Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2]C(Cl)(Cl)Cl.[NH2:7][CH2:8][C:9]1([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C(Cl)(Cl)Cl>[CH:2]([NH:7][CH2:8][C:9]1([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:1]
Reactant: NCC1(N2CCCCC2)CCCCC1
Reactant: O=CC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=CNCC1(N2CCCCC2)CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
Chloral (4.65 g.) was added dropwise to a cooled solution of 1-[1-(aminomethyl)cyclohexyl]piperidine (5.9 g) in dry chloroform (30 ml). The mixture was stirred at room temperature for 16 hrs. and then heated under reflux for 30 mins. The solution was evaporated to dryness and the oily residue re-evaporated with ether. This residual brown oil (7.9 g) was distilled under high vacuum to give a viscous pale yellow oil of 1-[1-(formamidomethyl)cyclohexyl)piperidine (5.1 g.) b.p. 170°-2° C. at 1.7 mm.
Reaction SMILES: [CH3:1][NH2:2].C(O)C.Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][C:17]([C:19]3[C:20]([NH2:37])=[N:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[CH:27][CH:26]=4)[N:24]=3)=[N:16][N:15]=2)=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CO>[CH:34]([S:31]([C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:19]([C:17]3[O:18][C:14]([C:11]4[CH:10]=[CH:9][C:8]([CH2:7][NH:2][CH3:1])=[CH:13][CH:12]=4)=[N:15][N:16]=3)[C:20]([NH2:37])=[N:21][CH:22]=2)=[CH:26][CH:27]=1)(=[O:33])=[O:32])([CH3:35])[CH3:36]
Reactant: CN
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccc(CBr)cc4)o3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CNCc1ccc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc3N)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
MeNH2 in ethanol (184.9 g, 243.6 mL of 33% w/w, 1.965 mol) was added in one portion to a stirred solution of 3-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]-5-(4-isopropylsulfonylphenyl)pyrazin-2-amine (10.11 g, 19.65 mmol) in CH2Cl2 (1.01 L) and methanol (1.01 L) and the resulting mixture stirred overnight at room temperature. Nitrogen was bubbled through reaction for 2 h and then the reaction mixture was concentrated in vacuo. The crude material was stirred in K2CO3 (393.0 mL of 0.25 M, 98.25 mmol) for 2 h and then isolated by filtration and washed with water. Triturated with warm acetonitrile to leave the product as a yellow solid (7.19 g, 75% yield); 1H NMR (400 MHz, DMSO) d 1.19-1.21 (d, 6H), 2.30 (m, 3H), 3.35-3.49 (m, 1H), 3.77 (m, 2H), 7.61-7.63 (d, 2H), 7.97-7.99 (d, 2H), 8.11-8.13 (d, 2H), 8.39-8.41 (d, 2H) and 9.06 (s, 1H) ppm; MS (ES+) 465.4
Reaction SMILES: [NH2:1][C:2](=[O:106])[CH2:3][NH:4][C:5](=[O:105])[C@@H:6]([NH:13][C:14](=[O:104])[C@@H:15]([N:17]([CH3:103])[C:18]([C@H:20]([CH2:92][C:93]([O:95]CC1C=CC=CC=1)=[O:94])[NH:21][C:22](=[O:91])[C@H:23]([CH2:84][C:85]1[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=1)[NH:24][C:25](=[O:83])[C@H:26]([CH:80]([CH3:82])[CH3:81])[NH:27][C:28](=[O:79])[C@H:29]([CH3:78])[NH:30][C:31](=[O:77])[C@H:32]([CH2:73][CH:74]([CH3:76])[CH3:75])[NH:33][C:34](=[O:72])[CH2:35][NH:36][C:37](=[O:71])[C@H:38]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[N:39]([CH3:63])[C:40](=[O:62])[C@H:41]([CH3:61])[NH:42][C:43](=[O:60])[C@H:44]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:19])[CH3:16])[CH2:7][O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(OCC)(=O)C.[H][H]>CO.O[Pd].[C]>[NH2:1][C:2](=[O:106])[CH2:3][NH:4][C:5](=[O:105])[C@@H:6]([NH:13][C:14](=[O:104])[C@@H:15]([N:17]([CH3:103])[C:18]([C@H:20]([CH2:92][C:93]([OH:95])=[O:94])[NH:21][C:22](=[O:91])[C@H:23]([CH2:84][C:85]1[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=1)[NH:24][C:25](=[O:83])[C@H:26]([CH:80]([CH3:82])[CH3:81])[NH:27][C:28](=[O:79])[C@H:29]([CH3:78])[NH:30][C:31](=[O:77])[C@H:32]([CH2:73][CH:74]([CH3:75])[CH3:76])[NH:33][C:34](=[O:72])[CH2:35][NH:36][C:37](=[O:71])[C@H:38]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[N:39]([CH3:63])[C:40](=[O:62])[C@H:41]([CH3:61])[NH:42][C:43](=[O:60])[C@H:44]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[NH:45][C:46](=[O:52])[O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:19])[CH3:16])[CH2:7][O:8][C:9]([CH3:10])([CH3:11])[CH3:12]
Reactant: [H][H]
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](COC(C)(C)C)C(=O)NCC(N)=O)C(C)C
Agent: O[Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(=O)O)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](COC(C)(C)C)C(=O)NCC(N)=O)C(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 83 %

Procedure:
Hydroxypalladium/carbon (277 mg, 50% wet w/w) was added to a solution of benzyl (6S,9S,12S,18S,21S,24S,27S,30S)-30-(((S)-1-(((S)-1-((2-amino-2-oxoethyl)amino)-3-(tert-butoxy)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamoyl)-6,12,27-tribenzyl-18-isobutyl-24-isopropyl-2,2,9,11,21-pentamethyl-4,7,10,13,16,19,22,25,28-nonaoxo-3-oxa-5,8,11,14,17,20,23,26,29-nonaazadotriacontan-32-oate synthesized according to a conventional method (Boc-Phe-Ala-MePhe-Gly-Leu-Ala-Val-Phe-Asp(OBn)-MeAla-Ser(OtBu)-Gly-NH2) (Compound SP-506) (831 mg, 0.563 mmol) in methanol (5 ml)-ethyl acetate (5 ml) under a nitrogen atmosphere, the atmosphere was replaced with hydrogen, and the mixture was then stirred at room temperature for 3.5 hours. The reaction solution was then filtered through celite, and the filtrate was concentrated under reduced pressure to afford the title compound (SP-505) (648 mg, 83%).
Reaction SMILES: Br.[Br:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5].[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([NH:20][C:21](=[O:38])[O:22][CH:23]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)[CH2:13]2.CCOCC>C(OCC)(=O)C>[Br-:2].[F:37][C:33]1[CH:32]=[C:31]([CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[O:22][C:21]([NH:20][C@@H:14]2[CH:15]3[CH2:16][CH2:17][N+:12]([CH2:3][C:4](=[O:5])[C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=4)([CH2:19][CH2:18]3)[CH2:13]2)=[O:38])[CH:36]=[CH:35][CH:34]=1
Reactant: O=C(N[C@H]1CN2CCC1CC2)OC(c1cccc(F)c1)c1cccc(F)c1
Reactant: O=C(CBr)c1ccccn1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(N[C@H]1C[N+]2(CC(=O)c3ccccn3)CCC1CC2)OC(c1cccc(F)c1)c1cccc(F)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.6 %

Procedure:
2-Bromo-1-(pyridin-2-yl)ethanone hydrobromide (39.2 mg, 0.14 mmol) was added to a solution of (R)-bis(3-fluorophenyl)methyl quinuclidin-3-ylcarbamate (52 mg, 0.14 mmol, prepared as in example 1) in ethyl acetate (2 ml). The reaction was stirred at room temperature for 16 hours, then Et2O (1 mL) was added, and the precipitate was collected by suction filtration and dried under vacuum at 40° C. overnight. The product was further purified by preparative HPLC to obtain (R)-3-((bis(3-fluorophenyl)methoxy)-carbonylamino)-1-(2-oxo-2-(pyridin-2-yl)ethyl)-1-azoniabicyclo[2.2.2]octane bromide (16.5 mg).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][C@H:28]1[CH2:33][NH:32][C@H:31]([CH3:34])[CH2:30][N:29]1[C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:32]2[CH2:33][C@@H:28]([CH3:27])[N:29]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]=3)[CH2:30][C@@H:31]2[CH3:34])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: C[C@@H]1CN(c2ccc3ccccc3n2)[C@@H](C)CN1
Product: C[C@@H]1CN(CCCCC2(C(=O)NCC(F)(F)F)c3ccccc3-c3ccccc32)[C@@H](C)CN1c1ccc2ccccc2n1

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(trans-2,5-dimethyl-piperazin-1-yl)-quinoline.
Reaction SMILES: [CH3:1][C:2]([S:28]([CH3:31])(=[O:30])=[O:29])([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][C:16]=1[CH3:27])[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].Cl.O1CCOCC1.CO>ClCCl>[OH:6][NH:5][C:3](=[O:4])[C:2]([CH3:1])([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][C:16]=1[CH3:27]
Reactant: Cc1cc(-c2ccccc2)ccc1CCC(C)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(-c2ccccc2)ccc1CCC(C)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 5.8 %

Procedure:
2-Methyl-4-(3-methylbiphenyl-4-yl)-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (170 mg, 0.382 mmol) was dissolved in 5 mL of dichloromethane at ambient temperature. To this was added a 4M HCl solution in dioxane (2.86 mL, 11.5 mmol) and the reaction was stirred at ambient temperature for 5 minutes. 0.5 mL of methanol was then added followed by silica gel and the mixture was concentrated to dryness. Silica chromatography (100% dichloromethane to 96% DCM 4% MeOH over 60 minutes) yielded product that contained impurities and was further triturated with a solution of 4:1 heptane:isopropanol afforded the title compound as a white solid (8 mg, 6%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:26])[N:15]4[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20][C:16]4=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:28][OH:29].C([O-])([O-])=O.[Na+].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:26])[N:15]4[CH2:24][CH2:23][C:22](=[N:28][OH:29])[CH2:21][CH2:20][C:16]4=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCc2nc3cc(C#Cc4cccc(F)c4)ccc3c(=O)n2CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=c1c2ccc(C#Cc3cccc(F)c3)cc2nc2n1CCC(=NO)CC2
Reaction time: 8 h

Procedure:
3-((3-fluorophenyl)ethynyl)-6,7,9,10-tetrahydroazepino[2,1-b]quinazoline-8,12-dione (0.1, 0.29 mmol, 1 equiv) was combined with hydroxylamine hydrochloride (40 mg, 0.58 mmol, 2 equiv) and aqueous Na2CO3 (0.5 mL) in a mixture of MeOH (10 mL) and water (1 mL). The mixture was stirred overnight. Then the reaction mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the desired product, which was purified by silica gel chromatography. MS (ESI): 362 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 8.15-8.13 (d, J=7.80 Hz, 1H), 7.76 (s, 1H) 7.64-7.59 (d, J=8.10 Hz, 1H), 7.52-7.48 (m, 3H), 7.36-7.33 (m, 1H), 4.46-4.35 (m, 2H), 3.15-3.08 (m, 2H), 2.84-2.73 (m, 2H), 2.59-2.55 (m, 2H). mGluR5 PAM EC50: +++. Fold shift at 10 μM: ++.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:16]([O:15][C:9](=[O:14])[C:10](=[CH:3][N:4]([CH3:5])[CH3:6])[C:11]([CH3:13])=[O:12])[CH3:17]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(=CN(C)C)C(C)=O
Reaction time: 3 h
Yield: 71.6 %

Procedure:
A mixture of 200 g (1.68 moles) of N,N-dimethylformamide dimethyl acetal, 145.68 g (1.12 moles) of ethyl acetoacetate, and 0.5 g (0.003 mole) of p-toluenesulfonic acid monohydrate was heated in a water bath with stirring for three hours. The color of the reaction mixture changed progressively from orange to red and finally to brown. Heating was discontinued, and the reaction mixture was allowed to sit at room temperature for approximately 18 hours. At the conclusion of this period, the mixture was distilled under vacuum, and six fractions having a boiling point in the range 145°-150° C. were analyzed by NMR spectroscopy. The NMR spectrum of each fraction was consistent with the proposed structure. These fractions were combined, yielding a total of 148.51 g of ethyl-2-dimethylaminomethyleneacetoacetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](I)[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:19][CH3:20])=[C:6]([F:11])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(F)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)OC)cc1F
Yield: 100.7 %

Procedure:
A solution of 3-fluoro-4-hydroxy-benzoic acid methyl ester (1.5 g, 8.82 mmol), K2CO3 (2.43 g, 17.6 mmol) and ethyliodide (2.75 g, 17.6 mmol) in DMF (15 ml) was heated to 80° C. for 2 hrs. Addition of excess Na2CO3 and extraction with EtOAc followed by washing with satd. NaCl, then drying with Na2SO4 and evaporation afforded the title compound (1.76 g, 101% yield) as an orange oil. MS: m/e=170 (M+).
Reaction SMILES: [OH-].[Na+:2].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1>O>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([O-:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1.[Na+:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Reaction time: 0.5 h

Procedure:
4 N Aqueous solution of sodium hydroxide was carefully added dropwise to a stirred suspension of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 52 g.) in water (100 ml.) below 5° C. to make a solution of pH 7.0 to 7.5. After filtration and washing, the combined filtrate and the washings (200 ml.) was added dropwise to ethanol (2 l.) under stirring over 30 minutes, and stirred at room temperature for 15 minutes and then at 5° to 10° C. for an hour. The precipitates were collected by filtration, washed with ethanol (200 ml.) and dried in vacuo at 30° C. to give amorphous sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 46.3 g.).
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13](Cl)(=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]>>[C:13]([O:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:1]([OH:3])(=[O:5])=[O:2])(=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: O=S(=O)(O)O
Reactant: Oc1ccccc1
Reactant: CC(C)CCCCCC(=O)Cl
Product: CC(C)CCCCCC(=O)Oc1ccccc1S(=O)(=O)O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
107 parts by weight of 96% sulfuric acid are added dropwise within 30 minutes to 94 parts by weight of phenol at a temperature between 40° and 50° C. The mixture is then stirred for a further 2 hours at 80° C. and 182 parts by weight of isononanoic acid chloride are then added dropwise at 40° to 45° C. within 1 hour and the mixture is stirred for 1 further hour. This gives an isononanoyloxybenzenesulfonic acid having an AS content of 40% which further drops on standing at 25° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:13]2[CH2:16][CH:15]([OH:17])[CH2:14]2)[C:5]([O:11][CH3:12])=[C:6]([CH:8](O)[CH3:9])[CH:7]=1.N1C(Cl)=NC(Cl)=NC=1[Cl:21]>CS(C)=O.CCOCC.O>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:13]2[CH2:16][CH:15]([OH:17])[CH2:14]2)[C:5]([O:11][CH3:12])=[C:6]([CH:8]([Cl:21])[CH3:9])[CH:7]=1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1C1CC(O)C1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1C1CC(O)C1
Reaction time: 8 h
Yield: 40.3 %

Procedure:
To a solution of 3-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]cyclobutanol (170 mg, 0.628 mmol) in dimethyl sulfoxide (1 mL) was added cyanuric chloride (64 mg, 0.34 mmol). After stirred overnight, the reaction mixture was diluted with ether and water. The aqueous layer was extracted with ethyl acetate once. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified with silica gel column to give the desired product (39.6 mg, 22%). LCMS calculated for C14H18ClO2(M−Cl)+: m/z=253.1; Found: 253.2.
Reaction SMILES: O1C2C(=CC=CC=2)C(=O)C(C(O)=O)=C1.S(Cl)(Cl)=O.[O:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[C:21]([C:30]([NH2:32])=O)=[CH:20]1>CN(C)C=O>[C:30]([C:21]1[C:22](=[O:29])[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:19][CH:20]=1)#[N:32]
Reactant: NC(=O)c1coc2ccccc2c1=O
Agent: O=C(O)c1coc2ccccc2c1=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: N#Cc1coc2ccccc2c1=O
Yield: 75 %

Procedure:
The present invention concerns a novel method of preparing these 3-cyanochromones from chromone-3-carboxylic acids. The reaction mechanism of the present invention may best be described by the following reaction scheme: ##STR4## Referring to the reaction scheme, chromone-3-carboxylic acid is initially converted to the acyl chloride by treating with thionyl chloride as disclosed in U.S. Pat. No. 3,849,446 to Von Strandtmann, et al., issued Nov. 19, 1974. The acyl chloride is then converted to the corresponding chromone-3-carboxamide, as disclosed in U.S. Pat. No. 3,862,143. The critical feature of the present invention is the further dehydration of the chromone-3-carboxamide with thionyl chloride in N,N-dimethylformamide to give the desired 3-cyanochromone in a high yield of at least 75%. Generally, a molar excess of thionyl chloride and a 30-40 molar excess of N,N-dimethylformamide are employed.
Reaction SMILES: [CH2:1]([C:3]1([C:36]([O:38]CC)=[O:37])[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:29]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[C:18]4[NH:19][C:20]([NH:22][C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[N:21][C:17]=4[CH:16]=3)=[CH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2].CC(C)([O-])C.[K+].O>CS(C)=O>[CH2:1]([C:3]1([C:36]([OH:38])=[O:37])[CH2:8][CH2:7][N:6]([C:9]2[N:10]=[CH:11][C:12]([C:15]3[CH:29]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[C:18]4[NH:19][C:20]([NH:22][C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[N:21][C:17]=4[CH:16]=3)=[CH:13][N:14]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)OCC)CC4)nc3)cc(-c3ccccn3)c2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)O)CC4)nc3)cc(-c3ccccn3)c2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.5 %

Procedure:
To an ice-cold solution of ethyl 4-ethyl-1-(5-(2-(3-ethylureido)-7-(pyridin-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)piperidine-4-carboxylate (0.20 g, 0.37 mmol) in DMSO (3.0 mL) was added potassium tert-butoxide (0.2.06 g, 1.84 mmol) and the mixture stirred at rt for 16 h. After completion of reaction (by TLC), water (10 mL) was added followed by extraction with EtOAc (3×25 mL) and the organic layer discarded. The pH of the aqueous layer was adjusted up to 4-5, extracted with EtOAc (3×25 mL) and the combined organic layer dried over Na2SO4, filtered and evaporated under reduced pressure. The residue thus obtained was triturated with n-pentane to afford Compound 229 as yellow solid (0.10 g, 53%). 1H NMR (DMSO-d6+D2O): δ 8.78 (m, 3H), 8.38 (m, 1H), 7.95-8.0 (m, 2H), 7.69 (s, 1H), 7.39 (br s, 1H), 4.44 (m, 2H), 3.22 (m, 2H), 3.13 (m, 2H), 2.06 (m, 2H), 1.51 (m, 2H), 1.34 (m, 2H), 1.11 (t, J=7.20 Hz, 3H) and 0.80 (t, J=7.20 Hz, 3H). LCMS: 515.19 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C1(O)C=CC=CC=1.[OH-].[Na+]>Br>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(S(=O)(=O)c3cccc(Cl)c3)C2)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Product: Cl
Product: O=S(=O)(c1cccc(Cl)c1)C1CCCNC1

Procedure:
A mixture of 13.79 g (0.033 mole) of 3-[(3-chlorophenyl)sulfonyl]-1-[(4-methylphenyl)sulfonyl]piperidine and excess phenol in 300 ml of 48% hydrobromic acid was refluxed for 11/2 hr and then was poured over ice. The aqueous mixture was made basic with 50% sodium hydroxide and extracted with methylene chloride. The methylene chloride extract was dried over magnesium sulfate and the solvent was evaporated in vacuo to give an oil, the free base of the title compound. A solution of the oil in methanol was treated with excess ethereal hydrogen chloride, ether was added to give the hydrochloric acid salt which was recrystallized from methanol-ether to give 8.03 g (81.5%) white crystals, m.p. 179°-181° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([O:8]C(=O)C)[C@@H:5]([CH3:12])[C@@H:4]([O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:3]1.[C:31]([O-])([O-])=[O:32].[K+].[K+].O.CC[O:40]CC>CO>[Si:14]([O:13][C@@H:4]1[C@H:5]([CH3:12])[C@H:6]([OH:8])[CH2:7][C@H:2]([C:1]([O:32][CH3:31])=[O:40])[CH2:3]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(=O)O[C@@H]1C[C@H](C)C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H]1C
Reactant: O=C([O-])[O-]
Reactant: CCOCC
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H]1C[C@@H](O)[C@@H](C)[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Reaction time: 0.17 h

Procedure:
To a stirred suspension of 2.1.c (R=Me, P=TBDPS, A=COOCH3) (392 mg, 0.992 mmol) in 10 ml of dry MeOH at room temperature was added dry K2CO3 (30 mg). After 10 min., a second portion of K2CO3 (19 mg) (total: 49 mg, 0.496 mmol) was added. The mixture was stirred for 6 h, then poured into water and Et2O (70 ml:50 ml). The organic layer was separated and the aqueous layer was extracted with Et2O (50 ml×3) and dried over MgSO4. Separation by flash chromatography on silica (isooctane/EtOAc) 9:1), gave hydroxy compound 2.2.c (R=Me, P=TBDPS, A=COOCH3) (344 mg, 98%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([NH:19][CH3:20])(=[O:18])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:30](S(Cl)(=O)=O)[CH2:31][CH2:32][CH2:33][CH3:34].C1(NC)CCCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([NH:19][CH2:20][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:17])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCCCCS(=O)(=O)Cl
Reactant: CNS(=O)(=O)CCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: CNC1CCCC1
Product: C[C@H](CCCS(=O)(=O)NCC1CCCC1)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 15 %

Procedure:
4-chloro-N-[2,5-dichlorophenyl]-N-[4-[[N-(cyclopentyl)methylamino]sulfonyl]-1(R)-methylbutyl]benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[4-[(methylamino)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide by reacting (4R)-4-[2,5-dichlorophenyl][4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride with N-(cyclopentyl)-methylamine. Yield=15%; MS (ESI+), 567 (M+H)+.