Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C@@H:10]([C@@:14]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:20][CH2:19][C:18](=[O:21])[N:17]([CH3:22])[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]2=3)[C:11]([OH:13])=[O:12])[N:3]=1.[CH:33](=O)[CH3:34]>>[CH2:33]([N:20]1[C@@:14]([C@H:10]([O:9][C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=2)[C:11]([OH:13])=[O:12])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:15]2[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=2[N:17]([CH3:22])[C:18](=[O:21])[CH2:19]1)[CH3:34]
Reactant: CC=O
Reactant: Cc1cc(C)nc(O[C@H](C(=O)O)[C@@]2(c3ccccc3)NCC(=O)N(C)c3ccccc32)n1
Product: CCN1CC(=O)N(C)c2ccccc2[C@@]1(c1ccccc1)[C@H](Oc1nc(C)cc(C)n1)C(=O)O

Procedure:
(±)-(S*)-((5S*)-4-ethyl-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid is prepared starting from (±)-(S*)-((5S*)-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid (Example 49) and acetaldehyde in analogy to Example 127. LC-MS1: tR=0.75 min, [M+1]+=461.16.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[S:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=c1[nH]c2ccc(-c3cccc([N+](=O)[O-])c3)cc2n1Cc1ccccc1
Product: O=[N+]([O-])c1cccc(-c2ccc3[nH]c(=S)n(Cc4ccccc4)c3c2)c1

Procedure:
Prepared according to the procedure for Example 24 from 1-benzyl-6-(3-nitrophenyl)-1,3-dihydro-2H-benzimidazole-2-one (0. 1g, 0.29 mmol) and Lawesson's reagent (0. 13g, 0.32 mmol). A yellow solid (0. 025g, 24%): mp 244-245° C.; 1H-NMR (DMSO-d6) δ 13.08 (s, 1H), 8.43 (s, 1H), 8.20 (dd, J=8.2, 1.7 Hz), 8.12 (d, 1H, J=7.8 Hz), 7.72-7.78 (m, 2H), 7.62 (d, 1H, J=8.3 Hz), 7.25-7.43 (m, 6H), 5.62 (s, 2H); MS (ESI) m/z 360 [M−H]−; Anal. Calc. For C20H15ClN2S.0.2H20: C, 65.81, H, 4.25, N, 11.51. Found: C, 65.56, H, 4.11, N, 11.29.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C@H:3]([CH3:11])[C@@H:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[NH2:5].C(N(CC)CC)C.[CH2:21]([O:28][C:29](ON1C(=O)CCC1=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.C(OCC)(=O)C>[CH2:21]([O:28][C:29]([NH:5][C@H:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C@H:3]([C:2]([F:12])([F:13])[F:1])[CH3:11])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)C(F)(F)F
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
23.5 g of ethyl (3R)-4,4,4-trifluorovalinate (diastereomer mixture, crude product about 70%) and 18.1 ml (130 mmol) of triethylamine were dissolved in 235 ml of THF, and 32.3 g (130 mmol) of N-(benzyloxycarbonyloxy)succinimide were added. The reaction mixture was stirred at RT overnight and then diluted with ethyl acetate. The mixture was washed successively with sat. sodium bicarbonate solution, 1 N hydrochloric acid and sat. sodium chloride solution. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 6:1). This gave 22.1 g of the target product (about 80% of theory, diastereomer ratio about 2:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[NH2:15])[N:11]=[CH:10][CH:9]=[N:8]2)=[O:4].[Cl:16]N1C(=O)CCC1=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([Cl:16])[C:14]=1[NH2:15])[N:11]=[CH:10][CH:9]=[N:8]2)=[O:4]
Reactant: COC(=O)c1cc2nccnc2cc1N
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc2nccnc2c(Cl)c1N
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 88.7 %

Procedure:
2.07 g (10.2 mmol) 7-amino-quinoxaline-6-carboxylic acid methyl ester and 1.36 g (10.2 mmol) N-chloro-succinimide is suspended in 5 ml DMF and heated at a temperature of 95° C. during 30 min. After cooling, the mixture is poured into 150 ml ice water. The mixture is stirred 15 min and filtered. The compound is dried and crystallised in hexane to give 2.15 g (88%) of the title compound. m.p.: 182-184° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].[CH3:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1COCC1.O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[S:13][CH3:12]
Reactant: CSc1ccccc1B(O)O
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CSc1ccccc1-c1cc([N+](=O)[O-])ccc1F
Temperature: 50 °C
Yield: 98.5 %

Procedure:
A mixture of 2-bromo-1-fluoro-4-nitrobenzene (5.89 g, 26.8 mmol), 2-(methylthio)benzeneboronic acid (5.62 g, 33.5 mmol) and potassium fluoride (5.13 g, 88.3 mmol) in THF (70 ml) was degassed with nitrogen for 30 min. This mixture was then treated with tris(dibenzylideneacetone)dipalladium(0) (496 mg, 0.541 mmol) followed by tri-tert-butylphosphine (5.35 ml of a 0.2 M solution in 1,4-dioxane, 1.07 mmol) and the reaction was degassed for a further 10 min. The resulting slurry was then heated at 50° C. for 16 h under nitrogen. After cooling, the reaction mixture was partitioned between ethyl acetate (300 ml) and water (300 ml). The organic layer was washed with saturated aqueous NaCl (200 ml), dried (Na2SO4), and evaporated. Purification by chromatography (silica gel, 5-10% EtOAc/isohexane) gave 6.95 g (99%) of the title compound as a pale yellow solid: 1H NMR (360 MHz, CDCl3) δ 2.42 (3H, s), 7.21-7.32 (3H, m), 7.37 (1H, d, J 7.4 Hz), 7.44 (1H, td, J 7.7, 1.6 Hz), 8.27-8.31 (2H, m).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[NH:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([NH2:27])=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([NH2:27])=[O:26])=[O:12])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5.27 g of Z-Thr(tBu)-OH and 1.56 g of H-Pro-NH2 are dissolved in 60 ml of acetonitrile, the solution is cooled to 0°C and 3.11 g of dicyclohexylcarbodiimide are added. After 1 hour at 0°C and 20 hours at room temperature the dicyclohexylurea is filtered off and the filtrate is evaporated and the residue taken up in ethyl acetate. The ethyl acetate solution is washed with dilute citric acid solution, soda solution and water, and is dried with sodium sulphate and evaporated. On thin layer chromatography on silica gel plates the colourless residue shows Rf45 = 0.76; Rf43c = 0.70; Rf52 = 0.62.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15](=[O:33])[C@@H:16]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:17][CH2:18]/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[C:9]1=[O:34])(C)(C)C.CCN(C(C)C)C(C)C.C(ON1C(=O)CCC1=O)(OC(C)(C)C)=O>ClCCl.FC(F)(F)C(O)=O.CN(C=O)C>[C:29]([O:28][C:26]([NH:25][C@@H:16]([CH2:17][CH2:18]/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[C:15]([NH:14][C:10]1[C:9](=[O:34])[N:8]([CH2:7][C:6]([OH:35])=[O:5])[CH:13]=[CH:12][CH:11]=1)=[O:33])=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)/C=C/CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccn(CC(=O)OC(C)(C)C)c1=O
Agent: CC(C)(C)OC(=O)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)/C=C/CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccn(CC(=O)O)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
590 mg of (S,E)-methyl 7-(1-(2-tert-butoxy-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl-amino)-6-(tert-butoxycarbonylamino)-7-oxohept-2-enoate (ZED1209, 1.20 mmol) are dissolved in 10 mL of dichloromethane and to this solution 10 mL of trifluoroacetic acid is added. It is stirred at RT for 1 h. The solvent is removed in vacuo and the residue is dried under high vacuum. The obtained oil is further reacted without purification. The oil is taken up in 15 mL of DMF and treated with 173 μL of DIPEA. By successive addition of DIPEA the pH value is adjusted to ca. 7. To this solution, 285 mg of Boc-OSu (1.1 eq) are added and stirred at RT overnight. The solvent is removed in vacuo and the residue is purified by preparative HPLC (30% ACN in water, 8 mL/min, gradient 1% pro min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[C:10]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])(C(OCC)=O)[N:9]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:9]=1
Reactant: CCOC(=O)CCC1(C(=O)OCC)N=C(c2ccccc2Cl)c2cc(CC)sc2-n2c(C)nnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc2c(s1)-n1c(C)nnc1C(CCC(=O)O)N=C2c1ccccc1Cl
Temperature: 60 °C
Reaction time: 6 h
Yield: 72.9 %

Procedure:
Ethyl 4-(2-chlorophenyl)-6-(2-ethoxycarbonylethyl)-2-ethyl-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine-6-carboxylate (23 g) was dissolved in ethanol (92 ml). A 4M sodium hydroxide aqueous solution (92 ml) was added and the mixture was stirred at 60° C. for 6 hours. 2M Hydrochloric acid was added to adjust the aqueous solution to pH 2. The solution was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated. The obtained crystals were taken out, and washed with diisopropyl ether to give 13.5 g of 3-(4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-6-yl)propionic acid.
Reaction SMILES: [C:1]([NH:5][C:6]([CH3:13])([CH3:12])[CH2:7][S:8]([OH:11])(=[O:10])=[O:9])(=[O:4])[CH:2]=[CH2:3].[CH3:14]O>OS(O)(=O)=O.O=S(=O)=O>[C:1]([NH:5][C:6]([CH3:13])([CH3:12])[CH2:7][S:8]([O:11][CH3:14])(=[O:9])=[O:10])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)NC(C)(C)CS(=O)(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: C=CC(=O)NC(C)(C)CS(=O)(=O)OC
Reaction time: 0.17 h

Procedure:
A 25-gram portion of 65% oleum (containing 0.203 mole of sulfur trioxide) is poured over 20 grams (0.097 equivalent) of 2-acrylamido-2-methylpropanesulfonic acid. The mixture warms as the acid dissolves in the oleum. The viscous mixture is stirred for 10 minutes and is then poured into 300 ml. (7.42 equivalents) of methanol, while the vessel containing the latter is cooled with ice. After the mixture becomes homogeneous it is stripped to about 100 ml. and extracted with chloroform. The chloroform extracts are combined and dried over sodium sulfate, and the desired methyl 2-acrylamido-2-methylpropanesulfonate is obtained upon stripping the chloroform.
Reaction SMILES: [ClH:1].C(O)C.O[N:6]=[C:7]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9]>[Pd]>[ClH:1].[NH2:6][CH:7]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=NO)C(=O)C(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(N)C(=O)C(C)C
Reaction time: 8 h

Procedure:
10 g of HCl are introduced into 200 ml of ethanol. 46 g of ethyl 2-hydroxyimino-4-methyl-3-oxopentanoate are dissolved in this mixture, 5 g of Pd (10% on carbon) are added and the mixture is stirred under atmosphere of hydrogen (5 bar) for 8 hours. The reaction mixture is filtered through Celite and the solvent is removed under reduced pressure. This gives 45 g of ethyl 2-amino-4-methyl-3-oxopentanoate hydrochloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:24])[NH:12][CH2:13][C:14]2[NH:15][C:16]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][C:58]1=[O:63].ClCl>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:60]1[CH2:61][CH2:62][N:57]([CH3:56])[C:58](=[O:63])[CH2:59]1)=[O:6])[C:11]([NH:12][CH2:13][C:14]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:16]=2[N:15]=1)=[O:24]
Reactant: CN1CCNCC1=O
Reactant: O=C(NCc1nc2ccc(Cl)cc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)CC1=O
Yield: 8.7 %

Procedure:
Prepared analogously to Example 19c from 2-chloro-4-[N-(5-chlorobenzimidazol-2-ylmethyl)carbamoyl]benzoic acid, TBTU, diisopropylethylamine, and N-methylpiperazinone in N,N-dimethylformamide. Yield: 8.7%; C21H19Cl2N5O3 (460.32); mass spectrum: (M+H)+=460/462/464 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24]([OH:26])=[O:25])[N:13]([C@H](C4C=CC=CC=4)[C@@H](O)C4C=CC=CC=4)[C:12]43[CH2:46][CH2:45][C:44]([CH3:48])([CH3:47])[CH2:43][CH2:42]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[NH4+].[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24]([OH:26])=[O:25])[NH:13][C:12]43[CH2:46][CH2:45][C:44]([CH3:48])([CH3:47])[CH2:43][CH2:42]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CCC2(CC1)N([C@H](c1ccccc1)[C@@H](O)c1ccccc1)[C@@H](C(=O)O)[C@H](c1ccnc(Cl)c1F)C21C(=O)Nc2cc(Cl)ccc21
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: CO
Solvent: O
Product: CC1(C)CCC2(CC1)N[C@@H](C(=O)O)[C@H](c1ccnc(Cl)c1F)C21C(=O)Nc2cc(Cl)ccc21
Reaction time: 0.5 h
Yield: 32.8 %

Procedure:
The compound (630 mg, 0.94 mmol) obtained in Step 1 of Example 16 was dissolved in acetonitrile (10 ml) and water (4 ml), potassium carbonate (130 mg, 0.94 mmol) was added and the resulting mixture was heated to reflux at 85° C. for 16 hours. After cooling, anhydrous magnesium sulfate (113 mg, 0.94 mmol) was added and the resulting mixture was stirred at room temperature for 15 minutes. After extraction with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give (4′S,5′R)-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-1′-[(1R,2S)-2-hydroxy-1,2-diphenylethyl]-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylic acid (650 mg, 100%) as a pale orange amorphous solid [MS (ESI) m/z: 688 (M+H)+.]. The carboxylic acid (650 mg, 0.94 mmol) obtained was dissolved in methanol (30 ml) and water (8 ml), cerium (IV) diammonium nitrate (1.55 g, 2.82 mmol) was added under ice cooling and the resulting mixture was stirred at the same temperature for 30 minutes. Potassium carbonate (780 mg, 5.64 mmol) was added under ice cooling and the resulting mixture was stirred at the same temperature for 1 hour. Insoluble matter was removed by filtration through celite, then the filtrate was concentrated under reduced pressure and water was added to the residue obtained, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [chloroform:methanol=20:1→4:1 (v/v)] to give 152 mg (33%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1([CH2:22][C:23](=[O:26])[O:24][CH3:25])[O:9][N:8]=[C:7]([C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=2[CH2:17][CH2:18][C:19](O)=[O:20])[CH2:6]1.[NH:28]1[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>O.CN(C=O)C.C(N(CC)CC)C>[CH3:25][O:24][C:23](=[O:26])[CH2:22][C:5]1([CH2:4][C:3](=[O:27])[O:2][CH3:1])[O:9][N:8]=[C:7]([C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=2[CH2:17][CH2:18][C:19]([N:28]2[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]2)=[O:20])[CH2:6]1
Reactant: COC(=O)CC1(CC(=O)OC)CC(c2cc(O)ccc2CCC(=O)O)=NO1
Reactant: CCOC(=O)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1CCN(C(=O)CCc2ccc(O)cc2C2=NOC(CC(=O)OC)(CC(=O)OC)C2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(2-(5,5-bis(2-methoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-hydroxyphenyl)propanoic acid (820 mg), ethyl piperidine-4-carboxylate (0.366 mL), WSC (497 mg), HOBt (350 mg), triethylamine (0.362 mL), and DMF (8 mL) was stirred overnight at room temperature. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (760 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:11][CH2:12][CH2:13][C:14](O)=[O:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:14](=[O:15])[CH2:13][CH2:12][SH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCc1ccccc1
Reactant: O=C(O)CCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(CCS)OCCCc1ccccc1
Temperature: 25 °C

Procedure:
Into a 100 ml reaction flask equipped with reflux condenser, hot plate (with stirring apparatus within) and spin bar are placed 13.6 grams phenylpropyl alcohol; 4.0 grams of 3-mercaptopropionic acid; and 0.1 grams of para-toluene sulphonic acid. The reaction mass is heated to reflux and refluxed for a period of 10 hours with stirring. At the end of the 10 hour period, the reaction mass is cooled to room temperature and fractionally distilled on a micro distillation apparatus yielding the compound having the structure: ##STR70## (as confirmed by GLC, NMR, mass spectral and IR analyses).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[N:8]=1)=[O:2].[Cl-].[NH4+].C(O)C.O>O1CCCC1.[Fe]>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[N:8]=1)=[O:2]
Reactant: O=CNc1nc(CSc2ccc([N+](=O)[O-])cc2)cs1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(SCc2csc(NC=O)n2)cc1
Yield: 80.9 %

Procedure:
To a mixture of 2-formylamino-4-(4-nitrophenylthiomethyl)thiazole (2.2 g) and ammonium chloride (0.5 g) in a mixture of tetrahydrofuran (30 ml), ethanol (50 ml) and water (10 ml) was added portionwise the iron powder at 80° C. with stirring. The mixture was refluxed for 2 hours with stirring. The reaction mixture was filtered by suction and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-formylamino-4-(4-aminophenylthiomethyl)thiazole (1.6 g, yield: 81%). mp: 180°-182° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[OH-].[K+]>>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:6]2[CH2:5][CH2:4][N:3]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:2]([CH3:1])[CH2:7]2)=[CH:10][CH:11]=1
Reactant: C[C@@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Product: C[C@@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2R)-2-methyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate (D24) using a method similar to that described for D22 in Description 22 although aqueous 2M KOH solution was used in place of solid KOH and the reaction time was 0.5 h. MS (ES): MH+ 306.2, MNa+ 328.2.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([Cl:17])=[CH:12][C:11]=1[S:18](Cl)(=[O:20])=[O:19]>>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([Cl:17])=[CH:12][C:11]=1[S:18]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2cc(Cl)c(Cl)cc2Cl)c1Br
Yield: 67 %

Procedure:
2,4,5-Trichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,4,5-trichlorobenzenesulfonyl chloride according to the procedures described in Example 30. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 179-182° C., yield 67%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].Cl.[CH2:14]([O:16]CC)C>>[F:1][C:2]1[CH:3]=[C:4]([N:5]=[C:14]=[O:16])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Reactant: CCOCC
Agent: Cl
Product: O=C=Nc1cc(F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Fluoro-5-trifluoromethylaniline (2 g, 11.2 mmol) was dissolved in 20 mL diethylether and added concentrated hydrochloric acid (37%, 1.5 mL, 18 mmol). Upon stirring for 1 hour at 25° C. the solvent was removed in vacuo and the white solid was stripped with toluene (3×20 mL). Diphosgene (20 mL) was added to the hydrochloride salt and the mixture was refluxed over night. Excess diphosgene was removed in vacuo and the clear oil was stripped with toluene (3×20 mL). The obtained isocyanate was used without further purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[CH3:17])(=O)=O.[Cl-:20].[Li+]>CN(C=O)C>[Cl:20][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[CH3:17]
Reactant: [Cl-]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1OS(=O)(=O)C(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Cl

Procedure:
2,6-Dimethyl-4-nitrophenyl trifluoromethanesulfonate (8.54 g) and 3.63 g of lithium chloride in 40 ml DMF are heated at 150° for four hours. Solvent is then evaporated, the residue stirred with water and ethyl acetate, filtered, and the filtrate separated. The ethyl acetate is then dried, filtered and stripped, and the residue chromatographed on silica gel with 98:2 hexane:ethyl acetate, affording 4-chloro-3,5-dimethyl-nitrobenzene. NMR (CDCl3): δ2.5 (6H,s), 7.9 (2H,s).