Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:5]=1[Cl:19].[C:21](=O)([O-])[O-].[Cs+].[Cs+].Cl[C:28]1[CH:33]=[CH:32][C:31](C)=[CH:30][N:29]=1>O1CCOCC1.C(#N)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:31]2[CH:30]=[N:29][C:28]([CH3:21])=[CH:33][CH:32]=2)[CH:7]=[CH:6][C:5]=1[Cl:19]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1Cl
Reactant: Cc1ccc(Cl)nc1
Agent: [Pd]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccc(C)nc2)ccc1Cl
Temperature: 25 °C
Yield: 31.5 %

Procedure:
To a mixture of 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (628 mg, 2.12 mmol), cesium carbonate (1.38 g, 4.25 mmol), tetrakis(triphenylphosphine) palladium (62 mg, 0.08 mmol) and molecular sieves (2 g, 4 Å) in 1,4-dioxane (10 mL) was added 2-chloro-5-methylpyridine (226 mg, 1.77 mmol). The mixture was stirred for a few minutes at room temperature then warmed to 80° C. for 4 h. A further portion of tetrakis(triphenylphosphine) palladium (120 mg, 0.10 mmol) was added and the resulting mixture was stirred at 80° C. for 16 h. A second portion of 2-chloro-5-methylpyridine (117 mg, 0.66 mmol) was added. The resulting mixture was stirred at 80° C. for a further 5 h. The reaction mixture was diluted with acetonitrile (30 mL) and filtered through a pad of celite. The filtrate was concentrated in vacuo and purified by flash column chromatography (gradient 5-100% ethyl acetate-hexane) to afford the title compound (146 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].Cl[C:13]1[C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1>O.[OH-].[Na+]>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:13]1[C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: O=C(O)c1cccnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1[nH]cnc1CSCCNc1ncccc1C(=O)O

Procedure:
An intimate mixture of powdered 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.71 g; 0.010 moles) and 2-chloropyridine-3-carboxylic acid (1.73 g; 0.011 moles) was heated to 150° for 6 hours. The resulting cooled glass was dissolved in a little water and neutralised by slow addition of 2 N sodium hydroxide solution. At pH6, solid precipitated out of solution. This was filtered off, and recrystallised from water to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amino pyridine 3-carboxylic acid as small, colourless crystals (1.04 g) which sublimed at 98°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[NH:4][C@@H:5]([CH2:23][CH2:24]SC)[C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10]1)=[O:7].C(Cl)Cl.CI>CO>[CH3:1][O:2][C:3](=[O:27])[NH:4][C@H:5]1[CH2:23][CH2:24][N:8]([C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10]2)[C:6]1=[O:7]
Reactant: COC(=O)N[C@@H](CCSC)C(=O)N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: CO
Solvent: CI
Product: COC(=O)N[C@H]1CCN([C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl[(2S)-1-({trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}amino)-4-(methylsulfanyl)-1-oxobutan-2-yl]carbamate (2.0 g), methylene chloride (20 mL) and methanol (20 mL) was added methyl iodide (15.5 mL), followed by stirring at room temperature overnight. The solvent was evaporated under reduced pressure, and to a mixture of the residue and dimethylformamide (10 mL) was added cesium carbonate (4.8 g), followed by stirring overnight. To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and then the solvent was evaporated under reduced pressure. To the residue was added ethanol, and the resulting solid was collected by filtration and dried under reduced pressure to obtain methyl[(3S)-1-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-2-oxopyrrolidin-3-yl]carbamate (0.65 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[C:12]([N:31]2C[CH2:34][C@@H:33]([OH:36])[CH2:32]2)=[N:13][CH:14]=[C:15]([CH:30]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)=[O:17].Cl.OC1CNC1>CC(O)C.CCOC(C)=O>[Br:10][C:11]1[C:12]([N:31]2[CH2:34][CH:33]([OH:36])[CH2:32]2)=[N:13][CH:14]=[C:15]([CH:30]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:21][CH:20]=1)=[O:17]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl
Agent: OC1CNC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(O)C2)c(Br)c1
Temperature: 140 °C
Reaction time: 1.5 h

Procedure:
DIPEA (3.67 mL, 21.0 mmol) was added to (R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.2, 2.77 g, 7.0 mmol) and 3-hydroxyazetidine HCl (0.920 g, 8.40 mmol) in iPrOH (7.0 mL) in a vial which was sealed and the RM mixture was stirred at 140° C. for 1.5 h. After cooling to RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the title product as a yellow foam. HPLC (Condition 4) tR=5.37 min, UPLC-MS (Condition 3) tR=1.09 min, m/z=432/434 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=C[C:19]([C:22]3[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:26][CH:27]=3)=[CH:18][C:17]=2F)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O.C(#[N:54])C>O>[CH3:31][S:28]([N:25]1[CH2:26][CH:27]=[C:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:11]3[CH2:10][CH2:9][N:8]([CH2:45][C:46]([F:49])([F:48])[F:47])[CH2:13][CH2:12]3)=[CH:21][N:54]=2)[CH2:23][CH2:24]1)(=[O:30])=[O:29]
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(C3=CCN(S(C)(=O)=O)CC3)cc2F)CC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)N1CC=C(c2ccc(OCC3CCN(CC(F)(F)F)CC3)cn2)CC1
Temperature: 85 °C

Procedure:
To a solution of Preparation 6 (0.05 g, 0.14 mmol) in acetonitrile (1.50 mL) are added potassium carbonate (0.07 g, 0.56 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.06 g, 0.28 mmol). The reaction mixture is heated at 85° C. for 1 h in a microwave, cooled to room temperature and diluted with water. The mixture is extracted with ethyl acetate and the combined organic extracts are dried over sodium sulfate, filtered, and concentrated. The residue is purified by flash column chromatography over silica gel to obtain 30 mg of the title compound as an off-white solid. MS (m/z) 433 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:21])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:20])=[CH:11]/[CH2:12][S:13][CH2:14][C@H:15]([NH2:19])[C:16]([OH:18])=[O:17].C([O-])([O-])=O.[K+].[K+].[C:29]1(=[O:36])[O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30]1.Cl>C1COCC1>[C:16]([C@@H:15]([NH:19][C:29](=[O:36])[CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:14][S:13][CH2:12]/[CH:11]=[C:10](\[CH3:20])/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:21])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:22])[CH3:1])([OH:18])=[O:17]
Reactant: O=C1CCCC(=O)O1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)CCCC(=O)O)C(=O)O
Temperature: 5 °C
Reaction time: 3 h

Procedure:
S-trans, trans-Farnesyl-L-cysteine (500 mg, 1.54 mmol) was dissolved in mixture of THF (6 mL) and first portion of K2CO3 (3 mmol) and the resulting solution was cooled to 5° C. with vigorous stirring. To this stirred solution glutaric anhydride (263 mg, 2.30 mmol) was added slowly while maintaining the pH at 9.0-9.5 with another portion of K2CO3 (3 mmol). The mixture was stirred at RT for 3 h, TLC showed completion of the reaction. The pH of the reaction mixture then adjusted to 2.0 by the addition of 2 N hydrochloric acid. The acidic solution was extracted with ethyl acetate (10 mL×3). The combined organic extract was washed with water, brine and dried over Na2SO4, the solvent was removed on rotary evaporator to afford crude Compound E, which was further purified by preparative HPLC (459 mg, 68%) to yield Compound E. 1H-NMR (500 MHz, CD3OD): δ 1.60 (s, 6H), 1.70 (s, 3H), 1.72 (s, 3H), 2.02-1.95 (m, 4H), 2.15-2.05(m, 4H), 2.32 (t, 2H), 2.40 (t, 2H), 2.75 (m, 2H), 3.05 (dd, 1H), 3.15 (dd, 1H), 3.30 (d, 2H), 4.60 (dd, 1H), 5.14 (t, 2H), 5.25 (t, 1H). 13C-NMR (125 MHz, CD3OD): δ 16.1, 17.7, 18.4, 22.2, 26.3, 27.4, 27.7, 35.7, 40.6, 53.3, 121.5, 125.2, 125.4, 131.8, 136.1, 140.1, 173.7, 175.3, 177.6; ES-MS: mass calcd for Chemical Formula: C23H37NO5S 439.6. Found (M+Na) m/z 462.3.
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:6]=[C:7]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:14])=[O:13])[CH:8]=[N:9][C:10]=1Cl.[NH2:23][NH2:24]>O>[Cl:4][C:5]1[CH:6]=[C:7]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:14])=[O:13])[CH:8]=[N:9][C:10]=1[NH:23][NH2:24]
Reactant: NN
Reactant: O=S(=O)(Nc1cccc(O)c1)c1cnc(Cl)c(Cl)c1
Solvent: CCO
Solvent: O
Product: NNc1ncc(S(=O)(=O)Nc2cccc(O)c2)cc1Cl
Yield: 80.3 %

Procedure:
To 500 ml ethanol was added 5,6-dichloro-3'-hydroxy-3-pyridinesulfonanilide (10.4 g, 42 mmol) and 95 percent hydrazine (60 mmol). The reaction mixture was refluxed overnight. The completely reacted mixture was chilled, and the precipitate was filtered off and washed with ethanol. The filtrate was concentrated so as to obtain a second crop, yielding a total of 16.5 g. The solid was stirred in 250 ml of water to remove any salts. The product was filtered, washed with water, and dried under vacuum at 50° C. to give 10.61 g (80 percent) of pure product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][NH:10][C:11](=[O:12])[C:3]=12.C(N(C(C)C)CC)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][N:10]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:11](=[O:12])[C:3]=12
Reactant: Cc1cc(C)c2c(=O)[nH]sc2n1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cn1sc2nc(C)cc(C)c2c1=O
Reaction time: 5 h
Yield: 51.5 %

Procedure:
To enhance the selectivity of N-alkylation over O-alkylation, pyridinothiazolone 4 (500 mg, 2.77 mmol) was suspended in CH2Cl2 (20 mL) containing of diisopropylethylamine (DIEA, 1.5 mL, 8.61 mmol) and Cs2CO3 (700 mg, 3.07 mmol). Methyl 2-bromoacetate (900 mg, 5.88 mmol) was then added at room temperature. The mixture was stirred for 5 h, concentrated under reduced pressure, and purified by chromatography on a silica gel column with elution of EtOAc/hexane (1:4) to give the title compound 7 (360 mg, 55% yield) accompanied by an O-alkylation side product (7%). Compound 7: C11H12N2O3S; white solid; mp 89-91° C.; IR vmax (neat) 2928, 1766, 1728, 1664, 1561, 1523, 1435, 1375, 1324, 1210 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.92 (1H, s), 4.54 (2H, s), 3.76 (3H, s), 2.70 (3H, s), 2.57 (3H, s); 13C NMR (100 MHz, CDCl3) δ 167.4, 164.3, 162.6, 162.3, 149.6, 122.4, 113.8, 52.8, 44.2, 24.9, 17.8; ESI-HRMS calcd for C11H13N2O3S: 253.0647. found: m/z 253.0657 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C@H:22]([OH:24])[CH3:23])=[CH:17][CH:16]=1>>[OH:24][C@H:22]([CH3:23])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C[C@@H](O)Cc1ccc(N)cc1
Product: CC(=O)c1ccc(Nc2ccc(C[C@@H](C)O)cc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 1-(4-chloro-3-nitrophenyl)ethanone and (2R)-1-(4-aminophenyl)-2-propanol (step 2).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1)#[N:3].C[O:13][C:14](=O)[C:15]1[C:20]([I:21])=[C:19]([F:22])[CH:18]=[CH:17][C:16]=1[CH2:23]Br.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:22][C:19]1[C:20]([I:21])=[C:15]2[C:16]([CH2:23][N:3]([CH2:2][C:4]3[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=3)[C:14]2=[O:13])=[CH:17][CH:18]=1
Reactant: COC(=O)c1c(CBr)ccc(F)c1I
Reactant: N#Cc1ccc(CN)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(CN2Cc3ccc(F)c(I)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 25.5 %

Procedure:
A mixture of 4-cyano-benzyl amine hydrochloride (0.218 g, 5.0 mmol), 2-bromomethyl-5-fluoro-6-iodo-benzoic acid methyl ester (0.373 g, 1.0 mmol), and K2CO3 (0.276 g, 2 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. The resulting mixture was filtered and concentrated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 6-fluoro-7-iodo-2-(4-cyano-benzyl)-2,3-dihydro-isoindol-1-one (0.100 g, 26%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.19 (s, 2H), 4.84 (s, 2H), 7.22-7.68 (m, 6H). GC-MS: m/z 392 (M)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[NH3:15]>CO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH2:15])=[O:13])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: COC(=O)c1ccc2nccnc2c1
Solvent: CO
Product: NC(=O)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of methyl quinoxaline-6-carboxylate (2.00 g) in methanol (7.0 mL) and 28-30% ammonia (14 mL) was stirred in a sealed tube at room temperature for 16 h. The precipitated solid was filtered, washed with water and dried under high vacuum to give quinoxaline-6-carboxamide as a white powder. A portion of this material (0.10 g) was suspended in anhydrous dichloromethane and treated with oxalyl chloride (1.0 mL of a 2M solution in dichloromethane) under a nitrogen atmosphere. The mixture was heated at reflux for 16 h and concentrated under reduced pressure. The residue was dissolved in anhydrous tetrahydrofuran (1 mL) and added to an ice-cooled solution of 3-aminobiphenyl (0.98 g) in anhydrous tetrahydrofuran (1 mL). The mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue taken up in methanol and filtered to give N-{[(3-phenylphenyl)-amino]carbonyl}quinoxalin-6-ylcarboxamide as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH2:20][C@@H:21]3[N:27]([CH:28]=2)[C:26](=[O:29])[C:25]2[CH:30]=[C:31]([O:72][CH3:73])[C:32]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]4[C:69]([O:70][CH3:71])=[CH:68][C:42]5[C:43](=[O:67])[N:44]6[CH:59]=[C:58](S(C(F)(F)F)(=O)=O)[CH2:57][C@H:45]6[C:46](=[O:56])[N:47]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:41]=5[CH:40]=4)=[CH:33][C:24]=2[N:23]([CH2:74][O:75][CH2:76][CH2:77][Si:78]([CH3:81])([CH3:80])[CH3:79])[C:22]3=[O:82])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[NH2:1][C:2]1[CH:3]=[C:4]([C:58]2[CH2:57][C@@H:45]3[N:44]([CH:59]=2)[C:43](=[O:67])[C:42]2[CH:68]=[C:69]([O:70][CH3:71])[C:39]([O:38][CH2:37][CH2:36][CH2:35][O:34][C:32]4[C:31]([O:72][CH3:73])=[CH:30][C:25]5[C:26](=[O:29])[N:27]6[CH:28]=[C:19]([C:16]7[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=7)[CH2:20][C@H:21]6[C:22](=[O:82])[N:23]([CH2:74][O:75][CH2:76][CH2:77][Si:78]([CH3:79])([CH3:81])[CH3:80])[C:24]=5[CH:33]=4)=[CH:40][C:41]=2[N:47]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:53])([CH3:54])[CH3:55])[C:46]3=[O:56])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(S(=O)(=O)C(F)(F)F)C[C@H]5C(=O)N6COCC[Si](C)(C)C)cc4N(COCC[Si](C)(C)C)C(=O)[C@@H]3C2)cc1
Reactant: Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7cccc(N)c7)C[C@H]5C(=O)N6COCC[Si](C)(C)C)cc4N(COCC[Si](C)(C)C)C(=O)[C@@H]3C2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
Solid 3-aminobenzeneboronic acid (0.143 g, 0.92 mmol) was added to a solution of the mono triflate (17)(0.619 g, 0.58 mmol), sodium carbonate (195 mg, 1.84 mmol) and palladium tetrakis triphenylphosphine (26.6 mg, 0.023 mmol) in toluene (10 mL), ethanol (5 mL) and water (5 mL). The reaction mixture was allowed to stir at room temperature for overnight at 30° C. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulphate. Excess solvent was removed by rotary evaporation under reduced pressure and the resulting residue was subjected to flash column chromatography (silica gel; gradient elution EtOAc/hexane 70/3085/15). Removal of excess eluent from selected fractions afforded the desired product (0.502 g, 0.49 mmol, 85%).
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])(=[O:3])[NH2:2].[N+:14](=[CH2:16])=[N-:15]>C(OCC)C>[S:1]([C:5]1[CH:6]=[C:7]([C:8](=[O:9])[CH:16]=[N+:14]=[N-:15])[CH:11]=[CH:12][CH:13]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)c1cccc(C(=O)Cl)c1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)c1cccc(S(N)(=O)=O)c1

Procedure:
11 g of 3-sulfamoylbenzoyl chloride were reacted as prescribed in Example 66b) with diazomethane in diethyl ether and the crystals were filtered off. Melting point: 142° C.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([C@H:22]3[CH2:27][CH2:26][C@H:25]([O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[O:15])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[CH:17]=[CH:18][C:19]([C@H:22]3[CH2:27][CH2:26][C@H:25]([O:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CO[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
90 mg of tert-butyl trans-{4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]cyclohexyloxy}acetate (0.18 mmol, 1 eq.) are placed in 1 mL of dichloromethane. 0.13 mL of trifluoroacetic acid (1.77 mmol, 10 eq.) is added and the reaction medium is stirred for 18 hours at room temperature. The solvent is evaporated off. The residue is triturated in ethyl acetate and methanol to give 15 mg of trans-{4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]cyclohexyloxy}acetic acid.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].Cl[S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8].[NH2:13][CH2:14][CH:15]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1.C(N(CC)C(C)C)(C)C>ClCCl>[C:29]([O:28][C:27]([NH:26][CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)[CH2:14][NH:13][S:7]([NH:10][C:11](=[O:12])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:9])=[O:8])=[O:33])([CH3:30])([CH3:32])[CH3:31]
Reactant: CC(C)(C)O
Reactant: CC(C)(C)OC(=O)NC(CN)c1cccc(C(F)(F)F)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CNS(=O)(=O)NC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 110 mg (1.48 mmol) of tert-butanol in 2 ml of dichloromethane was cooled to 0° C. and admixed dropwise with a solution of 129 μl (1.48 mmol) of chlorosulphonyl isocyanate in 2 ml of dichloromethane. The mixture was stirred at RT for 1 h. In a syringe, 820 μl of this solution were taken and were added dropwise to a solution of 90 mg (296 μmol) of the compound from Example 22A in 2 ml of dichloromethane. Then 103 μl of N,N-diisopropylethylamine were added and the reaction mixture was stirred further at RT for 2 h. The volatile constituents were removed on a rotary evaporator. The residue was dissolved in a little acetonitrile and admixed with 1 ml of 1M hydrochloric acid, and the solution obtained was purified by preparative HPLC [Method 23]. The product-containing fraction was freed from the solvents on a rotary evaporator and the residue was dried in an HV. This gave 111 mg (76% of theory) of the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:9][CH:8]=1.N1C=CC=CC=1.Cl>O>[C:11]([C:10]1[CH:9]=[CH:8][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:20][CH:19]=1)(=[O:12])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(C(=O)c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
Methanesulfonyl chloride (35.0 g., 0.305 mole) is added dropwise over a 20 min. period with stirring to a solution of 4-aminobenzophenone (60.2 g., 0.305 mole) in 475 ml. of pyridine cooled at 0°-10°C. After the addition is completed, stirring at 0°-10°C. is continued for 4 hrs., and then for an additional 12 hrs. at room temperature. The solution is then heated to 90°C. for 1 hr., allowed to cool, poured into 1.0.1. of water, and then acidified with concentrated hydrochloric acid to pH 1.0. The precipitate which forms is collected on a filter, washed with water, and recrystallized from isopropanol without previous drying to give 70.0 g. (83% yield), m.p. 145-147°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:19]([N-]C(C)C)(C)[CH3:20].[Li+].ICC.[Cl-].[NH4+]>C1COCC1>[CH2:19]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:8][CH2:7]1)[CH3:20]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCOC(=O)C1(CC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
0.2 g (0.78 mmol) of tert-butyl 4-ethoxycarbonylpiperidine-1-carboxylate is dissolved in 4 mL of THF at −10° C. 0.8 mL (1.56 mmol) of lithium diisopropylamide is added dropwise. After 15 minutes, 0.09 mL (1.2 mmol) of iodoethane is added and the mixture is warmed to room temperature. It is stirred for 30 minutes and then poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried and then concentrated to dryness. The oil obtained is chromatographed on silica gel (eluent: 95/5 heptane/ethyl acetate). 183 mg of tert-butyl 4-ethyl-4-ethoxycarbonylpiperidine-1-carboxylate in the form of a yellow oil are obtained in a yield of 82%.