Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:12]1[CH:17]=[CH:16][C:15]([C:2]2[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ccc(Br)s1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(-c2ccncc2)s1
Temperature: 100 °C
Yield: 65.7 %

Procedure:
A mixture of ethyl 5-bromothiophene-2-carboxylate (1.560 g, 6.65 mmol), pyridine-4-boronic acid (0.98 g, 7.98 mmol), tetrakis(triphenylphosphine)palladium(0) (768 mg, 0.665 mmol) and cesium carbonate (6.50 g, 19.9 mmol) in 1,4-dioxane (20 mL) and water (3.35 mL) was stirred and heated at 100° C. under an atmosphere of nitrogen overnight. The reaction was a clear light orange with a small amount of a second liquid phase on the bottom of the flask. An aliquot was taken, quenched into water, and extracted with ethyl acetate. A TLC on silica gel (1:1 DCM:hexane) indicated that all of the starting material had been consumed. A major new product with Rf ˜0.4 was seen. The reaction was cooled to room temperature then was quenched into stirring water and extracted with ethyl acetate. The ethyl acetate extracts were washed with saline, dried over sodium sulfate, filtered, and evaporated to leave crude product as an off-white solid. The crude product was dissolved in minimal DCM then was purified by column chromatography on silica gel (gradient 100% DCM to 50% ethyl acetate) to afford product 1.02 g (66% yield) as white solid. LC/MS (FA) ES+ 234. 1H NMR (400 MHz, DMSO) δ 8.68-8.60 (m, 2H), 7.91-7.83 (m, 2H), 7.78-7.71 (m, 2H), 4.37-4.27 (d, J=7.1 Hz, 2H), 1.35-1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([OH:31])([C:22]1[CH:27]=[C:26]([Cl:28])[C:25]([Cl:29])=[C:24]([Cl:30])[CH:23]=1)[CH2:4][NH:5][C:6]1[CH:17]=[CH:16][C:9]([CH2:10][NH:11][C:12](=[O:15])[CH2:13][CH3:14])=[C:8]([C:18]([F:21])([F:20])[F:19])[CH:7]=1.[CH2:34]=O>C1(C)C=CC=CC=1>[Cl:30][C:24]1[CH:23]=[C:22]([C:3]2([C:2]([F:32])([F:1])[F:33])[O:31][CH2:34][N:5]([C:6]3[CH:17]=[CH:16][C:9]([CH2:10][NH:11][C:12](=[O:15])[CH2:13][CH3:14])=[C:8]([C:18]([F:19])([F:20])[F:21])[CH:7]=3)[CH2:4]2)[CH:27]=[C:26]([Cl:28])[C:25]=1[Cl:29]
Reactant: CCC(=O)NCc1ccc(NCC(O)(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Reactant: C=O
Solvent: Cc1ccccc1
Product: CCC(=O)NCc1ccc(N2COC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 5 h
Yield: 39.1 %

Procedure:
N-[4-{[3,3,3-Trifluoro-2-hydroxy-2-(3,4,5-trichlorophenyl)propyl]amino}-2-(trifluoromethyl)benzyl]propane amide (250 mg) and formaldehyde (70 mg) were added to toluene (20 mL), and stirred at 90° C. for 5 hours. After the reaction, the solvent was distilled off under reduced pressure and the residues were purified by silica-gel column chromatography to give N-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-1,3-oxazolidin-3-yl]-2-(trifluoromethyl)benzyl}propane amide (100 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1([Cl:22])[CH2:18][CH:17]1[C:19](Cl)=[O:20]>O1CCCC1>[Cl:15][C:16]1([Cl:22])[CH2:18][CH:17]1[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:20]
Reactant: O=C(Cl)C1CC1(Cl)Cl
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Solvent: C1CCOC1
Product: O=C1CCC(c2ccc(NC(=O)C3CC3(Cl)Cl)cc2)=NN1
Yield: 72.5 %

Procedure:
6.0 g (31.7 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone and 6.6 g (38.1 millimoles) of 2,2-dichlorocyclopropanecarboxylic acid chloride in 100 ml of absolute tetrahydrofuran are refluxed for 6 hours. The product is filtered off at 10° C., washed first with tetrahydrofuran and then with water, and recrystallized from dimethylformamide/water. 7.5 g (73% of theory) of 6-[p-(2,2-dichlorocyclopropylcarbonylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone are obtained as colorless crystals, of melting point 267°-268° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Br.C(O)(=O)C>O>[Cl:1][C:2]1[N:3]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COc1ccc(Nc2nc(Cl)cc3ccccc23)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(Nc2nc(Cl)cc3ccccc23)cc1
Yield: 101.9 %

Procedure:
A mixture of 3-chloro-1-[N-(4-methoxyphenyl)amino]isoquinoline (1.90 g), hydrogen bromide (10 ml of 48%) and glacial acetic acid was heated under reflux for a period of 9.5 hours. The reaction mixture was poured into water, and the aqueous mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure to give 4-[N-(3-chloroisoquinolin-1-yl)amino]phenol (1.84 g) as pale yellow crystals mp 170° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23](O)=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.[CH3:29][NH:30][CH3:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([N:30]([CH3:31])[CH3:29])=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CNC
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ncc(C(=O)O)s3)C[C@H]2OC)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ncc(C(=O)N(C)C)s3)C[C@H]2OC)nc1Cl
Yield: 93.2 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylic acid obtained in Example (11b) (40 mg, 0.09 mmol), dimethylamine hydrochloride (9 mg, 0.11 mmol), WSC hydrochloride (61 mg, 0.32 mmol), HOBT (22 mg, 0.16 mmol), diisopropylethylamine (0.020 mL, 0.12 mmol), dichloromethane (0.75 mL) and DMA (0.75 mL), to obtain 37 mg of the title compound as a white solid (87%).
Reaction SMILES: [Cl:1][C:2]1[N:6](S(N(C)C)(=O)=O)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:1][C:2]1[NH:6][N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: CN(C)S(=O)(=O)n1nc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cc(Cl)[nH]n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 77.9 %

Procedure:
In a round bottom flask with magnetic stirrer, 5-chloro-N,N-dimethyl-3-(trifluoromethyl)-1H-pyrazole-1-sulfonamide (4.38 g, 15.8 mmol) (i.e. the product of Example 13, Step B) was cooled to 0° C. and treated with trifluoroacetic acid (2.7 mL, 35 mmol). The reaction mixture was stirred at 0° C. for 1.5 h. The resulting solution was diluted with water (15 mL) and basified with sodium carbonate to pH 12. The reaction mixture was extracted with diethyl ether. The extract was dried over MgSO4 and concentrated under reduced pressure giving 2.1 g of the title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[OH-].[Na+].C(OC(O)=O)(O)=O.[C:21](=O)([O:27]C(C)(C)C)[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>O1CCOCC1.O>[C:23]([O:22][C:21]([NH:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7])=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: O=C(O)OC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)c(O)c1
Yield: 55.5 %

Procedure:
4-Aminosalicylic acid (5.00 g, 32.6 mmol) was suspended in dioxane (35 ml) and water (35 ml), and the suspension was added with aqueous sodium hydroxide (2N) and a solution of di-tert-butyl carbonate dicarbonate (8.5 g, 39.0 mmol) in dioxane (35 ml), and then the mixture was stirred at room temperature for seven days. After the dioxane of the reaction mixture was evaporated, the residue was made weakly acidic (pH˜4) with 1N hydrochloric acid, and then extracted with ether. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated. The resulting syrup was solidified with hexane and ethyl acetate to obtain the title compound (4.58 g, yield; 55%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1)[CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH2:12]1.[Li+].[OH-]>O1CCOCC1.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)[CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc(CN(c2nc3ccccc3[nH]2)C2CCC(C(C)(C)C)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)O)cc2)c2nc3ccccc3[nH]2)CC1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To the title compound of Example 1 Step C (0.21 mmol, 90 mg) in 2 mL of dioxane was added a solution of LiOH (2.1 mmol, 52 mg) in 0.6 mL of H2O. The reaction was stirred at 40° C. for 3 h. The product was partitioned into EtOAc/H2O acidified with 2 N HCl. The aqueous phase was washed with EtOAc and the combined organic phase was dried with MgSO4 and concentrated under reduced pressure affording a yellow solid. HPLC A: 1.98 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][CH:7]=1>>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:4][CH2:3][CH2:2][OH:1])=[CH:8][CH:7]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: NCCO
Product: OCCNCc1ccc(Cl)cc1

Procedure:
2-Hydroxyethylamine was reacted with 4-chlorobenzyl bromide according to Method B2a to give N-(4-chlorobenzyl)-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-(4-chlorobenzyl)-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 4-cyano-2-ethylphenyl isothiocyanate to give 2-(4-cyano-2-ethylphenylimino)-3-(4-chlorobenzyl)-1,3-thiazolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([OH:24])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:31](Cl)(=O)[C:32](Cl)=O.N1C(C)=CC=CC=1C.NC1C=CN(CC2(O)CC2)N=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3([OH:24])[CH2:32][CH2:31]3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Agent: Nc1ccn(CC2(O)CC2)n1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC3(O)CC3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 248 mg, 0.75 mmol) was dissolved in methylene chloride (4 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (0.376 mL, 0.75 mmol) was added and the reaction stirred at 25° C. for 15 min. The solution was chilled to 0° C. and 2,6-lutidine (175 μL, 1.50 mmol) was added dropwise. The reaction continued to stir at 0° C. for 15 min. The 1-(3-amino-pyrazol-1-ylmethyl)-cyclopropanol (115 mg, 0.75 mmol) was added as a pre-dissolved reaction in methylene chloride (4 mL), the ice bath was removed and the reaction continued to stir at 25° C. for 25 min. The reaction was diluted with methylene chloride (50 mL), washed with water (2×25 mL), saturated aqueous brine solution (1×20 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 80% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(1-hydroxy-cyclopropylmethyl)-1H-pyrazol-3-yl]-propionamide (158 mg, 45%) as a white brittle foam: ESI-LRMS m/e calcd for C22H28ClN3O4S [M+] 465.15, found 466.20 [M+H+], 488.11 [M+Na+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.65-0.72 (m, 2H, CH2), 0.87-0.92 (m, 2H, CH2), 1.08-1.25 (m, 2H, CH2), 1.44-1.98 (m, 8H, 4×CH2), 2.15-2.38 (m, 1H, CH), 3.24 (brs, 1H, OH), 3.28 (s, 3H, SO2CH3), 3.60 (t, J=7.5 Hz, 1H, CH), 4.06 (s, 2H, NCH2), 6.71 (d, Jo=2.3 Hz, 1H, Ar), 7.32 (d, Jo=2.3 Hz, 1H, Ar), 7.49 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.62 (d, Jm=1.7 Hz, 1H, Ar), 8.09 (d, Jo=8.2 Hz, 1H, Ar), 8.12 (s, 1H, NH).
Reaction SMILES: [N:1]#[C:2][C@@H:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:4][C:5](=O)[CH2:6][CH3:7].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:23]2)=CC=1>O1CCCC1>[NH2:1][C:2]1[S:23][C:5]([CH2:6][CH3:7])=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)[C@H](C#N)NC(=O)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(CC)sc1N
Temperature: 70 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
A mixture of ethyl 3-nitrilo-N-propionylalaninate (10 g), 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (24.1 g) and tetrahydrofuran (150 mL) was stirred at 70° C. for 16 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. After purification by silica gel column chromatography, the obtained residue was recrystallized from ethyl acetate-hexane to give the title compound as colorless crystals (3.8 g, 38%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.CCOCC>[CH:12]([C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Temperature: -78 °C
Yield: 100.8 %

Procedure:
To an oven-dried 500-mL 3-neck flask purged with nitrogen was added oxalyl chloride (5.32 mL, 60.8 mmol) and anhydrous dichloromethane (125 mL), and the solution cooled to −78° C. A solution of anhydrous DMSO (7.30 mL, 103 mmol) in anhydrous dichloromethane (25 mL) was added dropwise from a constant-pressure addition funnel over 20-min period. A solution of (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (9.41 g, 46.8 mmol) in anhydrous dichloromethane (50 mL) was added dropwise from a constant-pressure addition funnel over 20-min period, then stirred reaction mixture at −78° C. for 30 min. Added triethylamine (32.6 mL, 234 mmol) dropwise via syringe over a 5-min period and stirred the thick white mixture in an ice-water bath for 30 min. Quenched reaction with 10% (w/v) aq. citric acid (30 mL), poured reaction into a separatory funnel with Et2O (550 mL) and 10% (w/v) aq citric acid, separated layers, and washed organic phase with water and brine. Dried the organic phase over anhydrous Na2SO4, filtered, and concentrated to afford a yellow oil (9.4 g), which was used directly in the next reaction.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:30][CH:31]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[F:30][CH:31]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:29][CH2:28][C:25]2[CH:24]=[CH:23][C:22]([CH2:21][N:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=3)=[CH:27][CH:26]=2)=[CH:40][CH:39]=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: OCc1ccc(CN(CCc2ccccc2)c2nc(-c3ccccc3)cs2)cc1
Reactant: CCOC(=O)C(F)Cc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)C(F)Cc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
To a solution of [4-[[(2-phenylethyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl]phenyl]methanol (725 mg, 1.81 mmol), ethyl 2-fluoro-3-(4-hydroxyphenyl)propanoate (300 mg, 1.81 mmol) and tributylphosphine (550 mg, 2.72 mmol) in tetrahydrofuran (30 mL) was added 1,1′-(azodicarbonyl)-dipiperidine (685 mg, 2.72 mmol), and the mixture was stirred at room temperature for 16 hr. The insoluble materials were filtered off and the filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:97-40:60) to give the title compound (798 mg, yield 78%, 2 steps) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=O)([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:52][S:53]([NH2:56])(=[O:55])=[O:54].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:26])([CH3:25])[C:27]([NH:56][S:53]([CH3:52])(=[O:55])=[O:54])=[O:29])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(F)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(F)ccc2OC(C)(C)C(=O)NS(C)(=O)=O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
A solution of racemic (2′S,3S,4′R)-6-chloro-4′-[5-fluoro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (100 mg, 0.18 mmol) and CDI (58 mg, 0.36 mmol) in DMF (5 mL) was heated at 60° C. for 0.5 h. Then to this solution was added a mixture of methanesulfonamide (475 mg, 5 mmol) and NaH (200 mg, 60%, 5 mmol) in DMF (5 mL), which had been stirred for 1 h at room temperature. After the resulting mixture was stirred at room temperature for 0.5 h, it was poured into water (5 mL) and the aqueous solution was acidified to “pH” 2-3 by concentrated aqueous hydrochloride. After the aqueous phase was extracted with EtOAc twice, the combined organic phases were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (80 mg).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[C:13]([SH:24])=[N:14][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:16][CH:17]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.II>>[N:18]1([C:15]2[N:14]=[C:13]3[S:24][N:9]([CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:10](=[O:11])[C:12]3=[CH:17][N:16]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=C(NCCN1CCCCC1)c1cnc(N2CCOCC2)nc1S
Agent: II
Product: O=c1c2cnc(N3CCOCC3)nc2sn1CCN1CCCCC1
Yield: 50.3 %

Procedure:
Using the procedure of Example 20, 5.2 g (14.8 mmol) of 4-mercapto-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (2-piperidin-1-yl-ethyl)-amide were treated with 3.81 g (15.0 mmol) of iodine to give 2.6 g of the title compound after recrystallization from aqueous isopropanol, mp 98-100° C.
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:7]2=[CH:8][C:9]3[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH:24]1(Br)[CH2:26][CH2:25]1>CS(C)=O.O>[CH:24]1([O:15][C:11]2[CH:12]=[CH:13][C:14]3[N:6]4[CH2:5][CH2:4][CH2:3][C:7]4=[CH:8][C:9]=3[CH:10]=2)[CH2:26][CH2:25]1
Reactant: BrC1CC1
Reactant: Oc1ccc2c(c1)cc1n2CCC1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Product: c1cc2c(cc1OC1CC1)cc1n2CCC1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
6.00 g sodium hydride 55-65% in oil in portion was added during ca 30 min at room temperature to a solution of 23.5 g 2,3-dihydro-1H-3a-aza-cyclopenta[a]inden-6-ol in 200 mL dimethylsulfoxide. 18.75 g potassium carbonate and 1.700 g potassium iodide and 34 mL cyclopropylbromide was added to the resulting solution. The resulting suspension was stirred under argon at 100° C. for 48 h. Another 17 mL cyclopropylbromide was added. The resulting suspension was stirred under argon at 100° C. for 24 h. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was purified by chromatography on silica gel with hexane:dichloromethane=1:1 to yield 17.75 g 6-Cyclopropoxy-2,3-dihydro-1H-3a-aza-cyclopenta[a]indene as a white crystalline solid melting at 61-63° C.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([F:20])([F:19])([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.O>C(O)(=O)C>[C:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([F:20])([F:16])([F:17])([F:18])[F:19])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Acetic anhydride was added during 5 minutes to a stirred solution of 4-aminophenylsulphur pentafluoride (30.2 g) in acetic acid at 40° C. and then heated at 65° C. for 0.5 hour. The cooled mixture was added to water, stirred for 1 hour and filtered. The solid was washed with water, sodium bicarbonate solution and water, dried and purified by stirring with hexane to give 4-acetamidophenylsulphur pentafluoride (27.0 g), m.p.131°-132° C.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH2:11][CH3:12])[C:3]1=[S:4].C(N(CC)CC)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[C:23]([O:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:22]=1.Cl>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[C:9](=[O:10])[CH:8]([C:28](=[O:29])[NH:27][C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][C:23]=2[O:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:6](=[O:7])[N:5]([CH2:11][CH3:12])[C:3]1=[S:4]
Reactant: CCN1C(=O)CC(=O)N(C)C1=S
Reactant: O=C=Nc1ccc(Cl)cc1Oc1ccc(Cl)cc1
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CCN1C(=O)C(C(=O)Nc2ccc(Cl)cc2Oc2ccc(Cl)cc2)C(=O)N(C)C1=S
Temperature: 40 °C

Procedure:
3.4 g (20 mmol) of 1-methyl-3-ethyl-2-thiobarbituric acid are suspended in 80 ml of xylene. 1 g (8 mmol) of triethylamine is added, the mixture is heated to 40° C. and a solution of 5.6 g (20 mmol) of 4-chloro-2-(4-chlorophenoxy)phenylisocyanate in 30 ml of xylene is added dropwise with stirring at 40° C. The mixture is subsequently stirred for 2 hours at 40° C. and then cooled. 50 ml of 2N HCl are added, the crystalline precipitate is isolated by filtration, washed with water and dried at 80° C., affording a product with a melting point of 250°-251° C.