Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.CN(C)C=O.[C:18](N1C=CN=C1)(N1C=CN=C1)=[S:19].[N:30](=[C:32]([C:34]1[C:38]([OH:39])=[C:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)[N:36]([CH3:50])[N:35]=1)[CH3:33])[NH2:31]>O>[OH:39][C:38]1[C:34]([C:32](=[N:30][NH:31][C:18](=[S:19])[NH:1][C:2]2[CH:12]=[CH:11][C:5]3[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=3[CH:3]=2)[CH3:33])=[N:35][N:36]([CH3:50])[C:37]=1[C:40]1[CH:41]=[CH:42][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:44][CH:45]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2c(c1)OCC(=O)N2
Reactant: CC(=NN)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=S)Nc1ccc2c(c1)OCC(=O)N2)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Yield: 49 %

Procedure:
7-Amino-4H-benzo[1,4]oxazin-3-one (33 mg, 0.203 mmol) was stirred with a dimethylformamide solution of thiocarbonyldiimidazole (0.1 M, 2.03 mL, 0.203 mmol) at room temperature for 1 hour and then with a dimethylformamide solution of 3-(1-hydrazonoethyl)-1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-ol prepared in Reference Synthetic Example 14 (0.1 M, 1.36 mL, 0.135 mmol) at room temperature for 4 hours Water was added, and the precipitated solid was collected by filtration, washed with water and dried. After addition of chloroform, the solid was collected by filtration washed with chloroform and dried to give 33.6 mg of the desired product (yield 49%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=3)[N:7]=[C:6]([C:30]#[N:31])[C:5]=2[N:4]=[N:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=[N:56][C:51]2[CH:52]=[CH:53]C=N[C:50]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1C(=[O:71])CCC1>CCOC(C)=O>[NH2:56][C:51]1([C:50]([N:23]2[CH2:22][CH2:21][CH:20]([CH2:19][CH2:18][O:17][C:14]3[CH:15]=[CH:16][C:11]([C:8]4[N:7]=[C:6]([C:30]#[N:31])[C:5]5[N:4]=[N:3][N:2]([CH3:1])[C:10]=5[CH:9]=4)=[CH:12][C:13]=3[C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24]2)=[O:71])[CH2:53][CH2:52]1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)cc21
Reactant: CN1CCCC1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCN(C(=O)C5(N)CC5)CC4)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 52 %

Procedure:
1-Methyl-6-(4-(2-(piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (76 mg), Boc-1-aminocyclopropane-1-carboxylic (71.1 mg) and DIPEA (146 μl) were dissolved in NMP (2 ml) and HATU (0.265 mmol, 101 mg) was then added. The reaction was stirred at room temperature for 72 hours then diluted with EtOAc (20 ml) and washed with 1:1 saturated sodium bicarbonate solution/water (3×15 ml). Organics were dried over sodium sulphate and solvent evaporated under reduced pressure. The resulting residue was re-dissolved in DCM (1 ml) and acetonitrile (200 μl) and trifluoroacetic acid (200 μl) added. The mixture was stirred for 30 minutes at room temperature then solvent evaporated under reduced pressure. Toluene (500 μl) was added and then removed under reduced pressure. The resulting brown residue was purified by flash chromatography (10 g silica column, DCM to 5% MeOH in DCM gradient). Solvent was evaporated under reduced pressure and the resulting solid was washed with DCM and ether and dried under vacuum to afford desired product 6-(4-(2-(1-(1-aminocyclopropanecarbonyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (52% yield) as a solid.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#N.[OH-:17].[K+].C(O)C[OH:21]>O>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)([OH:21])=[O:17]
Reactant: [OH-]
Reactant: OCCO
Reactant: N#CC1(c2ccc(F)cc2)CCC(=O)CC1
Agent: [K+]
Solvent: O
Product: O=C1CCC(C(=O)O)(c2ccc(F)cc2)CC1
Yield: 93 %

Procedure:
A mixture of 18.17 g. (0.07 mole) of 4-cyano-4-(4-fluorophenyl)cyclohexanone, ethylene ketal (prepared in Example 20 and 15 g. of potassium hydroxide in 150 ml. of ethylene glycol is heated at reflux for about 16 hours. The resulting solution is allowed to cool, diluted with water and washed with ether. The aqueous layer is covered with ether and then cautiously acidified. The aqueous layer is extracted with two additional portions of ether and the extracts combined. The extracts are evaporated to dryness to give 18.2 g. (93% yield) of 4-carboxy-4-(4-fluorophenyl)cyclohexanone, ethylene ketal, having a melting point of 117° to 122°C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>CN(C=O)C>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([S:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Reactant: Fc1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(SCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.3 %

Procedure:
To a stirred solution of 4-fluorobenzyl mercaptan (23.34 g, 164 mmol) in DMF (150ml) under argon, cooled in a bath at -2° C. as added portionwise 60% NaH in oil (6.57 g, 164 mmol) over 12 minutes. The mixture was then stirred at room temperature for 15 minutes before recooling in bath at -2° C. and adding by cannular, over 13 minutes, a solution of 4-bromo-1(tert-butoxycarbonyl)piperidine (10.84 g, 41.0 mmol) in DMF (50ml). The mixture was then stirred at room temperature for 24 h before partitioning between water (500ml) and diethyl ether (500ml). The aqueous layer was reextracted with more diethyl ether (500ml) and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 10-15% EtOAc/hexane) to give 4.58 g (34%) of the title compound as a colourless oil. δH (360 MHz, CDCl3) 1.45 (9H, s), 1.49 (2H, m), 1.86 (2H, m), 2.67 (1H, m), 2.88 (2H, m), 3.73 (2H, s), 3.92 (2H, m), 6.99 (2H, t, J=8.6 Hz), 7.28 (2H, m). m/e (ES+) 326 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH2:11]([C:18]1([N:25]([CH3:27])[CH3:26])[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:11]([C:18]1([N:25]([CH3:26])[CH3:27])[CH2:23][CH2:22][CH:21]([NH:1][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC1CCc2ccccc21
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C)C1(Cc2ccccc2)CCC(NC2CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
266 mg 1-aminoindane and 462 mg 4-benzyl-4-dimethylamino-cyclohexanone (see example 3) were dissolved in dry 1,2-dichloroethane under argon and the solution was stirred with 2 g sodium sulfate for 24 hours at RT. 600 mg sodium triacetoxyborohydride were added to this mixture and the mixture was stirred for two hours at RT. For working up, the reaction mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product was chromatographed over silica gel with ethyl acetate. 696 mg 1-benzyl-N′-indan-1-yl-N,N-dimethyl-cyclohexane-1,4-diamine were obtained as a colorless oil. For preparation of the hydrochloride, the base was dissolved in 2-butanone (10 ml), and 1.85 M ethanolic hydrochloric acid (2.80 ml) was added. The solid which had precipitated out was filtered off with suction and dried. 540 mg of a mixture of cis- and trans-1-benzyl-N′-indan-1-yl-N,N-dimethyl-cyclohexane-1,4-diamine dihydrochloride were obtained as a white solid (m.p. 170-172° C.)
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].Br[C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)[CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: Brc1nccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCO[C@@H]1CN(c2nccs2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 40.2 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol), 2-bromothiazole (0.040 mL, 0.44 mmol) and sodium carbonate (157 mg, 1.48 mmol) were suspended in DMF (3 mL). The suspension was subjected to the same operation as in Example (131b) to obtain 45.8 mg of the title compound as a colorless oily substance (40%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]1[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:14]=1[Cu]>C1(C)C=CC=CC=1>[F:12][C:13]1[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:14]=1[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH2:5][OH:7].[F:12][C:13]1[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:14]=1[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(I)c1
Reactant: Fc1c(F)c(F)c([Cu])c(F)c1F
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(-c2c(F)c(F)c(F)c(F)c2F)c1
Product: OCc1cccc(-c2c(F)c(F)c(F)c(F)c2F)c1
Temperature: 25 °C
Yield: 191.2 %

Procedure:
3-(2,3,4,5,6-Pentafluorophenyl)benzyl alcohol was prepared as follows: Under an argon atmosphere, methyl 3-iodobenzoate (2.3 g. 0.009 mole) and 2,3,4,5,6-pentafluorophenyl copper (2.0 g, 0.009 mole) were added to 50 ml of toluene. The stirred reaction mixture was heated under reflux for 2 hours, then cooled to room temperature. The mixture was filtered and the filtrate evaporated under reduced pressure to a residual solid. The solid was recrystallized from methanol to give methyl 3-(2,3,4,5,6-pentafluorophenyl)benzoate (2.6 g); mp, 104°-106°.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=O.[CH3:21][C:22](=O)[CH2:23][C:24](=[O:26])[CH3:25]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[C:23]([C:24](=[O:26])[CH3:25])=[C:22]([CH3:21])[N:1]=[C:2]3[S:6][C:5]4[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=4[C:3]=23)=[CH:14][CH:15]=1
Reactant: CC(=O)CC(C)=O
Reactant: COc1ccc(C(=O)c2c(N)sc3c2CCCC3)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(-c2c(C(C)=O)c(C)nc3sc4c(c23)CCCC4)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
To a stirred solution of 50 mg (0.17 mmol) (2-amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-yl)-(4-methoxy-phenyl)-methanone in 1.5 ml acetic acid was added 0.018 ml (0.18 mmol) of pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 9:1) afforded 38 mg (62%) 1-[4-(4-methoxy-phenyl)-2-methyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as a light yellow solid. ES-MS m/e (%): 352 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.[I-].[NH2:18][N+:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][N:11]=3)=[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]3[N:18]=2)=[CH:4][CH:3]=1
Reactant: N[n+]1ccccc1
Reactant: O=C(Cc1ccncn1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: Fc1ccc(-c2nn3ccccc3c2-c2ccncn2)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A solution of 1-(4-fluorophenyl)-2-(4-pyrimidinyl)-ethanone (21.6 g, 0.1 mol), 1-aminopyridinium iodide (22.2 g, 0.1 mol) and potassium carbonate (41.4 g, 0.3 mol) in a mixture of water (300 mL) and isopropanol (300 mL) was heated and stirred at 100° C. for 16 hours. The isopropanol was removed under vacuum and the resulting aqueous phase extracted with dichloromethane (5×200 mL). The dichloromethane extracts were combined and the solvent evaporated under reduced pressure to leave a red solid which was purified by silica gel chromatography eluting with a hexane/ethyl acetate to give the title compound as a yellow solid, 9.16 g (32%). 1H NMR (DMSO-d6): δ 7.07 (d, J=5.4 Hz, 1H), 7.14 (t, J=6.8 Hz, 1H), 7.32 (t, J=8.7 Hz, 2H), 7.35 (t, J=7.8 Hz, 1H), 7.60 (dd, J=5.7, 8.7 Hz, 2H), 8.40 (d, J=8.9 Hz, 1H), 8.54 (d, J=5.3 Hz, 1H), 8.83 (d, J=7.1 Hz, 1H), 9.16 (s, 1H), APESI+MS m/z 291 (M+1).
Reaction SMILES: [Li].C1C2C(=CC=CC=2)C=CC=1.[CH3:12][C:13]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:17][CH2:16][CH2:15][CH:14]1[NH:18]S(C1C=CC(C)=CC=1)(=O)=O>C(COC)OC>[NH2:18][CH:14]1[CH2:15][CH2:16][CH2:17][C:13]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)NC2CCCC2(C)NC(=O)OC(C)(C)C)cc1
Agent: [Li]
Solvent: c1ccc2ccccc2c1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1(C)CCCC1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of lithium granules (7.17 g, 1195 mmol) and naphthalene (57.39 g, 448.36 mmol) in dry dimethoxyethane (1900 ml) was stirred at room temperature for 2 hours. The deep blue solution was then cooled to 0° C. and a solution of tert-butyl N-[1-methyl-2-(4-methylbenzenesulfonamido)cyclopentyl]carbamate (55.0 g, 149.45 mmol) in dry dimethoxyethane (300 ml) was added drop wise over 30 minutes. The mixture was stirred at 0° C. for 3 hours. The un-dissolved lithium was removed by filtration and 1M HCl solution (aq, 720 ml) was added to the filtrate. The organic layer was washed with further 1M HCl (aq, 2×600 ml). The combined aqueous layers were washed with diethyl ether (2×600), and then basified with 2M NaOH (aq) to give pH 12-14. The aqueous layer was then extracted with ethyl acetate (5×600 ml). The combined organics were dried over sodium sulfate and then concentrated in vacuo. This was then purified by column chromatography (silica, 0-4% methanol/DCM) to afford the title compound.
Reaction SMILES: O(C1C=C([Mg]Br)C=CC=1)[CH3:2].[C:11]([Cu])#[N:12].P(OC)(OC)OC.C(OC([N:28]1[C:32]2=NC=C(C3C=CSC=3)C=[C:31]2[C:30]([CH2:42][Cl:43])=[CH:29]1)=O)(C)(C)C>O1CCCC1.O>[Cl:43][C:42]1[CH:2]=[CH:11][N:12]=[C:29]2[C:30]=1[CH:31]=[CH:32][NH:28]2
Reactant: COc1cccc([Mg]Br)c1
Reactant: N#C[Cu]
Reactant: CC(C)(C)OC(=O)n1cc(CCl)c2cc(-c3ccsc3)cnc21
Agent: COP(OC)OC
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccnc2[nH]ccc12
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
Into a round bottom flask was added 1.0 M of 3-methoxylphenyl magnesium bromide in Tetrahydrofuran (1.0 mL) and Tetrahydrofuran (5.0 mL, 0.062 mol) under an atmosphere of Nitrogen. The reaction mixture was cooled to −20 Celsius, followed by addition of 0.7 M of CuCN.2LiCl in Tetrahydrofuran (1 mL). After 10 minutes, Trimethyl Phosphite (120 mg, 0.0010 mol) was added to the reaction mixture. To the reaction mixture, was added compound 18 (60.0 mg, 0.000172 mol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with biotage to give product 6 (M25 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:23])[CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22].[N:24]1([C:29](N)=[NH:30])C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]([CH2:2][CH2:3][N:4]([CH3:23])[CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22])[C:29]([NH2:30])=[NH:24]
Reactant: N=C(N)n1cccn1
Reactant: CN(CCN)C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCNC(=N)N)C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 8 h

Procedure:
To a stirred solution of 14e (218 mg, 0.67 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride50 (196 mg, 1.34 mmol) in anhydrous DMF (5 mL) was added DIEA (479 mg, 0.65 mL, 3.7 mmol) under nitrogen at 5° C. Stirring was continued at room temperature overnight. The reaction mixture was concentrated to dryness and the product was purified by column chromatography (silica gel 230-400 mesh, elution with 4:1:0.3 chloroform:methanol:NH4OH). The desired fractions were combined, concentrated, and dried in vacuo to give a white solid: yield 219 mg (89%), MS: m/z 366 (M+H)+; 1HNMR (DMSO-d6) δ 8.34 (s, 1H, H-8), 8.15 (s, 1H, H-2), 7.48, 7.37, 7.28 (bs, NHs), 5.87 (d, 1H, H-1′, J1′,2′=5.2 Hz), 5.50 (d, 1H, 2′-OH, J2′-2′OH=5.7 Hz), 5.28 (d, 1H, 3′-OH, J3′-3′OH=4.5 Hz), 4.65 (ddd, 1H, H-2′, J1′,2′=5.2 Hz, J2′,3′=5.1 Hz, J2′-2′OH=5.7 Hz), 4.12 (ddd, 1H, H-3′, J2′,3′=5.1 Hz, J3′,4′=4.6 Hz, J3′-3′OH=4.5 Hz), 4.0-4.10 (bm, 1H, H-4′), 3.30-3.50 (bm, 2H, 5′-CH2), 3.12-3.28 (bm, 2H, NH—CH2), 2.55-2.65 (bm, 2H, N(CH3)—CH2), 2.25 (bs, 3H, N—CH3); UV λmax, nm, pH 1, 256.3 (∈ 10,900), pH 7, 259 (∈ 11,300), pH 13, 259 (∈ 11,000). Anal. (C14H23N9O3.0.05CHCl3.3.5H2O) C, H, N.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[C:6]([CH:14](Br)[CH:15]([CH3:26])[C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[C:1]([S:3][CH:14]([C:6](=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:15]([CH3:26])[C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: CC(C(=O)N1CCC[C@H]1C(=O)O)C(Br)C(=O)c1ccccc1
Agent: [K+]
Solvent: CCO
Product: CC(=O)SC(C(=O)c1ccccc1)C(C)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 18 h

Procedure:
To a suspension of 0.47 g of potassium thioacetate in 10 ml. of ethanol is added 1.25 g. of 1-(3-benzoyl-3-bromo-2-methylpropionyl)-L-proline (Example 11, 3-bromo derivative of isomer A). The mixture is stirred for 18 hours, the solvent is removed in vacuo and the residue is partitioned between dichloromethane and water. The organic layer is washed with water, then sodium chloride solution and dried over magnesium sulfate. The solvent is removed in vacuo giving a yellow glass which is dissolved in 10 ml. of ethanol. A 0.47 g. portion of potassium thioacetate is added and the above procedure is repeated giving a yellow glass. This glass is purified by chromatography on a silica gel column with ethyl acetate-hexane-acetic acid (75:25:2) giving 0.28 g. of the desired product as a yellow glass.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:12]=3[NH:13][N:14]=2)=[CH:6][CH:5]=1)=[C:2]=[O:3].CCN(CC)CC.[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33][NH2:34])[CH3:30]>C1(C)C=CC=CC=1>[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33][NH:34][C:2]([NH:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:12]=3[NH:13][N:14]=2)=[CH:8][CH:9]=1)=[O:3])[CH3:30]
Reactant: O=C=Nc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reactant: CCN(CC)CCN
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CC)CCNC(=O)Nc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 95 °C
Yield: 57 %

Procedure:
A suspension of of 3-(4-isocyanatophenyl)-1,4-dihydroindeno[1,2-c]pyrazole, 2 (75 mg, 0.274 mmol), Et3N (0.191 mL, 1.37 mmol), N,N-diethylethylenediamine (0.112 mL, 1.37 mmol) in toluene (3 mL) was heated to about 95° C., for about 3 hours. The white solid was filtered off and washed with EtOAc and dried under vacuum to afford 61 mg (57%) of pure product. LC/MS 390 (M+1); LC retention time 2.76 minutes.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:29]([O:31][C:32](=[O:48])[CH2:33]P(OCC(F)(F)F)(OCC(F)(F)F)=O)[CH3:30].[S:49]1[CH:53]=[CH:52][C:51]([CH:54]=O)=[CH:50]1>C1COCC1>[CH2:29]([O:31][C:32](=[O:48])[CH:33]=[CH:54][C:51]1[CH:52]=[CH:53][S:49][CH:50]=1)[CH3:30]
Reactant: CCOC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: O=Cc1ccsc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccsc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
Potassium bis(trimethylsilyl)amide (3.92 g, 19.7 mol) was added to a solution of 18-Crown-6 (9.95 g, 37.6 mmol) and [Bis-(2,2,2 trifluoro-ethoxy)-phosphoryl]-acetic acid ethyl ester (6.54 g, 19.7 mmol) in dry THF (200 mL) at −78° C. After 30 minutes of stirring at this temperature, thiophene-3-carbaldehyde (2.0 g, 19.7 mmol) was added and the reaction was stirred for 3 hours at −78° C. after which the reaction was quenched with saturated ammonium chloride (200 mL). The reaction mixture was allowed to come to room temperature and was extracted with ethyl acetate (3×250 mL) and the combined organic extracts were washed with 10% HCl (200 mL), brine (200 mL) and dried with MgSO4 Evaporation of the solvent in vacuo gave the crude product that was purified by silica-gel chromatography using a 0-40% ethylacetate-hexane gradient to afford the subtitle compound (2.7 g, 82.7%). MS calculated for C9H10O2S +H: 183, observed: 183; 1H NMR (300 MHz, CDCl3, ppm) 1.31 (t, J=7 Hz, 3H); 4.22 (q, J=7 Hz, 2H); 5.83 (d, J=13 Hz, 1H); 6.87 (d, J=7 Hz, 1H); 7.24-7.28 (m, 1H); 7.54 (dd, J1=5 Hz, J2=1 Hz, 1H); 8.07 (br d, J=3 Hz, 1H).
Reaction SMILES: [CH2:1](O)[CH3:2].S(=O)(=O)(O)O.[C:9]([NH:17][C@H:18]([C:22]([OH:24])=[O:23])[CH:19]([CH3:21])[CH3:20])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:9]([NH:17][C@H:18]([C:22]([O:24][CH2:1][CH3:2])=[O:23])[CH:19]([CH3:21])[CH3:20])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Yield: 71 %

Procedure:
Dissolve in 100 ml of ethanol 0.045 mol (10 g) of N-benzoylvaline obtained in the preceding Step, add 5 ml of concentrated sulphuric acid, then heat at reflux for 24 hours. Evaporate to dryness, take up in ether, wash with water then with a 10% potassium bicarbonate solution, dry, filter and evaporate to dryness. Ethyl N-benzoylvalinate is obtained.