Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[K+].[NH:12]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C@H:13]([C:15]([NH:17][C@H:18]([C:22]([N:24]1[CH2:32][CH2:31][CH2:30][C@H:25]1[C:26]([CH2:28]Br)=[O:27])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:16])[CH3:14]>>[NH:12]([C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])[C@H:13]([C:15]([NH:17][C@H:18]([C:22]([N:24]1[CH2:32][CH2:31][CH2:30][C@H:25]1[C:26]([CH2:28][O:8][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9])=[O:27])=[O:23])[CH:19]([CH3:20])[CH3:21])=[O:16])[CH3:14]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)CBr
Reactant: O=C(O)c1ccccc1
Agent: [F-]
Agent: [K+]
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)COC(=O)c1ccccc1

Procedure:
Benzoic acid (0.275 g, 2.25 mmol), KF (0.131 mg, 2.25 mmol), 13 (0.56 g, 1.13 mmol).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[N:2]1.C([N-]C(C)C)(C)C.[Li+].[CH:23]12[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[C:24]1=[O:33])[CH2:30]2.O>O1CCCC1>[OH:33][C:24]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:3]2[N:4]=[CH:5][NH:1][N:2]=2)[CH:23]2[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]1[CH2:26]3)[CH2:30]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: N#Cc1ccc(Cc2nc[nH]n2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(c2nc[nH]n2)C2(O)C3CC4CC(C3)CC2C4)cc1
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
5 g of 4-[1-(1,2,4-triazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -50° with 19.8 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour, further stirred with 4.25 g of adamantanone for 1 hour at -70°, and heated to 25°. Then water is added, the mixture is extracted twice with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, yielding 9 g of crude 4-(2-hydroxyadamant-2-yl-1-(1,2,4-triazolyl)methyl]benzonitrile.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([OH:12])(=[O:11])[C:8]([CH3:10])=[CH2:9].[C:13](=[O:21])([O:17][CH2:18][CH2:19]Cl)[O:14][CH2:15][CH3:16].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[C:13](=[O:21])([O:17][CH:18]([O:11][C:7](=[O:12])[C:8]([CH3:10])=[CH2:9])[CH3:19])[O:14][CH2:15][CH3:16]
Reactant: C=C(C)C(=O)O
Reactant: CCOC(=O)OCCCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OC(C)OC(=O)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.5 %

Procedure:
Potassium tert. butoxide (3.70 g, 0.033 mol ) was added to a solution of methacrylic acid (2.84 g, 0.033 mol) in DMF (100 ml). Ethyl chloroethyl carbonate (5.08 g, 0.033 mol) from Example 1q(i) above was added to the resulting suspension. 18-crown-6 (0.61 g, 2.3 mmol) was then added and the reaction mixture was left with stirring at room temperature for 3 days. The reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was dissolved in chloroform (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (50 ml) and water (50 ml). The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. Flash chromatography gave 2.50 g (38%) of the title product. (Adjusted for recovered starting material the yield was 75%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH:13][C:14]2[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][C:17]([OH:23])=[CH:16][C:15]=2[CH:24]([CH3:26])[CH3:25])=[O:12])[CH2:6][CH2:5]1.[CH:27](N(CC)C(C)C)(C)C.C[Si](C=[N+]=[N-])(C)C.[OH-].[Na+]>C(#N)C.CO>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH:13][C:14]2[C:19]([CH:20]([CH3:21])[CH3:22])=[CH:18][C:17]([O:23][CH3:27])=[CH:16][C:15]=2[CH:24]([CH3:26])[CH3:25])=[O:12])[CH2:6][CH2:5]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)c1cc(O)cc(C(C)C)c1NC(=O)CN1CCN(CCO)CC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: COc1cc(C(C)C)c(NC(=O)CN2CCN(CCO)CC2)c(C(C)C)c1
Reaction time: 12 h
Yield: 82.8 %

Procedure:
Into a solution of the acetamide (640 mg, 1.76 mmol) in a mixed solvent (10 ml) of methanol and acetonitrile (1:4) were dropped N,N-diisopropylethylamine (0.43 ml, 2.46 mmol) and trimethylsilyl diazomethane (1.23 ml, 2.46 mmol) and the mixture was stirred for 12 hours. The residue obtained by evaporation of the solvent was made alkaline by adding 2N sodium hydroxide and then extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous sodium sulfate and the solvent was evaporated therefrom to provide 550 mg (yield 83%) of 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-(2,6-diisopropyl-4-methoxyphenyl)acetamide as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:15]([CH2:16][OH:17])[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].I([O-])(=O)(=O)=[O:26].[Na+].C(OCC)(=O)C.O>C(#N)C.[Ru](Cl)(Cl)Cl>[C:21]([O:20][C:18]([N:11]1[CH2:10][C@@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C@H:15]([C:16]([OH:26])=[O:17])[O:14][CH2:13][CH2:12]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CO)[C@H](c2ccc(Cl)c(Cl)c2)C1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10 %

Procedure:
To a mixed solution of tert-butyl (6R,7R)-6-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (3.0 g) and sodium periodate (3.41 g) in acetonitrile (16 mL)/ethyl acetate (16 mL)/water (24 mL) was added ruthenium (III) chloride (17 mg), and the mixture was stirred at room temperature for 10 min. The solid was filtered off through celite, and the filtrate was concentrated. The residue was crystallized from ethyl acetate to give the title compound (311 mg) as a colorless amorphous powder.
Reaction SMILES: [CH3:1][C:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH:11]=O)[CH2:7][CH2:6]1)([CH3:4])[CH3:3].[O-:13][CH2:14][CH3:15].[Na+].[CH3:17][CH2:18][OH:19]>>[CH2:14]([O:13][C:18](=[O:19])/[CH:17]=[CH:11]/[C@H:8]1[CH2:7][CH2:6][C@H:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:10][CH2:9]1)[CH3:15]
Reactant: CC[O-]
Reactant: CC(C)(C)[C@H]1CC[C@H](C=O)CC1
Reactant: CCO
Agent: [Na+]
Product: CCOC(=O)/C=C/[C@H]1CC[C@H](C(C)(C)C)CC1
Temperature: 40 °C
Reaction time: 1.6 h

Procedure:
To a solution of trans-4-(1,1-dimethylethyl)cyclohexanecarboxaldehyde (200 mg, 1.19 mmol) in abs. EtOH (5.4 mL) at room temperature was added triethyl phosphonoacetate (96% pure, 0.389 mL, 1.96 mmol). The reaction mixture was warmed to 40° C. and a solution of sodium ethoxide (prepared from 41 mg of Na in 1.49 mL of abs. EtOH, 1.78 mmol) was added dropwise. The reaction mixture was stirred at 40° C. for 1.6 h and was quenched by the addition of HOAc/ether (1:3) to pH 6 followed by few drops of sat. NaHCO3. The excess EtOH was removed under reduced pressure and the residue was partitioned between ethyl ether (150 mL) and H2O (50 mL). The aqueous layer was extracted with ether (2×50 mL). The combined ether layers were washed with brine (75 mL), dried over MgSO4 and concentrated to give crude product (300 mg). Purification by flash chromatography eluting with 2 % EtOAc/hexane yielded trans-(E)-3-[4-(1,1-dimethylethyl)cyclohexyl]-2-propenoic acid ethyl ester (239 mg, 1.00 mmol) in 84% yield.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].N1C=CN=C1.[OH:14][CH2:15][C@@H:16]([CH3:48])[C@H:17]([NH:28][C:29]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C(Cl)Cl>[Si:5]([O:14][CH2:15][C@@H:16]([CH3:48])[C@H:17]([NH:28][C:29]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=2[C:36]2[C:41]1=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: C[C@H](CO)[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Reaction time: 14.25 h

Procedure:
TBDMS-Cl (48 mg, 0.312 mmol) followed by imidazole (28.8 mg, 0.423 mmol) were added to a CH2Cl2 (3 ml) solution of (2S,3S)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate (119.5 mg, 0.258 mmol), and the mixture was stirred at ambient condition for 14.25 hr. The reaction mixture was then diluted with CH2Cl2 (30 mL) and washed with water (15 mL), and the organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The resultant crude material was purified with a Biotage (40 g silica gel; 5% EtOAc/hexanes) to afford (2S,3S)-benzyl 4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate, contaminated with TBDMS based impurities, as a colorless viscous oil (124.4 mg). (2S,3R)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate was elaborated similarly to (2S,3R)-benzyl 4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate. (2S,3S)-silyl ether isomer: 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz), 7.82 (d, J=4.1, 1H), 7.80 (d, J=4.0, 1H), 7.38-7.07 (m, 16 H), 4.70 (d, J=12.4, 1H), 4.42 (d, J=12.3, 1H), 3.28-3.19 (m, 3H), 2.56 (dd, J=10.1, 5.5, 1H), 1.61 (m, 1H), 0.90 (d, J=6.8, 3H), 0.70 (s, 9H), −0.13 (s, 3H), −0.16 (s, 3H). LC (Cond. 1, where the run time was extended to 4 min): RT=3.26 min; LC/MS: Anal. Calcd. for [M+H]30 C37H44NO3Si: 578.3 1; found 578.40. (2S,3R)-silyl ether isomer: 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz), 7.82 (d, J=3.0, 1H), 7.80 (d, J=3.1, 1H), 7.39-7.10 (m, 16H), 4.66 (d, J=12.4, 1H), 4.39 (d, J=12.4, 1H), 3.61 (dd, J=9.9, 5.6, 1H), 3.45 (d, J=9.5, 1H), 3.41 (dd, J=10, 6.2, 1H), 2.55 (dd, J=9.5, 7.3, 1H), 1.74 (m, 1H), 0.77 (s, 9H), 0.61 (d, J=7.1, 3H), −0.06 (s, 3H), −0.08 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:15][C:16]([CH:18]=[CH2:19])=[O:17]>C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:19][CH2:18][C:16](=[O:17])[CH3:15])[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: C=CC(C)=O
Solvent: CC(C)O
Product: CC(=O)CCN1CCC(Cc2ccc(F)cc2)CC1
Yield: 100.1 %

Procedure:
To a solution of 4-(4-fluorobenzyl)piperidine (0.50 g, 2.2 mmol) in isopropanol (5 mL) was added methylvinyl ketone (0.25 mL, 3.0 mmol). The resulting solution was stirred at reflux for 1 h then concentrated under reduced pressure to afford the title compound as a pale yellow oil (0.58 g, 99%): 1H NMR (CDCl3) δ1.15-1.35 (m, 2H), 1.38-1.56 (m, 1H), 1.603 (bd, J=12.6 Hz, 2H), 1.894 (t, J=11.7 Hz, 2H), 2.155 (s, 2H), 2.486 (d, J=6.9 Hz, 2H), 2.615 (s, 3H), 2.8-2.9 (m, 2H), 6.9-7.0 (m, 2H), 7.0-7.1 (m, 2H); IR (film) 2928, 1720, 1514, 1219 cm−1.
Reaction SMILES: [CH3:1][C:2]([N:6]1[Si:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][Si:7]1([CH3:14])[CH3:13])([CH3:5])[C:3]#[CH:4].[CH2:15]([Li])CCC.CI>O1CCCC1>[CH3:5][C:2]([N:6]1[Si:7]([CH3:14])([CH3:13])[CH2:8][CH2:9][Si:10]1([CH3:11])[CH3:12])([CH3:1])[C:3]#[C:4][CH3:15]
Reactant: [Li]CCCC
Reactant: C#CC(C)(C)N1[Si](C)(C)CC[Si]1(C)C
Solvent: C1CCOC1
Solvent: CI
Product: CC#CC(C)(C)N1[Si](C)(C)CC[Si]1(C)C
Temperature: -5 °C

Procedure:
The product from Step 1 (13.0 g) in dry tetrahydrofuran (140 ml) was cooled to −70° C. under an atmosphere of nitrogen with stirring and a solution of n-butyl lithium (23.1 ml of 2.5M solution in hexanes) was added at −65 to −70° C. during 5 minutes. The mixture was allowed to warm to −5° C. and methyl iodide (3.93 ml) was added dropwise over 10 minutes. The reaction mixture was allowed to warm to 10° C. when an exothermic reaction occurred. The mixture was maintained at 20° C. by cooling for 2 hours then evaporated under reduced pressure to a small volume. The residue was dissolved in hexane, filtered to remove the insoluble material and evaporated under reduced pressure to give 1-(1,1-dimethyl-2-butynyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane as a yellow oil, 13.0 g.
Reaction SMILES: [F:1][C:2]1([F:13])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=[O:11])[NH:4][CH:3]1[CH3:12].[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[F:13][C:2]1([F:1])[C:8]([CH3:9])([CH3:10])[O:7][CH2:6][C:5](=[O:11])[NH:4][C@@:3]1([C:16]1[CH:17]=[C:18]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=2)[CH:20]=[CH:21][C:15]=1[F:14])[CH3:12]
Reactant: Nc1ccc(F)cc1
Reactant: CC1NC(=O)COC(C)(C)C1(F)F
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(Nc3ccc(F)cc3)ccc2F)C1(F)F
Yield: 55.7 %

Procedure:
Prepared in an analogous manner as described for intermediate A9A or A13A from (R)-545-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (intermediate A16B) (300 mg, 819 μmol) and commercially available 4-fluoroaniline [CAS no 371-40-4] 4-fluoroaniline (157 μL, 1.64 mmol). The (R)-6,6-difluoro-5-(2-fluoro-5-(4-fluorophenylamino)phenyl)-5,7,7-trimethyl-1,4-oxazepan-3-one (181 mg, 55.7%) was obtained as a light yellow foam. MS (ISP): m/z=397.0 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28]>C1COCC1.[Pt](=O)=O>[Br:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH2:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28]
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccc(Br)c(C(F)(F)F)c4)cc3)C2=N1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2CCCC(c3ccc(Oc4ccc(Br)c(C(F)(F)F)c4)cc3)C2=N1
Reaction time: 8 h
Yield: 15.5 %

Procedure:
A mixture of platinum (IV) oxide (30 mg) and 9-{4-[4-bromo-3-(trifluoromethyl)phenoxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (192 mg) in THF (20 mL) was stirred under a hydrogen atmosphere overnight. To the reaction mixture was added activated carbon, and the mixture was filtered through basic silica gel and celite. To the filtrate was added silica gel and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) and concentrated under reduced pressure. The residue was separated by HPLC (C18, mobile phase:water/acetonitrile (0.1% TFA containing system)). To the obtained fraction was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from THF and diisopropyl ether to give the title compound (30 mg) as a white solid.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)SC)[C:4]([NH2:6])=[O:5])#[N:2].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.O.[NH2:31][NH2:32]>CCO>[NH2:2][C:1]1[NH:32][N:31]=[C:7]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][CH:22]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NN
Reactant: CSC(SC)=C(C#N)C(N)=O
Reactant: Nc1ccc(N2CCC(N3CCCC3)CC2)cc1
Solvent: CCO
Solvent: O
Product: NC(=O)c1c(Nc2ccc(N3CCC(N4CCCC4)CC3)cc2)n[nH]c1N
Temperature: 75 °C

Procedure:
Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 1-(4-aminophenyl)-4-(1-pyrrolidinyl)piperidine (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: CC(CC1C=CC=CC=1)C(O)=[S:4].[Mg+2].[N+:14]([C:17]1[CH:30]=[CH:29][C:20]([CH2:21][O:22][C:23](=O)[CH2:24][C:25]([O-:27])=O)=[CH:19][CH:18]=1)([O-:16])=[O:15].C(O[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N+]([O-])=O)=[CH:41][CH:40]=1)(=O)CC([O-])=O.[C:48](#N)[CH3:49]>C(OCC)(=O)C>[O:27]=[C:25]([CH:48]([CH3:49])[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:24][C:23]([O:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:30][CH:29]=1)=[S:4]
Reactant: O=C([O-])CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(Cc1ccccc1)C(O)=S
Reactant: CC#N
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: CC(Cc1ccccc1)C(=O)CC(=S)OCc1ccc([N+](=O)[O-])cc1

Procedure:
2-Methyl-3-phenylthiopropionic acid (4.60 g; 23.44 mmole) was dissolved in dry acetonitrile (20 ml), and 1,1-carbonyldiimidazole (4.56 g; 28.13 mmole) was added thereto with ice-cooling, and the resultant mixture was stirred at the same temperature for 30 minutes. The reaction mixture was dropwise added to a solution of malonic acid p-nitrobenzyl ester magnesium salt (17.53 g; 35 mmole) in dry acetonitrile (70 ml) at 50° C., and the resultant mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, the reaction mixture was returned to room temperature and diluted with ethyl acetate. The organic layer was washed successively with lN hydrochloric acid, water, a saturated sodium bicarbonate solution, water and an aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give p-nitrobenzyl 3-oxo-4-methyl-5-phenylthiopentanoate.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1N)([O-:3])=[O:2].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[N:23]1C=CC=CC=1>>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]([NH2:23])=[O:21])([O-:3])=[O:2]
Reactant: c1ccncc1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Product: NC(=O)c1ccccc1-c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of 73.2 g. (0.4 m.) of 2,4-dinitroaniline in 400 ml. of pyridine with stirring and slight warming was added 56.2 g. (0.4 m.) of benzoyl chloride in about 10 min.; the temperature rose from 40° to 50°. Then the dark solution was heated at reflux for 21/2 hours. After standing overnight, the yellow solid was collected, washed with H2O until no pyridine odor was detectable. This 90 g. of crude product was recrystallized from about 2.1 of CH3CN to yield 44 g. (38%) of yellow product melting at 201°-205°.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([N:9]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]2=[O:16])=[N:5][N:6]([CH3:8])[CH:7]=1.[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[S:22]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29])(=[O:24])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH3:15][C:11]1([CH3:14])[CH2:12][CH2:13][N:9]([C:4]2[C:3]([NH:2][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([S:22]([C:18]4[S:17][CH:21]=[CH:20][N:19]=4)(=[O:24])=[O:23])[CH:26]=3)=[CH:7][N:6]([CH3:8])[N:5]=2)[C:10]1=[O:16]
Reactant: O=C(O)c1cccc(S(=O)(=O)c2nccs2)c1
Reactant: Cn1cc(N)c(N2CCC(C)(C)C2=O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(NC(=O)c2cccc(S(=O)(=O)c3nccs3)c2)c(N2CCC(C)(C)C2=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 1-(4-amino-1-methyl-1H-pyrazol-3-yl)-3,3-dimethylpyrrolidin-2-one hydrochloride (30 mg) and 3-(1,3-thiazol-2-ylsulfonyl)benzoic acid (33.0 mg) in DMF (0.61 mL) were added HATU (56 mg) and diisopropylethylamine (43 μL). The reaction mixture was stirred overnight at room temperature, and poured into water, and the precipitate was collected by filtration, purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (40 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([NH:23][C:24](=[O:48])[CH:25]([CH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1)[CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)[C:7]([NH:9][CH:10]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:11]([OH:18])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[O:8].[CH3:49][N:50]=[C:51]=[S:52]>C(Cl)(Cl)Cl>[OH:18][CH:11]([CH:10]([NH:9][C:7](=[O:8])[CH:6]([NH:23][C:24](=[O:48])[CH:25]([CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)[CH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1)[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:51]([NH:50][CH3:49])=[S:52])[CH2:19][CH:20]([CH3:22])[CH3:21])[C:12]([O:14][CH:15]([CH3:16])[CH3:17])=[O:13]
Reactant: CN=C=S
Reactant: CC(C)CC(NC(=O)C(CCCCN)NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12)C(O)C(=O)OC(C)C
Solvent: ClC(Cl)Cl
Product: CNC(=S)NCCCCC(NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12)C(=O)NC(CC(C)C)C(O)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
[2R-[2R*,3S*(S*)]]-3-[[6-amino-2-[[3-(1-naphthalenyl)-2-(1-naphthalenylmethyl)-1-oxopropyl]amino]-1-oxohexyl]amino]-2-hydroxy-5-methylhexanoic acid, 1-methylethyl ester (Example K), 3.44 g (5.3 mmol), is dissolved in 65 ml of chloroform, 0.42 g (5.7 mmol) of methyl isothiocyanate is added, and the reaction mixture is stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture is concentrated and 2.05 g (53% yield) of the title compound is obtained after flash chromatography over silica gel 60 (230-400 mesh) and elution with hexane-ethyl acetate (1:4); mp softens at 89° C., melts at 93°-95° C.
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[C:5]([F:21])[CH:4]=1.[H][H]>[Pt].[C].CC(O)C>[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[C:5]([F:21])[CH:4]=1
Reactant: CC(C)(C)OC(=O)n1cccc1-c1ccc(N)cc1F
Reactant: [H][H]
Agent: [Pt]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(N)cc1F

Procedure:
5 ml of water and 660 mg of 5% platinum-carbon catalyst were added to a 2-propanol (50 ml) solution of 2.2 g of t-butyl 2-(4-amino-2-fluoro-phenyl)-pyrrole-1-carboxylate, and stirred in a hydrogen atmosphere under a pressure of 50 kgf/cm2 at 50° C. for 1 day. The catalyst was removed through filtration through Celite, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1) to obtain the entitled compound as a brown oily substance.