Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OP([O-])([O-])=O.[K+].[K+].OP([O-])(O)=O.[K+].ClC1N=C(Cl)N=C(Cl)N=1.C[CH2:24][C@@H:25]([C@H:27]([NH:77][C:78]([C@@H:80]([NH:89][C:90]([C@@H:92]([NH:96][C:97]([C@@H:99]([NH:107][C:108]([C@@H:110]([NH2:115])[CH2:111][C:112]([OH:114])=[O:113])=[O:109])[CH2:100][CH2:101][CH2:102][N:103]=[C:104]([NH2:106])[NH2:105])=[O:98])[CH:93]([CH3:95])[CH3:94])=[O:91])[CH2:81][C:82]1[CH:87]=[CH:86][C:85]([OH:88])=[CH:84][CH:83]=1)=[O:79])[C:28]([NH:30][C@H:31]([C:38]([N:40]1[C@H:44]([C:45]([NH:47][C@H:48]([C:56](N[C@H](C(N[C@H](C(O)=O)CC(C)C)=O)CC2NC=NC=2)=[O:57])[CH2:49]C2C=CC=CC=2)=[O:46])[CH2:43][CH2:42][CH2:41]1)=[O:39])[CH2:32][C:33]1[NH:37][CH:36]=[N:35][CH:34]=1)=[O:29])[CH3:26].[OH2:116]>O1CCOCC1.CO>[CH3:49][C@H:48]([NH:47][C:45]([C@H:44]1[N:40]([C:38]([C@@H:31]([NH:30][C:28]([C@@H:27]([NH:77][C:78]([C@@H:80]([NH:89][C:90]([C@@H:92]([NH:96][C:97]([C@@H:99]([NH:107][C:108]([C@@H:110]([NH2:115])[CH2:111][C:112]([OH:114])=[O:113])=[O:109])[CH2:100][CH2:101][CH2:102][NH:103][C:104]([NH2:106])=[NH:105])=[O:98])[CH:93]([CH3:94])[CH3:95])=[O:91])[CH2:81][C:82]2[CH:87]=[CH:86][C:85]([OH:88])=[CH:84][CH:83]=2)=[O:79])[CH:25]([CH3:24])[CH3:26])=[O:29])[CH2:32][C:33]2[NH:37][CH:36]=[N:35][CH:34]=2)=[O:39])[CH2:41][CH2:42][CH2:43]1)=[O:46])[C:56]([OH:57])=[O:116]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(=O)O)C(C)C)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)O
Reactant: O
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CC(=O)O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)O)C(C)C
Reaction time: 0.5 h

Procedure:
A 25 μl aliquot of the enzyme suspension was added to the above reaction-broth mixture and incubated at 37° C. for 30 minutes. The enzyme reaction was quenched by placing the mixture in a boiling water bath for 10 minutes. A blank was prepared by adding the enzyme aliquot to the reaction mixture after the boiling water treatment. A positive control consisted of a 10 μl mixture of methanol and water (1:1). A 1.0 ml portion of 0.2M K2HPO4 --KH2PO4 buffer (pH=8.3) was added to each boiled mixture and then 0.5 ml of 3% 2,4,6-trichloro-S-triazine in dioxane (3% TT) was added and the mixture vortexed. The solutions were centrifuged and the supernatant from each solution was measured for optical density (O.D.) at 382 nm. The percentage of inhibition of the angiotensin I-converting enzyme was defined by the equation: ##EQU1## Broth samples from medium 3 (see Table I) showing at least 90% inhibition were deemed positive. For the other media listed, a minimum inhibition percentage of 80% indicated a positive result. A positive assay result indicated that the cultured broth was producing the desired compound, 176.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][NH:4][N:3]=1.[F:12][CH:13]([F:29])[C:14](=O)[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)=O.CO.S(=O)(=O)(O)O>C(O)(=O)C.[OH-].[K+].O>[F:29][CH:13]([F:12])[C:14]1[N:3]2[N:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[C:2]2[N:1]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=2)[CH:15]=1
Reactant: O=C(CC(=O)C(F)F)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1c[nH]nc1N
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 57.4 %

Procedure:
A stirred mixture of commercially available 3-amino-4-ethoxycarbonyl-pyrazole (3.38 g, 22 mmol) and 4,4-difluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (5.8 g, 22 mmol) in acetic acid (45 ml) was heated under reflux conditions for 1.5 h. The reaction mixture was evaporated and the crude product (yellow solid, 8.5 g, 22 mmol) was dissolved in a mixture of 2M KOH in methanol (176.5 ml, 0.35 mol) and water (85 ml). The reaction mixture was stirred at 60° C. for 1.5 h, poured into ice/water (200 ml), acidified with 3N sulfuric acid (pH=4) and stirred at room temperature for 30 min. The precipitate was collected by filtration and further purified by crystallization from diethylether/methanol to give the title compound (4.51 g, 57%) as an off-white solid. MS (ISP) 356.1 [(M−H)−]; m.p. 261° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][N:7]=1.[C:9](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH3:9])[N:7]=1
Reactant: O=c1ccc(Cl)n[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(Cl)ccc1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a solution of 6-chloropyridazin-3(2H)-one (600 mg, 4.23 mmol) were added potassium carbonate (1.2 g, 8.46 mmol) and methyl iodide (1.2 g, 8.46 mmol) in DMF (3 mL). The resulting mixture was stirred at 25° C. for 4 h. After the reaction, water was added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give the residue which was purified by column chromatography to give 6-chloro-2-methylpyridazin-3(2H)-one (550 mg, 91%). 1H NMR (CDCl3): 3.76 (s, 3H), 6.92 (d, 1H), 7.19 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[C:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][CH2:29]Br)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C(=O)C>[C:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][CH2:29][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COc1cccc(-c2[nH]c(=O)c3ccccc3c2O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cccc(-c2[nH]c(=O)c3ccccc3c2OCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
To a solution of 3.79 g (14.19 mmol) of 4-hydroxy-3-(3-methoxy-phenyl)-2H-isoquinolin-1-one in N,N-dimethylacetamide (90 mL), 3.18 g (14.19 mmol) of (2-bromo-ethyl)-carbamic acid tert-butyl ester and 5.09 g (15.6 mmol) of cesium carbonate were added and the resulting mixture was stirred at room temperature for 2 hours under argon. Water was added to the reaction mixture and this was extracted twice with ethyl acetate. The combined organic layers were washed at least three times with water and then evaporated to dryness. The crude was purified by flash chromatography (eluant: ethyl acetate/hexane 1/1) to afford 3.2 g of the title compound (55%).
Reaction SMILES: [CH3:1][N:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[F:18][C:19]1[C:20]([C:25](Cl)=[O:26])=[N:21][CH:22]=[CH:23][CH:24]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:10])/[CH:3]=[C:4](/[C:25](=[O:26])[C:20]1[C:19]([F:18])=[CH:24][CH:23]=[CH:22][N:21]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C(Cl)c1ncccc1F
Reactant: CCOC(=O)/C=C/N(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(=C\N(C)C)C(=O)c1ncccc1F
Temperature: 83 °C
Reaction time: 1.5 h
Yield: 16.6 %

Procedure:
To a light yellow solution of (E)-ethyl 3-(dimethylamino)acrylate (5.15 g, 36.0 mmol) in toluene (50 mL) was added triethylamine (3.64 g, 5.02 mL, 36.0 mmol) at room temperature. To this, a dark brown suspension of 3-fluoropicolinoyl chloride (30) (4.79 g, 30 mmol) in toluene (50 mL, heated to dissolve, but not dissolved completely) was added in one portion using a funnel. Then, the resulting dark brown solution was heated to 83° C. and stirred for 1.5 h at this temperature. During this period, it turned to a dark brown solution and TLC analysis indicated the presence of a new spot. Then, the heating was stopped and the dark brown mixture was diluted with ethyl acetate (200 mL) and the brown solution was washed with water, brine solution, and dried over anhydrous MgSO4. Filtration and concentration gave the crude brown mixture which was purified using ISCO (120 g) column chromatography, eluting with ethyl acetate in hexanes (0 to 100%) and then 5 to 20% methanol in dichloromethane. The desired fractions were combined and the solvent was removed under vacuum to obtain the (Z)-ethyl 3-(dimethylamino)-2-(3-fluoropicolinoyl)acrylate (31) (1.33 g, 15% yield) as a dark brown paste.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[CH2:3]1.S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20]>>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:19]([O-:21])=[O:20])[CH:10]=2)[NH:5][C:4](=[O:12])[CH2:3]1
Reactant: CC1(C)CC(=O)Nc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC1(C)CC(=O)Nc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 17.5 g. (0.1 mole) 1,2,3,4-tetrahydro-4,4-dimethylquinolin-2-one in 200 ml. 80% sulphuric acid is added dropwise, while cooling with ice, a mixture of 5 ml. 96% nitric acid and 20 ml. 80% sulphuric acid, followed by stirring for 1 hour at ambient temperature. Subsequently, the reaction mixture is poured on to ice and the crystallisate is filtered off with suction and then washed with water. The crude product is purified by column chromatography on silica gel with butan-2-one/ethyl acetate (20/1 v/v) as elution agent. Yield 17.2 g. (78% of theory); m.p. 202°-204° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[CH3:13].N1C=CC=CC=1.[O:20](S(C(F)(F)F)(=O)=O)[S:21]([C:24]([F:27])([F:26])[F:25])(=O)=[O:22].C(OCC)(=O)C>C(Cl)Cl>[CH3:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([O:1][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:22])=[O:20])[CH:3]=2)[O:8][C:7](=[O:12])[CH:6]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(=O)oc2ccc(O)cc12
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(=O)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-Hydroxy-4-methyl-chromen-2-one (25 mg, 0.142 mol) and pyridine (300 mL) were dissolved in CH2Cl2 (200 mL) at room temperature and the reaction mixture was cooled to 0° C. and then treated with Tf2O (40 mL). After 1 hour, ethyl acetate (900 mL) was poured into the reaction mixture and the reaction mixture was transferred into a separation funnel. The reaction mixture was then washed with 5% sodium bicarbonate (2×450 ml), water (450 ml) and then brine. The organic layer was dried over sodium sulfate and concentrated. Flash column chromatography on silica gel eluted with 20-50% ethyl acetate in hexane yielded the title compound as a foam.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([F:21])([F:20])[CH2:9][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH:12]=1)(=O)=O.[OH:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.C(O)(=O)C>[CH2:13]([N:10]1[CH2:11][CH:12]=[C:7]([C:28]2[CH:29]=[CH:30][C:25]([OH:24])=[CH:26][CH:27]=2)[C:8]([F:21])([F:20])[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(OC1=CCN(Cc2ccccc2)CC1(F)F)C(F)(F)F
Reactant: OB(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc(C2=CCN(Cc3ccccc3)CC2(F)F)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
To a mixture of 1-benzyl-3,3-difluoro-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (1.13 g), 4-hydroxyphenylboronic acid (0.43 g) and sodium carbonate (1.01 g) in DMF (10 mL) was added dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) (73 mg) under nitrogen atmosphere. The reaction mixture was stirred at 90° C. for 3 hr. The reaction mixture was added to water, and the mixture was adjusted to pH=5 with acetic acid, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (725 mg).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[H-].[Na+].Cl[C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[CH:14][N:13]=1>CS(C)=O>[C:3]1([CH3:8])[CH:4]=[CH:5][C:6]([O:7][C:12]2[C:17]([C:18]#[N:19])=[CH:16][N:15]=[CH:14][N:13]=2)=[CH:1][CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: N#Cc1cncnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(Oc2ncncc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41.6 %

Procedure:
p-Cresol (1.0 equiv.) was placed in a round bottom flask with DMSO (1.0 M) and sodium hydride (0.9 equiv). The reaction mixture was stirred at ambient temperature for 5 min. To the mixture was added 4-chloropyrimidine-5-carbonitrile (1.0 equiv.). The reaction was stirred at 25° C. for 2 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine (3×) and dried over sodium sulfate. Volatile organic solvents were removed under reduced pressure to give 4-(p-tolyloxy)pyrimidine-5-carbonitrile (41.6% yield) as a light brown solid which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.24 (s, 1H), 8.94 (s, 1H), 7.29 (dd, J=0.8, 8.6 Hz, 2H), 7.21-7.16 (m, 2H), 2.34 (s, 3H). MS (ESI) m/z 211.7 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.CC[N:17](CC)CC.ClC(OCC)=O.N.O>C1COCC1>[Br:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH2:17])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc(Cl)c(Br)cc1[N+](=O)[O-]
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cc(Cl)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
A mixture of 4-bromo-5-chloro-2-nitrobenzoic acid (1.3 g, 4.63 mmol), Et3N (1.4 g, 13.9 mmol) in THF (20 mL) at 0° C., ethyl chloroformate (1.5 g, 13.9 mmol) was added. The resulting mixture was stirred at 0° C. for 1 h. Then NH3.H2O (4 mL) was added and stirred for 0.5 h. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the crude product (900 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].CC(C)([O-])C.[K+].C1COCC1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[C:36]2[C:31](=[N:32][C:33](S(C)(=O)=O)=[N:34][CH:35]=2)[NH:30][N:29]=1>C(OCC)(=O)C.[Cl-].[NH4+].O>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[C:36]2[C:31](=[N:32][C:33]([O:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[N:34][CH:35]=2)[NH:30][N:29]=1
Reactant: CS(=O)(=O)c1ncc2c(-c3ccccc3Cl)n[nH]c2n1
Reactant: Oc1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc(Oc2ncc3c(-c4ccccc4Cl)n[nH]c3n2)c(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 158.8 %

Procedure:
To a neat sample of 2,4-difluorophenol (Aldrich) (379 mg, 3 eq) in a Microwave Reactor Vessel, at 0° C. was added dropwise a 1.0 M potassium tert-butoxide solution in THF (2.9 mL, 3.05 eq). The mixture was stirred 5 minutes and then warmed to room temperature. Solid 3-(2-chlorophenyl)-6-methylsulfonyl-1H-pyrazolo[3,4-d]pyrimidine (300 mg, 0.971 mmol) was added and the reaction mixture was placed in a Microwave Reactor and heated at 120° C. for 15 minutes. The reaction mixture was diluted with ethyl acetate (50 mL), saturated aqueous ammonium chloride (10 mL) and water (40 mL). The mixture was partitioned and the organic layer was collected. The aqueous layer was extract with ethyl acetate (40 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to provide the crude compound. Purification by Preparative Thin Layer Chromatography eluting with 1.8% methanol in dichloromethane, followed by crystallization from methylene chloride/hexanes gave the title compound as a white powder (553 mg, (M+H)+=359, M.P.=173.4-176.4° C.).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[N:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[S:39][CH2:40][C:41](=[O:43])[N:42]=2)[CH2:34][C@@H:33]1[CH2:44][OH:45])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[S:39][C:40](=[CH:11][C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[N:4]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[C:21]([F:24])([F:22])[F:23])[N:3]=[C:2]4[Cl:1])[C:41](=[O:43])[N:42]=2)[CH2:34][C@@H:33]1[CH2:44][OH:45])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)CS2)C[C@@H]1CO
Reactant: O=Cc1ccc2c(c1)c(Cl)nn2Cc1ccc(Cl)cc1C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(c3)c(Cl)nn4Cc3ccc(Cl)cc3C(F)(F)F)S2)C[C@@H]1CO

Procedure:
4-{5-[3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and 2-(R)-Hydroxymethyl-4-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester following general procedure D.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:28])[C:15](=[O:27])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([SH:26])[CH:17]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37].CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:28])[C:15]([C:16]2[CH:17]=[C:18]([S:26][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=2)=[O:27])=[C:4]([O:29][CH3:30])[CH:3]=1
Reactant: O=C(O)CCCCBr
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(S)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCCCCC(=O)O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-3-mercapto-N-methyl-5-(trifluoromethyl)benzamide (0.115 g, 264 μmol, Example 216, intermediate a) in acetonitrile (2 mL) were added 5-bromopentanoic acid (59.6 mg, 329 μmol) and DIPEA (85.1 mg, 115 μL, 659 μmol). After the addition of DIPEA the white suspension turned to a light yellow solution, which was stirred at room temperature for 18 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC (Flashmaster) system eluting with a gradient of CH2Cl2:MeOH (100:0 to 0:0). The product was further purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless solid (0.10 g; 70%). MS (ESI): m/z=537.15 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[C:17](OS(C(F)(F)F)(=O)=O)=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:13]3)=[O:7])=[CH:4][CH:3]=1.[C-:32]#[N:33].[K+]>O1CCOCC1.[Cl-].[Na+].O.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>[F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[C:17]([C:32]#[N:33])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:26]([NH2:29])(=[O:27])=[O:28])=[CH:13]3)=[O:7])=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: NS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc2cc(S(N)(=O)=O)ccc2c1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A mixture of 5-(4-fluorobenzoyl)-6-trifluoromethyl-sulfonyloxy-2-naphthalenesulfonamide (1.0 g, 2.1 mmol) [pre pared as described in step 2 above], potassium cyanide (0.15 mg, 2.3 mmol), and tetrakis(triphenylphosphine)palladium(0) in dioxane (15 ml) was heated at reflux under argon. After 2 h, the reaction mixture was cooled to RT, poured into brine, and the product was extracted into ethyl acetate. The organic layer was dried with sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (gradient elution, 20-50% ethyl acetate/hexane) and then recrystallized from ethyl acetate-hexane to give 0.44 g of 5-(4-fluorobenzoyl)-6-cyano-2-naphthalenesulfonamide as a white solid (54% yield).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:19][C:20]([F:26])([F:25])[S:21](Cl)(=[O:23])=[O:22]>ClCCl>[F:19][C:20]([F:26])([F:25])[S:21]([O:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:23])=[O:22]
Reactant: COC(=O)c1ncccc1O
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ncccc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-hydroxypyridine-2-carboxylate (80 g, 523 mmol) in anhydrous dichloromethane (250 ml) was added triethylamine (58.2 g, 575 mmol). The solution was cooled to 0° C., and trifluoromethanesulfonyl chloride (97 g, 575 mmol) was added dropwise. The reaction suspension was allowed to stir at 0° C. for 1 h, and it was then warmed to rt to stir for 4 h. The solid triethylammonium chloride was removed via filtration, and the filtrate was concentrated in vacuo to yield methyl 3-{[(trifluoromethyl)sulfonyl]oxy}pyridine-2-carboxylate as an oily residue (148.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[NH:11][CH2:12][C:13](O)=[O:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1(S(O)(=O)=O)C=CC=CC=1.O>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH2:12][NH:11][C:10]2=[O:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)CNC(=O)Nc1cc(Cl)cc(Cl)c1
Agent: O=S(=O)(O)c1ccccc1
Solvent: O
Solvent: Clc1ccccc1
Product: O=C1CNC(=O)N1c1cc(Cl)cc(Cl)c1
Temperature: 15 °C
Yield: 90.6 %

Procedure:
To a suspension of 3-(3,5-dichlorophenyl)-ureidoacetic acid (26.3 g.) in chlorobenzene (180 cc.) is added benzenesulphonic acid (1.2 g. representing 0.068 mol per mol of ureidoacetic acid). The water formed in the reaction is removed by azeotropic distillation. After 30 minutes' distillation, a limpid solution is obtained. After cooling to about 15° C, the precipitate formed is filtered off and washed on the filter with ethanol (25 cc.) at 10° C. After drying, 3-(3,5-dichlorophenyl)-hydantoin (22.2 g.) melting at 199° C is obtained. Yield: 90.5%.