Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1>[S:27]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([C:24]1[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)propanoate (intermediate 179.1) (9.6 g, 34.49 mmol, 1.00 equiv) in anhydrous pyridine (12 mL). The mixture was cooled to 0° C. and 4-methylbenzene-1-sulfonyl chloride (7.9 g, 41.44 mmol, 1.20 equiv) was added slowly in several portions. The resulting solution was stirred at 0° C. for 1-2 h and then the flask containing the reaction mixture was sealed and placed in a refrigerator at 0° C. overnight. The mixture was poured into 120 mL of water/ice, and the aqueous layer was extracted with 3×50 mL of DCM. The combined organic layers were washed with 2×50 mL of cold 1.0 N hydrogen chloride and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to yield 13.4 g (90%) of tert-butyl 3-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)propanoate as pale yellow oil.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])[CH2:5]Br.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[C:4](=[N:3][O:2][CH3:1])[CH2:5][N:19]1[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]2[C:15]1=[O:25]
Reactant: CON=C(CBr)c1ccc(Cl)cc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CON=C(CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.1 %

Procedure:
To 2.17 g of 2-bromo-1-(2,4-dichlorophenyl)ethanone-O-methyloxime in 20 ml of N,N-dimethylformamide, 3.03 g of potassium phthalimide and 1.61 g of potassium carbonate were added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 40 ml of water and extracted with ethyl acetate (50 ml×1), the resulting organic layer was washed with water (20 ml×1) and then dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 2.10 g of the desired product as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH2:11][C:10](=[O:13])[C:9]=2[CH:14]=1)=[O:4].[C:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O)([OH:17])=[O:16].Cl.O>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH:11](/[CH:21]=[C:20]3/[CH2:19][C:18](=[CH:25][CH:24]=[CH:23]/3)[C:15]([OH:17])=[O:16])[C:10](=[O:13])[C:9]=2[CH:14]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)C(=O)CO2
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)C(=O)C(/C=C1\C=CC=C(C(=O)O)C1)O2

Procedure:
5-Methoxycarbonylbenzofuran-3-(2H)one (4.9 g) was dissolved in warm dioxan (50 ml). 3-Carboxybenzaldehyde (4.5 g) was then added followed by concentrated hydrochloric acid (10 ml). The mixture was heated on a steam bath for 15 minutes with formation of yellow crystals. After cooling and addition of an equal volume of water, the crystalline product was filtered off and recrystallised from dimethylformamide to give the title compound, m.p. 280° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1.[C:31]([CH2:35][C:36](Cl)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[CH3:32][C:31]([CH3:34])([CH3:33])[CH2:35][C:36]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1)=[O:37]
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCNCC2)cn1
Reactant: CC(C)(C)CC(=O)Cl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCN(C(=O)CC(C)(C)C)CC2)cn1

Procedure:
Following the procedure for Example 21; 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (1-piperidin-4-yl-1H-imidazol-4-yl)-amide was coupled with t-butylacetylchloride to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 18.9, 30.2, 31.6, 33.0, 33.8, 36.0, 40.6, 43.0, 44.9, 45.7, 53.0, 55.7, 102.6, 102.8, 103.1, 105.8, 112.3, 112.4, 112.5, 112.6, 131.5, 137.8, 138.8, 138.9, 161.8, 162.0, 164.3, 164.5, 169.3, 169.5, 170.6; MS 518.30 m/z (M+1).
Reaction SMILES: C(=O)(O)[O-].[Na+].Br.Br[C:8]1[S:12][C:11]([NH2:13])=[N:10][CH:9]=1.[N:14]1([CH2:19][CH2:20][SH:21])[CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)(C)C>[N:14]1([CH2:19][CH2:20][S:21][C:8]2[S:12][C:11]([NH2:13])=[N:10][CH:9]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Nc1ncc(Br)s1
Reactant: SCCN1CCCC1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Nc1ncc(SCCN2CCCC2)s1
Temperature: 60 °C
Reaction time: 96 h
Yield: 30.5 %

Procedure:
Sodium bicarbonate ((1.232 kg, 14.7 mol) is added slowly in portions to a mixture of 5-bromo-thiazol-2-ylamine hydrobromide (1.53 Kg, 5.87 mol) in 7.5 L of isopropanol. 2-Pyrrolidin-1-yl-ethanethiol (1.060 Kg, 8.07 mol) is then added over 15 min, and the resulting mixture is stirred at 60° C. for 96 h. The temperature is increased to 70° C. for 1 h, and then the mixture is cooled to room temperature. Most of the isopropanol is removed under vacuum, and the residue is taken up in 4 L of an isopropanol/chloroform solution (1:9). Saturated aqueous sodium bicarbonate (4 L) is added, and the resulting mixture is stirred for 30 minutes. The layers are separated and the aqueous phase is extracted with three 4 L portions of an isopropanol/chloroform solution (1:9). The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue is triturated with 3 L of diethylether, and filtered off to give a first portion of the title compound as a pale-yellow solid (410 g). The filtrate is concentrated to an orange solid, which is triturated with 2 L of diethylether, and isolated as a beige solid by filtration. This solid is then dissolved in 2 L of methanol, and the solution is heated at 45° C. for 30 min. Upon cooling to room temperature, a solid is formed. This material is isolated by filtration, triturated with diethyl ether as above, and dried under vacuum to afford an additional 310 g of the title compound. MS (m/e): 230 [M+H]
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:14][N:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16](Cl)=[O:17]>>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:3][C:2]([O:1][C:16](=[O:17])[N:15]([CH3:14])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][CH:6]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(-c2ccccc2)cc1
Product: CN(C(=O)Oc1ccc(-c2ccccc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-hydroxybiphenyl and N-methyl-N-phenylcarbamoyl chloride applying. The crude product was recrystallized (ethanol) (75%, white crystals).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[C:7](=[CH2:13])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.[OH:14]I(C1C=CC=CC=1)OS(C1C=CC(C)=CC=1)(=O)=O>O.CO>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:13][C:7](=[O:14])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: C=C1CCCc2cc(OC)ncc21
Reactant: Cc1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Solvent: O
Solvent: CO
Product: COc1cc2c(cn1)CC(=O)CCC2
Yield: 66.5 %

Procedure:
3-Methoxy-8-methylene-5,6,7,8-tetrahydroisoquinoline (125) (1.27 g, 7.25 mmol) in a mixture of water (5 mL) and MeOH (45 mL) was treated with [hydroxy(tosyloxy)iodo]benzene (2.84 g, 7.25 mmol) in MeOH (7 mL). After about 30 min water (15 mL) was added then the mixture was concentrated under reduced pressure to remove most of the MeOH. The mixture was basified to about pH 10 with sat. aq. NaHCO3 then EtOAc (˜30 mL) was added. Insoluble material was removed by filtration. The filtrate layers were separated then the aqueous layer was extracted with EtOAc (20 mL). The combined organic solutions were washed with brine (˜25 mL) then dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure then the material was purified on silica gel (40 g) using a gradient from 0-100% EtOAc in heptane. Pure product fractions were combined and concentrated under reduced pressure to yield 3-methoxy-6,7-dihydro-5H-cyclohepta[c]pyridin-8(9H)-one (126) (0.922 g, 67%); LC/MS, method 3, Rt=1.66 min, MS m/z 192 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 6.57 (s, 1H), 3.92 (s, 3H), 3.63 (s, 2H), 2.93-2.85 (m, 2H), 2.61-2.54 (m, 2H), 2.04-1.94 (m, 2H).
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[Cl:11][C:12]1[C:13]([NH2:21])=[C:14]([NH2:20])[CH:15]=[C:16]([F:19])[C:17]=1[F:18]>Cl>[Cl:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]2[C:13]=1[NH:21][C:2](=[O:4])[C:1](=[O:8])[NH:20]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc(F)c(F)c(Cl)c1N
Agent: Cl
Product: O=c1[nH]c2cc(F)c(F)c(Cl)c2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (981 mg, 6.72 mmol) and 3-chloro-4,5-difluoro-1,2-diaminobenzene (120 mg, 0.670 mmol) was heated to reflux under N2 for 15 h. The reaction was allowed to cool to room temperature and the gray solid collected by vacuum filtration and rinsed with ice-cold EtOH (10 mL) and air dried. The solid was taken and dissolved in 5 mL 1N NaOH with heating. The solution was treated with activated charcoal and filtered through a pad of Celite. The resulting solution was carefully acidified with 1N HCl (pH=1). A white powder formed in the solution at pH=6, but a few drops 1N NaOH cleared the solution and upon addition of a few drops 1N HCl white needles slowly formed in the solution. These were collected by vacuum filtration, rinsed with 20 mL of H2O and dried under vacuum (0.1 torr, 78° C.) to yield 24.9 (16%) of pale yellow needles. 1H NMR (d6 -DMSO) δ 7.05 (dd, 1H, J =10.5, H-8), 11.6 (br s, 1H, NH), 12.0 (br s, 1H, NH). There was 13% 6,7-difluoro-1,4-dihydro-2,3-quinoxalinedione present by NMR.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][NH:10][C:11](=O)[CH2:12][CH2:13][CH:14]([OH:17])[CH2:15][CH3:16])=[CH:7][CH:6]=1.C(O)(=O)C>O1CCCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:17])[CH2:15][CH3:16])=[CH:19][CH:20]=1
Reactant: CCC(O)CCC(=O)NCc1ccc(OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC(O)CCCNCc1ccc(OC)cc1
Temperature: 22.5 °C
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran (121 gal, 458 L) and sodium borohydride (22.154 kg, 585.6 moles) were charged to a clean and dry nitrogen purged 500 gallon glass lined tank. The suspension was allowed to stir for 30 minutes at 20-25° C. then 4-hydroxyhexanoic acid 4-methoxy-benzylamide (45.75 kg, 182 moles) was added as a solid. After 30 minutes, the reaction was cooled to 5-10° C. and over a 4 to 8 hour period a solution of acetic acid (9.1 gallons, 34.4 L) in tetrahydrofuran (12 gal, 45.4 L) was added keeping the temperature at 0-10° C. A slight nitrogen bleed was kept on the tank to help remove the hydrogen. When the addition was complete the reaction was warmed to 20-25° C. and stirred for an hour. The temperature of the reaction was slowly increased to a gentle reflux (˜66° C.) and held there for 16 hours. The reaction was quenched by the addition of 1N HCl, keeping the temperature <25° C. Excess tetrahydrofuran was removed by atmospheric distillation. Ethyl acetate was added to the resulting aqueous solution to extract unreacted amide. The acidic aqueous was then brought to pH 11 to allow the product amine to be extracted into ethyl acetate and held for use in the next step. An aliquot of the ethyl acetate solution of product was worked up to project final yield and concentration. The yield for this large scale run was 55.0%, which was less than that achieved with small scale preparations (78.8%). The large scale procedure had 12.8% unreduced amide starting material after the quench which accounted in part for the lower yield.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[C:8]([CH2:12][CH:13]([N:15]([CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[CH2:16][CH2:17][CH3:18])[CH3:14])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+]>O.C(O)(=O)C>[C:2]([NH:5][C:6]1[CH:7]=[C:8]([CH2:12][CH:13]([N:15]([CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[CH2:16][CH2:17][CH3:18])[CH3:14])[CH:9]=[CH:10][CH:11]=1)(=[O:1])[NH2:3]
Reactant: N#C[O-]
Reactant: CCCN(CC1CCN(S(C)(=O)=O)CC1)C(C)Cc1cccc(N)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCCN(CC1CCN(S(C)(=O)=O)CC1)C(C)Cc1cccc(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.3 %

Procedure:
A solution of potassium cyanate (9 mg) in water (0.5 ml) was added to a solution of N-[2-(3-aminophenyl)-1-methylethyl]-N-propyl-(1-methanesulfonylpiperidin-4-ylmethyl)amine (40 mg) in water (2 ml) and acetic acid (1 ml). The mixture was stirred at ambient temperature for about 72 hours and then basified to pH 9 with 10% sodium hydroxide. The solution was extracted with dichloromethane, and the organic phase dried over sodium sulfate, filtered, evaporated in vacuo to give N-[2-(3-carbamoylaminophenyl)-1-methylethyl]-N-propyl-(1-methanesulfonylpiperidin-4-ylmethyl)amine (35 mg), M+H 411.2
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].C(N)[CH2:17][NH2:18]>CN(C)C=O.O>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:17]#[N:18])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: Nc1c([N+](=O)[O-])ccc2c(Br)cccc12
Reactant: NCCN
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc2c(N)c([N+](=O)[O-])ccc12
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of 1,6 g (5,9 mmol) 1-amino-5-bromo-2-nitronaphthalene in 50 ml dimethylformamide was added 1,1 g (11,8 mmol) cuprous cyanide. The reaction mixture was refluxed for 5 h, and then poured into a solution of 2,5 ml ethylenediamine in 80 ml water. Stirring was continued for 15 min., and then the precipitate was filtered off and washed with water and boiling ethyl acetate to give 1,0 g (80%) 1-amino-5-cyano-2-nitronaphthalene.
Reaction SMILES: CN[C:3](=[O:30])[CH2:4][N:5]1[C@H:14]2[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:25]([F:28])([F:27])[F:26])[C:7]=2[C:6]1=[O:29].Cl.[O:32]1CCOCC1>>[C:21]([O:20][C:18]([N:16]1[CH2:17][C@H:13]2[C@@H:14]([N:5]([CH2:4][C:3]([OH:30])=[O:32])[C:6](=[O:29])[C:7]3[C:8]([C:25]([F:28])([F:26])[F:27])=[CH:9][CH:10]=[CH:11][C:12]=32)[CH2:15]1)=[O:19])([CH3:22])([CH3:24])[CH3:23]
Reactant: C1COCCO1
Reactant: CNC(=O)CN1C(=O)c2c(cccc2C(F)(F)F)[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: Cl
Product: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3C(=O)N(CC(=O)O)[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of (3aR,9bS)-tert-butyl 4-(2-(methylamino)-2-oxoethyl)-5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate (30 mg, 0.07 mmol) in 4 mL of 1,4-dioxane was added 1 mL of 12N HCl. The resulting solution was stirred at ambient temperature for 1 h and then was concentrated. The residue was azeotroped with toluene and dried in vacuo to afford a foam. This foam was triturated 3× with ether and dried in vacuo to afford 20 mg (80%) of the title compound of Example 19 as a pale yellow powder. 1H NMR (DMSO-D6): δ 9.73 and 9.61 (broad singlets, 2H), 8.08 (m, 1H), 7.86 (d, 1H, J=8.3 Hz), 7.76 (t, 1H, J=7.7 Hz), 7.58 (d, 1H, J=7.2 Hz), 4.12 (s, 2H), 4.02-3.95 (m, 2H), 3.70-3.60 (m, 2H), 3.35-3.25 (m, 2H), 2.60 (d, 3H, J=5.0 Hz). LRMS (ESI): 328.17 (M+H)+.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:12](OC(Cl)(Cl)Cl)=[O:13]>C(Cl)Cl>[C:2]1([C:1]2[S:8][C:12](=[O:13])[NH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: NNC(=S)c1ccccc1
Solvent: ClCCl
Product: O=c1[nH]nc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of thiobenzhydrazide (3.7 g, 24.34 mmole) in methylene chloride (50 ml), equipped with magnetic stirrer, nitrogen inlet, and an outlet connected to a trap containing a diluted NAOH solution, was added trichloromethyl chloroformate (4 g, 20.2 mmole). The reaction mixture was stirred at room temperature for one hour. The mixture was diluted with methylene chloride (100 ml) and washed with water (3×50 ml) and brine. The organic layer was dried over MgSO4. After the drying agent was filtered off the filtrate was concentrated to a residue. The residue was triturated with hexane and the solid product was collected by suction-filtration to give 3.7 g as a powder. m.p.=140°-143° C.
Reaction SMILES: [C:1](OC(=O)CC)(=O)CC.[O:10]=[S:11]1(=[O:36])[CH:16]=[CH:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:34])[CH:31](F)F)[O:25][C:24]3=[O:35])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>N1C=CC=CC=1.ClCCl>[O:10]=[S:11]1(=[O:36])[CH:16]=[CH:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:34])[CH2:31][CH3:1])[O:25][C:24]3=[O:35])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1
Reactant: O=C(NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1)C(F)F
Reactant: CCC(=O)OC(=O)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1
Reaction time: 4 h
Yield: 84.1 %

Procedure:
Propionic anhydride (0.136 ml, 1.06 mmol) is added dropwise to the crude amine hydrochloride prepared in Step 1 of Example 15 (0.316 g, 0.88 mmol) in a mixture of pyridine (4 mL) and dichloromethane (4 mL). The mixture is stirred for 4 hours and then evaporated to dryness. The residue is purified by PTLC (10% methanol/dichloromethane) to give the title compound as white solid (0.28 g, 80%). M.p. 144-7° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[SH:43][CH2:44][C:45]([C:47]1[CH:52]=[CH:51][C:50]([NH:53][S:54]([C:57]2[CH:62]=[CH:61][C:60]([O:63][C:64]([F:67])([F:66])[F:65])=[CH:59][CH:58]=2)(=[O:56])=[O:55])=[CH:49][CH:48]=1)=[O:46]>C(Cl)Cl>[O:46]=[C:45]([C:47]1[CH:52]=[CH:51][C:50]([NH:53][S:54]([C:57]2[CH:62]=[CH:61][C:60]([O:63][C:64]([F:67])([F:65])[F:66])=[CH:59][CH:58]=2)(=[O:56])=[O:55])=[CH:49][CH:48]=1)[CH2:44][S:43][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: O=C(O)c1ccccn1
Reactant: O=C(CS)c1ccc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CSC(=O)c1ccccn1)c1ccc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 0.33 h
Yield: 14 %

Procedure:
Picolinic acid (0.25 g, 2.04 mmol) was dissolved in anhydrous, degassed DCM (5 ml), HATU (775 mg, 2.04 mmol) was added followed by DIEA (0.53 g, 4.1 mmol). The mixture was stirred for 20 min and N-[4-(2-Mercapto-acetyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide SII-4 (0.725 g, 1.85 mmol) was added in 5 ml anhydrous, degassed DCM and the mixture was stirred for 16 hours. The reaction was filtered and the solvent evaporated. The product was purified by flash chromatography (1:1 EtOAc:hexanes) to afford 125 mg (0.25 mmol, 14%) product as a white solid. 1H-NMR: (400 MHz, DMSO): 11.12 (s, 1H), 8.89 (d, 1H), 8.03 (t, 1H), 8.01 (d, 2H), 8.00 (d, 2H), 7.90 (d, 1H), 7.78 (t, 1H), 7.60 (d, 2H), 7.14 (d, 2H), 4.60 (s, 2H); LC-MS (ES+): 497 [MH]+ m/e.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[C:9]([N:11]1[CH2:28][CH2:27][CH2:26][C:13]2([C:17](=[O:18])[N:16]([CH3:19])[CH2:15][CH:14]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12]1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@H:8]([CH2:29][O:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=1)[C:9]([N:11]1[CH2:28][CH2:27][CH2:26][C:13]2([C:17](=[O:18])[N:16]([CH3:19])[CH2:15][CH:14]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:12]1)=[O:10]
Reactant: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccc(F)cc3)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@H](N)COCc3ccc(F)cc3)C2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of [(R)-1-(4-Fluoro-benzyloxymethyl)-2-(2-methyl-1-oxo-4-phenyl-2,7-diaza-spiro[4.5]dec-7-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (diastereomer 2 from step 1) (185 mg, 0.34 mmol) in DCM (4 ml) was treated with TFA (0.79 ml, 10.3 mmol). The resulting solution was stirred for 2 h at RT. The reaction mixture was diluted with DCM (20 ml) and quenched at 0° C. with 2M NaOH aqueous solution (10 ml). The organic phase was separated, washed with brine (5 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[NH:3]1.BrC1C=CC=CC=1CBr.[Br:31][C:32]1[CH:33]=[C:34]([S:40]([N:43]([CH3:45])[CH3:44])(=[O:42])=[O:41])[CH:35]=[CH:36][C:37]=1[CH2:38]Br>>[Br:31][C:32]1[CH:33]=[C:34]([S:40]([N:43]([CH3:44])[CH3:45])(=[O:41])=[O:42])[CH:35]=[CH:36][C:37]=1[CH2:38][N:3]1[C:2]([CH3:21])([CH3:1])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)[C:4]1=[O:20]
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: CN(C)S(=O)(=O)c1ccc(CBr)c(Br)c1
Agent: BrCc1ccccc1Br
Product: CN(C)S(=O)(=O)c1ccc(CN2C(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)c(Br)c1

Procedure:
Compound 146.2 was prepared as described for example 1.2, by reacting compound 1.1, instead of with 2-bromobenzyl bromide, with 3-bromo-4-bromomethyl-N,N-dimethylbenzenesulfonamide (146.3, prepared by reacting 3-bromo-4,N,N-trimethylbenzenesulfonamide with N-bromosuccinimide and N,N′-azobis(2-methylpropionitrile) in tetrachloromethane). 3-Bromo-4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-ylmethyl]-N,N-dimethylbenzenesulfonamide was obtained. (Molecular weight 572.03 (C22H20BrF3N4O4S); retention time Rt=2.38 min. [B]; MS (ESI): 573.25 (MH+).