:17])[CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CC(O)CC2=O
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1c2c(nc3ccccc13)CC(O)CC2O
Reaction time: 0.5 h

Procedure:
A suspension of 9-amino-3,4-dihydro-3-hydroxyacridin-1 (2H)-one (2.07 g) in tetrahydrofuran (125 ml), lithium triethylborohydride (1 molar in tetrahydrofuran, 27 ml) was allowed to stand for 0.5 hrs. The reaction mixture was quenched with methanol. The mixture was preadsorbed on silica, and flash chromatographed on silica gel (1:2:17-dichloromethane:triethylamine). The appropriate fractions were collected. Evaporation of the more polar fractions gave 0.541 (25.8%) of 9-amino-1,2,3,4-tetrahydro-1,3-acridinediol, mp 139°-141° C.
Reaction SMILES: C[O:2]C1C=CC(C(O)=O)=CC=1.C(C1CN1)#N.[CH:17]1([N:23]=[C:24]=[N:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCOCC1>[CH:26]1([NH:25][C:24]([NH:23][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:2])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N#CC1CN1
Solvent: C1COCCO1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 2 h

Procedure:
1.52 g. p-Methoxybenzoic acid is dissolved in 20 ml. dioxan and mixed at 10° C. with a solution of 0.68 g. 2-cyanoaziridine in 3 ml. dioxan. A solution of 2.06 g. dicyclohexylcarbodiimide in 4 ml. dioxan is added thereto and the reaction mixture is stirred for 2 hours at 8°-10° C. The crystals formed (2 g. 1,3-dicyclohexylurea; m.p. 225°-230° C.) are filtered off with suction and the filtrate is evaporated in a vacuum. The semi-solid evaporation residue (3.88 g.) is triturated with 3 ml. anhydrous diethyl ether, the crystals obtained (0.6 g.) are filtered off with suction, the filtrate is evaporated in a vacuum and the evaporation residue (2.45 g.) is again triturated with 3-4 ml. diethyl ether and filtered with suction to give 0.59 g. 1-p-methoxybenzoyl-2-cyanoaziridine; m.p. 81°-83° C. A further 0.18 g. of the desired product are obtained from the mother liquor by again evaporating and triturating the evaporation residue with diethyl ether.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:5]([N:7]([CH3:19])[C@@H:8]([C:16](O)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].[OH-].[Li+].C(O)C.Cl.C[O:31][C:32](=[O:43])[C@H:33]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH2:34]>CO.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:5]([N:7]([CH3:19])[C@@H:8]([C:16]([NH:34][C@H:33]([C:32]([OH:31])=[O:43])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6]
Reactant: COC(=O)[C@@H](N)CCc1ccccc1
Reactant: Cc1cc(C)cc(C(=O)N(C)[C@H](Cc2ccccc2)C(=O)O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCO
Product: Cc1cc(C)cc(C(=O)N(C)[C@H](Cc2ccccc2)C(=O)N[C@@H](CCc2ccccc2)C(=O)O)c1

Procedure:
Coupling of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanine (derived from the corresponding methylester described in example 78 by hydrolysis with lithium hydroxide in methanol/water: [a]D =+88° (c=1.0, ethanol)) with (L)-homo-phenylalanine methyl ester hydrochloride according to example 1 followed by hydrolysis of the methyl ester moiety according to example 12 gives N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanyl-(L)-homo-phenylalanine; FAB-MS m/e 473 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]=[O:26])=[CH:20][CH:19]=3)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C[Si](C)(C)[C:29]([F:32])([F:31])[F:30].[F-].C([NH+](CCCC)CCCC)CCC>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([OH:26])[C:29]([F:32])([F:31])[F:30])=[CH:22][CH:23]=3)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=CCc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Agent: CCCC[NH+](CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: OC(Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.4 %

Procedure:
To a solution of 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)acetaldehyde (0.114 g, 0.31 mmol) in THF (10 mL) was added trimethyl(trifluoromethyl)silane (0.053 g, 0.38 mmol). The mixture stirred at 0° C. for 1 h after which tributylammonium fluoride (1.0 M, 0.078 mL, 0.078 mmol) was added. The mixture stirred at rt for 16 h. After this time, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford the title compound (0.010 g, 7%) as a light yellow solid. MW=433.85. 1H NMR (DMSO-d6, 500 MHz) δ 8.82 (s, 1H), 8.30-8.22 (m, 2H), 7.75 (d, J=8.5 Hz, 2H), 7.56-7.49 (m, 2H), 7.31 (d, J=8.5 Hz, 2H), 6.20 (d, J=11.5 Hz, 1H), 4.23-4.12 (m, 1H), 2.95-2.85 (m, 4H), 2.76-2.68 (m, 1H), 2.10 (quin, J=7.5 Hz, 2H); APCI MS m/z 434 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1>O1CCCC1>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:11](=[O:12])[CH2:10][C:9](=[O:13])[CH3:8])[CH2:3]1
Reactant: OC1CCCNC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1CCCC(O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
A solution of 36.10 g (0.36 mol) of 3-hydroxypiperidine in 300 ml tetrahydrofuran was added dropwise to a solution of 30 g of diketene (0.36 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 53.53 g (0.29 mol, 81% yield) of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:21])[CH2:15][CH2:14]3)[N:10]([C:28]3[N:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[OH:21])[CH2:15][CH2:14]3)[N:10]([C:28]3[N:29]=[CH:30][CH:31]=[CH:32][N:33]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(CN1CCC(c2nc(-c3ccc(F)cc3)nn2-c2ncccn2)CC1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: OC(CN1CCC(c2nc(-c3ccc(F)cc3)nn2-c2ncccn2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of EXAMPLE 74 (90.0 mg, 0.20 mmol) in methanol (1.0 ml) was added sodium borohydride (15.4 mg, 0.407 mmol). After stirring at ambient temperature for 1 hour, the reaction mixture was diluted with EtOAc, and washed with water and brine. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using a silica gel cartridge (a gradient of 0-10% methanol in dichloromethane) to give racemic 2-{4-[3-(4-fluorophenyl)-1-(pyrimidin-2-yl)-1H-1,2,4-triazol-5-yl]piperidin-1-yl}-1-phenylethanol as a light yellow solid. LC-MS (m/z): 445.10 [M+H]+. 1H NMR (CDCl3, 500 MHz): δ 8.90 (d, J=4.8 Hz, 2H), 8.23-8.29 (m, 2H), 7.35-7.37 (m, 4H), 7.29-7.34 (m, 1H), 7.13-7.17 (m, 3H), 4.80 (dd, J=10.4 Hz, 3.4 Hz, 1H), 4.28-4.34 (br, 1H), 3.81-3.87 (br. 1H), 3.34 (d, J=11.4 Hz, 1H), 3.01 (d, J=1.4 Hz, 1H), 2.50-2.63 (m, 3H), 2.02-2.29 (m, 4H). The racemic 2-{4-[3-(4-fluorophenyl)-1-(pyrimidin-2-yl)-1H-1,2,4-triazol-5-yl]piperidin-1-yl}-1-phenylethanol was resolved using ChiralPak™ AD column using 60% IPA in heptane to give a faster eluting enantiomer and a slower eluting enantiomer.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].FC(F)(F)C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:30]([N:37]1[CH2:42][CH2:41][CH:40](O)[CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH:40]1[CH2:39][CH2:38][N:37]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:42][CH2:41]1)=[O:5]
Reactant: Nc1ncccc1C(=O)O
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
0.14 g (0.00101 mol) of 2-amino-nicotinic acid was suspended in 50 ml of THF and treated with 0.077 ml (0.00101 mol) of trifluoroacetic acid. The mixture was stirred at room temperature for 1 hr., whereby a solution resulted. To this was added 0.25 g (0.0015 mol) of carbonyidiimidazole and the mixture was stirred at room temperature for 2 hrs. Subsequently, 0.34 g (0.00178 mol) of 1-benyl-4-hydroxy-piperidine was added and the mixture was stirred at 60° for 72 hrs. After removing the solvent the residue was chromato-graphed over silica gel with ethyl acetate/hexane (1:1) as the eluent. 0.105 g (31%) of 1-benzyl-piperidin-4-yl 2-amino-nicotinate was obtained as white crystals. MS: me/e (% basic peak)=311 (C18H21N3O2+, 7.5), 173 (42), 91 (100), 82 (86).
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:25]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][C:28]=3[CH3:35])=[C:24]([F:36])[C:12]3[N:13]=[C:14](COCC[Si](C)(C)C)[NH:15][C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.Cl.[OH-].[Na+]>CCO>[CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:25]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][C:28]=3[CH3:35])=[C:24]([F:36])[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: Cc1cc(C#N)ccc1Nc1c(C(=O)NOCC2CC2)cc2[nH]c(COCC[Si](C)(C)C)nc2c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C#N)ccc1Nc1c(C(=O)NOCC2CC2)cc2[nH]cnc2c1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a slurry of a 1:1 mixture of N1:N3 isomers 6-(4-cyano-2-methyl-phenylamino)-7-fluoro-(2-trimethylsilanyl-ethoxymethyl)-benzoimidazole-5-carboxylic acid cyclopropylmethyoxy-amide 11zz (28 mg, 0.055 mmol) in 0.5 mL EtOH is added 0.5 mL 10% HCl. The reaction mixture is heated to 50° C. with stirring overnight (Whitten et al., J. Org. Chem., 1986, 51, 1891-1894). An additional 0.5 mL 10% HCl is added and the reaction mixture stirred at 70° C. overnight. The reaction mixture is cooled to room temperature and neutralized to pH ˜8 with 1.5 mL 1N NaOH. The reaction mixture is extracted with ethyl acetate, dried (MgSO4) and concentrated under reduced pressure to give 14 mg (60%) of 90% pure product as a mixture of rotatomers: MS APCI (+) m/z 380 (M+1) detected; MS APCI (−) m/z 378 (M−1) detected; 1H NMR (400 MHz, MeOH-d4) δ 8.41 (bs, 1H), 7.75 (m, 1H), 7.50 (s, 1H), 7.38 (d, 1H), 6.51 (m, 1H), 3.72 (d, 0.5 H), 3.65 (d, 1.5 H), 2.41 (s, 3H), 0.98 (1H, m), 0.58 (d, 1.5 H), 0.40 (d, 0.5 H), 0.25 (d, 1.5 H), 0.19 (d, 0.5 H).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7](O)(=O)=O)=CC=1.[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH:12]1([C:4]2[S:7][CH:1]=[CH:6][CH:5]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1ccccc1
Solvent: Cc1ccccc1
Product: c1csc(C2CCCCC2)c1

Procedure:
Synthesis substrates 4H-indeno[1,2-c]thiophen-4-one and 4H-indeno [1,2-c]thiophene and their derivatives are prepared in accordance with MacDowell and Jefferies, J. Org. Chem., 35, 871 (1970). Wherein treatment of 4-bromo-3-thienyllithium with a commonly available lower alkyl substituted cyclohexanone or cyclohexanone, such as 4-methylcyclohexanone, at -65° to -75° C. yields the corresponding cyclohexanol derivative which is dehydrated with para-toluenesulfonic acid in refluxing benzene or toluene to yield a cyclohexylthiophene product such as 3-bromo-4-(4-methyl-1'-cyclohexenyl)thiophene. Dehydrogenation with tetrachlorobenzoquinone in refluxing xylene for 8-24 hours yields the corresponding 3-bromo-4-phenylthiophene, e.g., 3-bromo-4-(4'-methylphenyl)thiophene. After purification by sublimation and/or chromatography over alumina, the bromide is subjected to halogen-metal exchange at -65° to -75° C. with n-butyllithium in ether, followed by carbonation with carbon dioxide. The isolated 3-phenyl-thiophene-4-carboxylic acid derivative, e.g., 3-(4'-methylphenyl)thiophene-4-carboxylic acid, is converted with thionyl chloride to the acid halide. Ring closure to the ketone via heating the aroyl chloride and aluminum chloride in carbon disulfide for 18-36 hours yields the corresponding ketone, such as 6-methyl-8H-indeno[1,2 -c]thiophen-8-one. This 8-one derivative, which may be further derivatized according to Method V, is converted (in accordance with Method I) into a hydantoin derivative. Wolff-Kishner reduction (Method VIII) of the 8-one derivative (and optional derivatization according to Method V) and spiro-derivatization in accordance with Methods II, III and IV yields the corresponding spiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimide derivatives respectively. These spiro-derivatives may be further derivatized according to Method VI.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]([C:13]([O-])=[O:14])[CH2:11][CH2:10][CH:9]1[C:16](OCC)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH:12]([CH2:13][OH:14])[CH2:11][CH2:10][CH:9]1[CH2:16][OH:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCC(C(=O)[O-])N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCC(CO)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
A solution of 96.4 grams of 1-benzyl-pyrrolidine-2,5-dicarboxylic acid, 2-ethyl ester, 5-methyl ester in 380 ml of anhydrous tetrahydrofuran is dripped rapidly into a solution of lithium aluminum hydride (437 mmol) in tetrahydrofuran (1.4 liter) at 0° C. After complete addition, the mixture is stirred for 3 hours at ambient temperature and then carefully quenched with 57.8 ml of water followed by 38.6 ml of 10% sodium hydroxide. The mixture is stirred overnight, filtered through Celite, the Celite washed with CH2Cl2 and the combined filtrate evaporated to provide 67.11 grams of crude (1-benzyl-5-hydroxymethyl-pyrrolidine-2-yl)-methanol.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:6]([CH3:8])=[O:7]>C1C=CC=CC=1>[CH2:5]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:3])=[O:14])=[CH:11][CH:10]=1)[C:6]([CH3:8])=[O:7]
Reactant: CC(=O)Cc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)Cc1ccc(C(=O)Cl)cc1

Procedure:
Thionyl chloride (1.45 ml) was added to 4-acetonylbenzoic acid (3.56 g) in benzene and the mixture refluxed for 1 hour. Benzene was evaporated to give the title compound as a yellow oil, 2.61 g, (bp 135°-140°/0.5 mm). γ (CDCl3) 7.78 (3H, s), 6.17 (2H, s), 2.63 (2H, d, J=9 Hz), 1.88 (2H, d, J=9 Hz).
Reaction SMILES: C([O:4][CH:5]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]#[CH:20])=[C:13]([O:21][CH3:22])[CH:12]=1)=[S:7])(=O)C.[OH-].[Na+].CO>O>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH:5]([OH:4])[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]#[CH:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[S:7])=[CH:28][CH:27]=1
Reactant: C#CCOc1ccc(CCNC(=S)C(OC(C)=O)c2ccc(Cl)cc2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#CCOc1ccc(CCNC(=S)C(O)c2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-acetoxy-2-(4-chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-thioacetamide (compound A1.03; 0.603 g), sodium hydroxide (1.4 ml 1 n solution in water) and methanol (5 ml) is stirred for 6 hours at room temperature. Water (30 ml) is added. The reaction mixture is extracted with ethyl acetate (2×100 ml). The organic layers are washed with brine (20 ml), dried and the solvent is evaporated. 2-(4-Chloro-phenyl)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-thioacetamide is obtained which is purified by flash-column-chromatography on silica gel using ethyl acetate/hexane, yielding a resin, 1H-NMR (300 MHz, CDCl3, δ(ppm)): 2.5(t, 1H), 2.9(t, 2H), 3.8(s, 3H), 3.85–4.05(m, 2H), 4.25 (s, 1H), 4.75(d, 2H), 5.1(s, 1H), 6.5(dd, 1H), 6.65(d, 1H), 6.9(d, 1H), 7.2(d, 2H), 7.3(d, 2H), 7.7–7.8(m, 1H).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[N:5][N:4]=[C:3]1[SH:13].[OH-].[Na+].[CH3:16]I>O>[NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]([CH3:10])([CH3:12])[CH3:11])=[N:5][N:4]=[C:3]1[S:13][CH3:16]
Reactant: CI
Reactant: CC(C)(C)c1nnc(S)n(N)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1nnc(C(C)(C)C)c(=O)n1N
Yield: 80.7 %

Procedure:
20 g (0.1 mole) of 4-amino-6-tert.-butyl-3-mercapto-1,2,4-triazin-5(4H)-one, the compound of formula (V), were introduced into a mixture of 97 g of 45% strength sodium hydroxide solution and 65 g of water, while stirring. After all of the product had dissolved, 16.5 g of methyl iodide were added in a manner such that internal temperature did not rise above 30° C. When the addition had ended, the reaction mixture was stirred at room temperature for a further 2 hours. The reaction product which had precipitated was then filtered off, washed with 100 ml of water and dried. 17.3 g (81% of theory) of 4-amino-6-tert.-butyl-3-methylthio-1,2,4-triazin-5-(4H)-one, the compound of formula(VI), of melting point 123° 125° C. were obtained.