Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH3:18])[CH2:3][O:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:20](OCC)=[O:21]>>[C:6]1([CH:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:4][CH2:3][C:2]([NH:1][CH:20]=[O:21])([CH3:19])[CH3:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC=O
Reactant: CC(C)(N)COC(c1ccccc1)c1ccccc1
Product: CC(C)(COC(c1ccccc1)c1ccccc1)NC=O
Yield: 99.6 %

Procedure:
A mixture of 2-amino-1-diphenylmethoxy-2-methylpropane (7.6 g -- see Preparation 1) and ethyl formate (6.7 g) was heated at 100° in a steel bomb for 18 hours and evaporated. The residue was purified by chromatography on silica (18 g) using hexane plus 0-100% methylene chloride as the eluant. Appropriate fractions were combined and evaporated to give the title compound as a colourless gum (8.4 g, 99%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=O)[CH3:11].[CH3:13][O:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[C:18]([CH2:23][C:24](O)=[O:25])=[CH:17][N:16]=1>>[CH3:13][O:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[C:18]([C:23]2[C:24](=[O:25])[O:1][C:2]3[C:3]([C:10]=2[CH3:11])=[CH:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=3)=[CH:17][N:16]=1
Reactant: COc1ncc(CC(=O)O)c(OC)n1
Reactant: COc1ccc(C(C)=O)c(O)c1
Product: COc1ccc2c(C)c(-c3cnc(OC)nc3OC)c(=O)oc2c1

Procedure:
The title product was prepared as a white solid according to the procedure described in Example 9 using 1-(2-hydroxy-4-methoxy-phenyl)-ethanone and (2,4-dimethoxy-pyrimidin-5-yl)-acetic acid as the starting material.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C@H:5]([OH:7])[C@@H:4]([CH2:8][OH:9])[CH2:3]1.[Cl:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=1.CCN(CC)CC>C(O)(C)C>[Cl:10][C:11]1[N:12]=[CH:13][N:14]=[C:15]([NH:1][C@H:2]2[CH2:6][C@H:5]([OH:7])[C@@H:4]([CH2:8][OH:9])[CH2:3]2)[CH:16]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: N[C@@H]1C[C@H](CO)[C@@H](O)C1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: OC[C@H]1C[C@@H](Nc2cc(Cl)ncn2)C[C@@H]1O
Temperature: 90 °C
Yield: 59.1 %

Procedure:
To a neat mixture of (1S,2R,4R)-4-amino-2-(hydroxymethyl)cyclopentanol (3.00 g, 22.9 mmol) and 4,6-dichloropyrimidine (3.70 g, 24.8 mmol) was added isopropyl alcohol (30.0 mL) and Et3N (8.00 mL, 57.4 mmol) and the resulting mixture was heated to 90° C. for 1 h. The mixture was then cooled to 23° C., filtered and concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 5 to 7% MeOH in DCM, and the compound was recrystallized from EtOAc to afford the title compound as a white solid (3.30 g, 59%). LC/MS: Rt=0.84 min, ES+ 244 (AA standard).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.O.C(=O)([O-])O.[Na+].[CH2:23](O)[CH3:24]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH2:23][CH3:24])=[O:6]
Reactant: CCO
Reactant: Cc1ccc(C(=O)O)cc1F
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(C)c(F)c1
Temperature: 0 °C
Yield: 94.4 %

Procedure:
To a solution of 3-fluoro-4-methylbenzoic acid (7.707 g, 50.00 mmol) in ethanol (35 ml) was added concentrated sulfuric acid (1.5 ml), and the mixture was heated under reflux for 6 hrs. The reaction mixture was cooled to 0° C., iced water and saturated aqueous sodium hydrogen carbonate were added, and the mixture was extracted twice with diethyl ether. The combined organic layer was washed twice with saturated aqueous sodium hydrogen carbonate and once with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give ethyl 3-fluoro-4-methylbenzoate (8.599 g, yield 94.4%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Cl:19][C:20]1[CH:26]=[CH:25][C:23](N)=[C:22]([F:27])[CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[C:22]([F:27])[CH:21]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(Cl)cc4F)c3c2s1
Yield: 56 %

Procedure:
Prepared from VII and 4-chloro-2-fluoroaniline. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 56%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 2231, 1638, 1614, 1583, 1476, 1413, 1380, 1356, 1309, 1273, 1200, 1170, 1120, 982, 901, 838, 820; 1H NMR (300 MHz, DMSO-d6) δ 8.55 (d, 1H, J=9.0 Hz), 8.24 (s, 1H), 7.79 (d, 1H, J=9.0 Hz), 7.45 (d, 1H, J=9.0 Hz), 7.34 (t, 1H, J=8.4 Hz), 7.26 (d, 1H, J=9.0 Hz); HRMS calcd for C16H8N5SClF (M+H+): 356.0173, found 356.0160.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:9]=[C:10]=[O:11])([CH3:8])[CH3:7])=[CH:4][CH:3]=1.[CH2:14]([NH:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH3:15]>CCCCCC>[CH:17]1([N:16]([CH2:14][CH3:15])[C:10]([NH:9][C:6]([CH3:8])([CH3:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:13][CH:12]=2)=[O:11])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(N=C=O)c1ccc(F)cc1
Reactant: CCNC1CCCCC1
Solvent: CCCCCC
Product: CCN(C(=O)NC(C)(C)c1ccc(F)cc1)C1CCCCC1
Reaction time: 8 h
Yield: 87.7 %

Procedure:
A solution of 1.8 g of p-fluoro-α,α-dimethylbenzyl isocyanate in 20 ml of n-hexane was added to 1.4 g of N-ethylcyclohexylamine, and the mixture was allowed to stand overnight. The solvent was then removed by distillation and the resulting crystals were washed with cold n-pentane to obtain 2.7 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Clc1ccncc1
Product: c1ccc(CN2CCC(Oc3ccncc3)CC2)cc1
Yield: 52 %

Procedure:
The title compound was prepared from 1-benzyl-4-hydroxypiperidine and 4-chloropyridine (979 mg, 8.62 mmol), using the same method as that described for preparation 25, as an oil in 52% yield. 1H NMR (CDCl3, 400 MHz) □: 1.81-1.96 (m, 2H), 1.98-2.18 (m, 2H), 2.30-2.48 (m, 2H), 2.70-2.83 (m, 2H), 3.52-3.70 (m, 2H), 4.40-4.50 (m, 1H), 6.72-6.80 (m, 2H), 7.22-7.39 (m, 5H), 8.40 (m, 2H); LRMS APCI m/z 269 [M+H]+
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:19]=[CH:18][C:12]([O:13][CH:14]2[CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.[CH3:22][N:23]=[C:24]=[O:25]>>[F:21][C:8]([F:7])([F:20])[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]2[CH2:15][N:16]([C:24]([NH:23][CH3:22])=[O:25])[CH2:17]2)=[CH:18][CH:19]=1
Reactant: CN=C=O
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Agent: O=C(O)C(=O)O
Product: CNC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Reaction time: 8 h

Procedure:
The oxalic acid salt of 3-[4-(trifluoromethyl)phenoxy]azetidine, weighing 13.0 g (0.042 mole), was partitioned between 50 ml of benzene and 50 ml of potassium hydroxide solution. The benzene layer was dried with Drierite and filtered, and to this stirring filtrate was added 2.6 g (0.046 mole) of methyl isocyanate. Stirring was continued overnight. The mixture was concentrated in vacuo, and the solid residue was recrystallized from a mixture of isopropyl ether-ethyl acetate to give 7.5 g (65%), mp 154°-157°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.O.NN.[O-]CC.[Na+]>C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Agent: CC[O-]
Agent: NN
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1Cc2ccc(Cl)cc2N1
Yield: 42.5 %

Procedure:
Reaction of 36.2 g of 6-chloroisatin with hydrazine hydrate followed by sodium ethoxide in ethanol, substantially according to C above, afforded 14.2 g of 6-chloro-2-oxindole, m.p. 196°-198° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:14][C:13]1([OH:20])[C:15]([O:17]CC)=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:14][C:13]1([OH:20])[C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(O)CC1NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1CC1(O)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
To a 0° C. solution of ethyl 2-(benzyloxycarbonylamino)-1-hydroxycyclopropanecarboxylate (6b, 12.5 g, 44.7 mmol) in THF (100 mL) was added K2CO3 (24.7 g, 179.0 mmol) as a solution in H2O (300 mL). The reaction was allowed to warm to room temperature and stirred for 4 h and then additional H2O (200 mL) was added. After stirring an additional 18 h at room temperature the reaction was concentrated to remove most of the THF. The remaining aqueous solution was washed with Et2O (2×500 mL), acidified with 2 N HCl to pH 2, and then extracted with EtOAc (5×200 mL). The combined EtOAc layers were washed with brine (500 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford the title compounds (7.75 g, 69%) as a mixture of diastereomers. The mixture was triturated with Et2O to afford a white solid as mostly the major diastereomers. The supernatant was concentrated and then triturated with Et2O to afford a clean mixture of both diastereomers. Major Diastereomer: 1H NMR (300 MHz, MeOD) δ 7.50-7.14 (m, 5H), 5.22-4.96 (m, 2H), 3.23-3.10 (m, 1H), 1.60 (dd, J=8.9, 6.3 Hz, 1H), 1.10 (t, J=6.2 Hz, 1H); Multimode (APCI+ESI) MS m/z 250 [M−H]−. Mixture of Diastereomers: 1H NMR (300 MHz, MeOD) δ 7.45-7.14 (m, 5H), 5.24-5.01 (m, 2H), 3.25-3.15 (m, 0.46H), 3.14-3.01 (m, 0.54H), 1.71-1.53 (m, 1H), 1.42 (dd, J=9.1, 6.4 Hz, 0.54H), 1.12 (t, J=6.2 Hz, 0.46H); Multimode (APCI+ESI) MS m/z 250 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][S:21][CH2:20][CH2:19]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].[OH:29]O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][S:21](=[O:29])[CH2:20][CH2:19]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: OO
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCSCC2)C1
Solvent: O
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCS(=O)CC2)C1
Reaction time: 8 h

Procedure:
To a stirred solution of 4-hydroxy-5-oxo-1-(2-thiomorpholin-4-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide (108 mg, 0.243 mmol) in water (20 mL) was added 30% hydrogen peroxide (0.3 mL). After stirring overnight the reaction mixture was lyophilized to give the title compound as a white powder. 1HNMR (500 MHz, CDCl3) δ: 7.42 (1H, d, J=8.5 Hz), 7.34 (1H, s), 7.10 (1H, d, J=8.2 Hz), 4.59 (2H, s), 4.28 (2H, s), 3.89 (2H, t, J=5.8 Hz), 3.74–3.70 (2H, m), 3.63 (2H, t, J=11.9 Hz), 3.29–3.24 (2H, m), 3.18 (2H, t, J=11.9 Hz), 3.07–2.99 (2H, m), 3.01 (3H, s). HRMS calcd for C19H24Cl2N3O4S (M+H): 460.0865. found: 460.0884.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][NH:11][C:12](=[O:17])[CH2:13]2)=[O:7])(C)(C)C.Br[C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[N:23][CH:24]=1>>[N+:25]([C:22]1[N:23]=[CH:24][C:19]([N:11]2[C:12](=[O:17])[CH2:13][CH:14]3[N:8]([C:6]([OH:5])=[O:7])[CH:9]([CH2:16][CH2:15]3)[CH2:10]2)=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)NC2
Product: O=C1CC2CCC(CN1c1ccc([N+](=O)[O-])nc1)N2C(=O)O
Yield: 58 %

Procedure:
Following general N—C coupling procedure 1, 4-Oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester, 1.86 g (7.72 mmoles) was combined with 5-Bromo-2-nitro-pyridine, 1.51 g (7.42 mmoles), which after recrystallized from CH2Cl2-Heptanes gave 3-(6-Nitro-pyridin-3-yl)-4-oxo-3,9-diaza bicyclo[4.2.1]nonane-9-carboxylic acid tea-butyl ester, (1.59 g) in 58% yield. TLC Rf ˜0.45 (75% Ethyl acetate-Heptane)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.I[CH2:9][C:10]([O-:12])=[O:11].[Na+].[H-].[Na+].O>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:9][C:10]([OH:12])=[O:11])[CH2:3][CH2:2]1
Reactant: O=C([O-])CI
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COC1CCOCC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of tetrahydro-2H-pyran-4-ol (286 μl, Acros) in tetrahydrofuran (4 ml) was added with sodium iodoacetate (624 mg), and successively added with sodium hydride (198 mg) as several portions at 0° C., and the mixture was stirred at the same temperature for 45 minutes, and then further stirred at room temperature for 23 hours. The reaction mixture was cooled again to 0° C., and then carefully added with water and then with chloroform, and the organic layer was separated. The aqueous layer was acidified (pH 4) with 1 N hydrochloric acid, and extracted three times with chloroform, and the combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure to obtain the title compound (43.4 mg).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([C@H:15]3[CH2:17][C@@H:16]3[C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]4[CH:26]=3)[CH:9]=2)[N:3]=1.[I:27]I>C(Cl)Cl>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([C@@H:15]3[CH2:17][C@H:16]3[C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]4[C:26]=3[I:27])[CH:9]=2)[N:3]=1
Reactant: II
Reactant: Cc1nc([C@H]2C[C@@H]2c2cn3ccccc3n2)cc(-n2nc(C)nc2C)n1
Solvent: ClCCl
Product: Cc1nc([C@@H]2C[C@H]2c2nc3ccccn3c2I)cc(-n2nc(C)nc2C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To Example 1 (142 mg, 0.41 mmol) in DCM (4 mL) was added iodine (2.1 g, 8.2 mmol) and the mixture was stirred at room temperature for 1 h. The reaction was quenched with aqueous saturated sodium thiosulfate (2 mL) and methanol (2 mL) and continued to stir at room temperature for 1 h. The reaction mixture was diluted with DCM (15 mL) and the organic layer was washed with saturated aqueous sodium bicarbonate (2×10 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (25-70% EtOAc/hexanes) to give Example 8 as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J=6.8 Hz, 1H), 7.60 (s, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.22 (app t, J=7.7 Hz, 1H), 6.89 (app t, J=6.7 Hz, 1H), 2.90 (s, 3H), 2.80-2.71 (m, 2H), 2.69 (s, 3H), 2.39 (s, 3H), 2.00-1.96 (m, 1H), 1.92-1.88 (m, 1H); MS: m/z=472.2 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]2[N:25]3[C:20]([C:21]([NH2:26])=[N:22][CH:23]=[N:24]3)=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:27]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]2[N:25]3[C:20]([C:21]([NH2:26])=[N:22][CH:23]=[N:24]3)=[C:19]([Br:27])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Nc1ncnn2c([C@@H]3CCCN(C(=O)OCc4ccccc4)C3)ccc12
Solvent: CN(C)C=O
Product: Nc1ncnn2c([C@@H]3CCCN(C(=O)OCc4ccccc4)C3)cc(Br)c12
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 194.6 %

Procedure:
The product of step 6 (3.59 g, 10.22 mmoL) was dissolved in 40 mL of DMF and cooled in an Ice/isopropanol/dry ice bath to −20° C. and 1,3-dibromo-5,5-dimethylhydantoin (1.46 g, 5.11 mmol) was added in 4 equal portions 15 minutes apart. The mixture was stirred for 10 minutes past the last addition and quenched by addition to a mixture of ice (400 g), saturated, aqueous Na2SO3 (20 mL) and 2M aq. Na2CO3 (20 mL) and the mixture was allowed to reach rt and vigorously stirred for 30 minutes. The solid was collected by filtration dried in a vacuum oven until a constant weight was obtained. The title compound (4.28 g) was obtained as a freely flowing solid. 1H NMR (300 MHz, CD3OD) δ 7.83 (s, 1H), 7.40-7.25 (m, 5H), 6.66 (s, 1H), 5.06 (bs, 2H), 4.19 (d, 1H), 3.92 (m, 1H), 3.22 (m, 1H), 3.12-2.83 (m, 3H), 1.99, (m, 1H), 1.78-1.62 (m, 2H), 1.48 (m, 1H). ES-MS m/z 430.1, 432.0 [M+H]+, HPLC RT (min) 2.98.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:7][S:8]([OH:11])(=O)=[O:9].[S:12]1[C:16]2[S:17][CH:18]=[CH:19][C:15]=2[CH:14]=[C:13]1[C:20]([O:22][CH3:23])=[O:21]>>[CH3:23][O:22][C:20]([C:13]1[S:12][C:16]2[S:17][C:18]([S:8]([Cl:7])(=[O:11])=[O:9])=[CH:19][C:15]=2[CH:14]=1)=[O:21]
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)c1cc2ccsc2s1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: COC(=O)c1cc2cc(S(=O)(=O)Cl)sc2s1
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
Crystals of phosphorus pentachloride (9.80 g., 47.1 mmoles) were added in portions to chlorosulfonic acid (9 ml., 15.4 g., 132 mmoles) in an inert atmosphere. The solution was stirred for 15 minutes. To this solution small portions of methyl thieno[2,3-b]thiophene-2-carboxylate (8.49 g., 42.8 mmoles) were slowly added, allowing for subsiding of effervescence between additions. After the addition was complete, the solution was stirred in an inert atmosphere for 25 minutes. The resulting solution was poured carefully onto ice-water. The resulting mixture was triturated and the off-white crystals were collected and washed with water and dried in vacuo over phosphorus pentoxide to give 11.58 g of 5-methoxycarbonylthieno[2,3-b]thiophene-2-sulfonylchloride. This was used in the next step without purification.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:19])[CH2:14][O:15][C:16](=[O:18])[CH3:17])=O)(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].C(O)(=O)C>>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[C:16]([O:15][CH2:14][C:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[O:19])(=[O:18])[CH3:17]
Reactant: CC(=O)OCC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC(=O)OCC(=O)[C@@H]1CCCN1

Procedure:
A solution of 1.00 g of the product of Example 2 can be kept in 10 ml of 1:1 trifluoracetic acid-acetic acid at 20° for 30 minutes. The solvents can then be removed under reduced pressure to give (S)-2-(2-acetoxy-1-oxoethyl)-pyrrolidine trifluoracetate.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][CH:37]=[C:36]2[CH2:42][C:43](O)=[O:44]>>[C:26]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:43](=[O:44])[CH2:42][C:36]4[C:35]5[C:39](=[CH:40][CH:41]=[C:33]([F:32])[CH:34]=5)[NH:38][CH:37]=4)[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Reactant: O=C(O)Cc1c[nH]c2ccc(F)cc12
Agent: Cl
Product: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)Cc3c[nH]c4ccc(F)cc34)C[C@H]21
Yield: 34.1 %

Procedure:
By working in accordance with the operating method of Example 4, starting from 0.8 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride and 0.39 g of (5-fluoro-3-indolyl)acetic acid, 0.36 g of (3aS,4S,7aS)-7,7-diphenyl-2-[(5-fluoro-3-indolyl)acetyl]-4-(2-methoxyphenyl)perhydroisoindol-4-ol is obtained in the form of white crystals which melt with decomposition at 170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:19])[C:17]=1[OH:18])[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>N1C=CC=CC=1>[C:20]([O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]([NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[C:17]([O:18][C:6](=[O:14])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:16]([Cl:19])[CH:15]=1)=[O:14])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(Nc1cc(Cl)c(O)c(Cl)c1)c1ccccc1O
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1C(=O)Nc1cc(Cl)c(OC(=O)c2ccccc2)c(Cl)c1)c1ccccc1
Yield: 88.2 %

Procedure:
3',5'-Dichloro-2,4'-dihydroxybenzanilide (1 g.) was dissolved in dry pyridine (15 ml.) in the cold at 0°- 5° C. and to it was added dropwise benzoyl chloride (1.2 ml.). With gentle stirring reaction was continued for several hours. The solution was then poured into ice-cold water and acidified with 1 N hydrochloric acid to pH 2, yielding oily material which was extracted by ethyl acetate. The ethyl acetate solution was washed with 1 N hydrochloric acid and 5% sodium bicarbonate solution in that order and dried with anhydrous sodium sulfate, followed by removal of the solvent by evaporation. The residue was subjected to recrystallization from ether and petroleum ether mixture to give white crystals (1.5 g.) of 2,4'-dibenzoyloxy-3',5'-dichlorobenzanilide. Yield: 88.2%. Melting point: 157°-160° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isobutyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J27) (328 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (360 mg, 65%).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[C:11]([C:23]([CH3:25])=[O:24])[CH:10]=1>OS(O)(=O)=O.C([O-])(O)=O.[Na+]>[OH:7][CH2:8][C:9]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[C:11]([C:23]([CH3:25])=[O:24])[CH:10]=1
Reactant: CC(=O)c1cc(COC2CCCCO2)c2c(c1)-c1ccccc1C2=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)c1cc(CO)c2c(c1)-c1ccccc1C2=O
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
1-(2-Tetrahydropyranyl)oxymethyl-3-methylcarbonyl-9-fluorenone (197 mg) was dissolved in 1% H2SO4 (5 ml) and allowed to stand at room temperature for 0.5 hour. The reaction mixture was diluted with excess NaHCO3 soln (10%). The MeOH was removed under reduced pressure and the residue was extracted with EtOAc, dried and evaporated gave the product (135 mg).