Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])=[C:4]([O:29][CH3:30])[CH:3]=1.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38].COC1CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>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.CCOC(C)=O>[Cl:31][C:32]1[CH:33]=[C:34]([C:2]2[CH:3]=[C:4]([O:29][CH3:30])[C:5]([N:9]3[C:18]4[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]5[CH:27]=[CH:26][O:25][N:24]=5)(=[O:21])=[O:20])=[CH:16][CH:17]=4)[CH:12]=[CH:11][C:10]3=[O:28])=[CH:6][C:7]=2[F:8])[CH:35]=[CH:36][C:37]=1[F:38]
Reactant: COc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COC1CCCC1
Product: COc1cc(-c2ccc(F)c(Cl)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 100 °C
Yield: 95.4 %

Procedure:
A vial was charged with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.310 g, 0.627 mmol). (3-chloro-4-fluorophenyl)boronic acid (0.175 g, 1.003 mmol), Pd(Ph3P)4 (0.072 g, 0.063 mmol). The vial was sealed with a septum cap and flushed with Ar (g), then CPME (3.14 ml) and sodium carbonate 1.9 M (0.990 ml, 1.881 mmol) were added via syringe. The mixture was heated to 100° C. for 1 h and then partitioned between water (20 mL) and EtOAc (30 mL). The layers were separated and the aqueous layer was acidified with 1N HCl. The aqueous layer was extracted with EtOAc (2×20 mL) and all the organic layers were combined, dried (Na2SO4) and concentrated for purification by MPLC (Biotage Isolera). The crude residue was taken up in minimal CH2Cl2 and absorbed onto a 5 g loading cartridge and passed through a Redi-Sep® Gold pre-packed silica gel column (40 g) using 90:10 Heptane: EtOAc to 100% EtOAc gradient to afford racemic 1-(3′-chloro-2,4′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.325 g, 0.598 mmol, 95% yield) as a light-yellow film. Racemic 1-(3′-chloro-2,4′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide was subjected to chiral separation by SFC using a Regis Whelk-0 (s,$) column and 50% MeOH in CO2. Peak 1 was (P)-1-(3′-chloro-2,4′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and peak 2 was (M)-1-(3′-chloro-2,4′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide. Data for peak 1: 1H NMR (500 MHz, DMSO-d6) δ 11.49-11.82 (br s, 1H), 8.71 (d, J=1.55 Hz, 1H), 8.37 (d, J=1.87 Hz, 1H), 8.17-8.28 (m, 1H), 7.94 (d, J=5.88 Hz, 1H), 7.86 (dd, J=1.98, 8.92
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH2:28]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[CH2:29][CH3:30]>C1COCC1>[CH2:28]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:34][CH:33]=1)[CH2:29][CH3:30]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCOc1ccc(C=O)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCOc1ccc(C=CCCCC(=O)O)cc1
Yield: 75.5 %

Procedure:
This compound was synthesized from 4-carboxybutyltriphenylphosphonium bromide (8.87 g, 20 mmol) and p-propoxybenzaldehyde (3.28 g, 20 mmol, synthesized from p-hydroxybenzaldehyde and 1-iodopropane) in THF (100 mL) by a Wittig reaction. Crystallization (petroleum ether) afforded the product (3.75 g, 76%) as white crystals (mp, 49-50° C.). IR: 3400-2500, 1725 cm-1 ; 1H-NMR: 1.00 (t, 3H), 1.75 (m, 4H), 2.35 (m, 4H), 3.90 (t, 2H), 5.55 (m, 1H), 6.35 (m, 1H), 7.00 (q, 4H), 11.30 (bs, 1H). Anal. Calcd. for C15H20O3 : C, 72.55, H, 8.12%; Found: C, 72.45, H, 8.13%. Z:E=35:65.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:32]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]5[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=5)=[CH:9][N:10]=4)[CH:7]=3)=[CH:31][CH:30]=[N:29]2)=[CH:26][CH:27]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(F)cc2)OC1(C)C
Reactant: CS(=O)(=O)c1ccc(-c2cnc3ccc(Br)cn23)cc1
Product: CS(=O)(=O)c1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(F)cc4)cn23)cc1

Procedure:
The title compound, white solid (79 mg, 64%), MS (ISP) m/z=433.6 [(M+H)+], mp 226° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridine (intermediate O) (0.1 g, 0.285 mmol) and 1-(4-fluoro-phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate A) (0.11 mg, 0.37 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.[CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(=O)(=O)(O)O>>[CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: c1ccccc1
Reactant: CC1=CCCCC1
Agent: O=S(=O)(O)O
Product: CC1(c2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 36.5 %

Procedure:
A mixed solution of 75.0 ml (632 mmol) of 1-methyl-1-cyclohexene and 56.4 ml (632 mmol) of benzene was added at 0° C. dropwise to 225.6 ml (2.53 mol) benzene solution of 231 g (2.36 mol) of sulfuric acid spending 1.5 hours, followed by stirring at 0° C. for 1.5 hours. The reaction solution was quenched by adding 300 ml of water, and the water layer was separated. The thus obtained organic layer was washed with 100 ml of saturated sodium hydrogen carbonate aqueous solution, 100 ml of water and 100 ml of saturated brine and dried with anhydrous sodium sulfate. After filtering the desiccant, the filtrate was concentrated to obtain crude 1-methylcyclohexylbenzene. By purifying the thus obtained crude 1-methylcyclohexylbenzene by distillation under a reduced pressure (from 110 to 113° C./10 mmHg), 40.2 g of the specified substance was obtained with a yield of 36.5%.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[CH2:27]([N:34]1[CH2:38][C@H:37]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([Cl:46])[CH:40]=2)[C@@H:36]([CH:47]=O)[CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([N:34]1[CH2:35][C@H:36]([CH:47]=[CH2:2])[C@@H:37]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([Cl:46])[CH:40]=2)[CH2:38]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a suspension of methyltriphenylphosphonium iodide (5.53 g, 0.0136 mol) in THF (50 mL) was added n-BuLi (1.6N in heptane, 6.5 mL, 0.0104 mol) dropwise at 0° C. and stirred for one hour. To this reaction mixture was added a solution of (3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carbaldehyde 2.68 g (0.008 mol) in THF (15 mL) dropwise at 0° C. and stirred for another one hour. The reaction was quenched by aq. ammonium chloride solution and extracted with ethylacetate. The separated organic layer was dired on anhydrous sodium sulfate and concentrated in vaccuo. The residue was purified by silica gel column chromatography eluted by a mixture of heptane and ethyl acetate (4:1) yielding 2.12 g (80%) of the title compound as a light yellow oil. ES-MS m/e: 332.1 (M+H+).
Reaction SMILES: [CH:1]1([C:5]#[N:6])[CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[O:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1.CN(C)P(N(C)C)(N(C)C)=O>C1COCC1>[OH:21][C:18]1([C:1]2([C:5]#[N:6])[CH2:4][CH2:3][CH2:2]2)[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1
Reactant: O=C1CCOCC1
Reactant: N#CC1CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#CC1(C2(O)CCOCC2)CCC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 44.1 %

Procedure:
To a solution of cyclobutanecarbonitrile (405 mg, 5 mmol) in THF (7 mL) was added 2.0M lithium diisopropylamide (2.5 ml, 5 mmol) dropwise at −78° C. and the reaction solution was stirred at −78° C. for 40 minutes. A solution of dihydro-2H-pyran-4(3H)-one (550 mg, 5.5 mmol) in hexamethylphosphoramide (268 mg, 1.5 mmol) was added and the mixture was warmed up to room temperature, and stirred for 3 hours. The reaction mixture was quenched with 1N aqueous HCl solution and extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (eluted with petroleum ether: EtOAc=20:1) to obtain the title compound as a corloless oil (0.40 g, yield 44%). 1H NMR (400 MHz, CDCl3): δ 3.97 (dd, J=11.4, 4.2 Hz, 1H), 3.60-3.50 (m, 2H), 3.40-3.33 (m, 1H), 2.66-2.57 (m, 2H), 2.30-2.16 (m, 3H), 1.99-1.87 (m, 2H), 1.72 (dd, J=8.8, 3.6 Hz, 2H), 1.63-1.58 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]2[CH:22]=[N:21][C:20]([C:23]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[OH:24])=[N:19]2)[CH2:13][CH2:12]1.[CH2:37]([O:44][C:45]1[CH:46]=[CH:47][C:48]([C@@H:56]([O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])[CH2:57]Br)=[C:49]2[C:54]=1[NH:53][C:52](=[O:55])[CH:51]=[CH:50]2)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([O:44][C:45]1[CH:46]=[CH:47][C:48]([C@@H:56]([O:59][Si:60]([C:63]([CH3:64])([CH3:66])[CH3:65])([CH3:62])[CH3:61])[CH2:57][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH:14]([CH2:17][N:18]3[CH:22]=[N:21][C:20]([C:23]([CH:31]4[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]4)([OH:24])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:19]3)[CH2:15][CH2:16]2)=[C:49]2[C:54]=1[NH:53][C:52](=[O:55])[CH:51]=[CH:50]2)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: NCCCCCCCCCN1CCC(Cn2cnc(C(O)(c3ccccc3)C3CCCCC3)n2)CC1
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCCCCCCCN1CCC(Cn2cnc(C(O)(c3ccccc3)C3CCCCC3)n2)CC1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Yield: 24 %

Procedure:
The title compound was prepared from (1-{[1-(9-aminononyl)piperidin-4-yl]methyl}-1H-1,2,4-triazol-3-yl)(cyclohexyl)phenylmethanol (Preparation 22, 150 mg, 0.303 mg) and 8-(benzyloxy)-5-[(1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl]quinolin-2(1H)-one (WO05/09286, 148 mg, 0.303 mmol) using the same method as described in preparation 7, to give a clear oil, in 24% yield, 66 mg.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][CH2:11][S:12][C:13]([F:16])([F:15])[F:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[F:35][C:36]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:37]=1[NH2:38]>C1COCC1.N#N>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]([C:17](=[O:19])[NH:38][C:37]1[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:36]=1[F:35])[CH2:10][CH2:11][S:12][C:13]([F:14])([F:15])[F:16])([CH3:5])([CH3:6])[CH3:7]
Reactant: Nc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N[C@@H](CCSC(F)(F)F)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CCSC(F)(F)F)C(=O)Nc1ccc(F)cc1F
Yield: 54.2 %

Procedure:
N-Boc-trifluoromethionine (212 mg, 0.851 mmol) was dissolved in dry THF in the presence of N2, and the temperature was adjusted to −78° C. Subsequently, N-methylmorpholine (0.11 ml, 1.000 mmol) was added thereto, and the mixture was stirred. Two minutes later, isobutyl chloroformate (0.13 ml, 0.999 mmol) was added thereto, and the mixture was stirred for 2 minutes. Finally, 2,4-difluoroaniline (0.10 ml, 0.982 mmol) was added thereto. TLC was performed to confirm disappearance of the starting compound, and the solid matters were filtered, followed by distillation of THF under reduced pressure. The residue was purified by column chromatography (Hex:AcOEt=80:20), thereby the product (191 mg, 54%) was obtained.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[O:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][CH:33]([C:36]([OH:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:41]1[N:46]2[CH:47]=[CH:48][N:49]=[C:45]2[CH:44]=[CH:43][CH:42]=1>O1CCOCC1.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.C1C=C(C([O-])=O)SC=1.[Cu+]>[N:49]1[CH:48]=[CH:47][N:46]2[C:41]([C:11]3[N:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[C:8]4[O:28][C:27]([CH2:29][N:30]5[CH2:31][CH2:32][CH:33]([C:36]([OH:39])([CH3:38])[CH3:37])[CH2:34][CH2:35]5)=[CH:26][C:9]=4[N:10]=3)=[CH:42][CH:43]=[CH:44][C:45]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2oc(CN3CCC(C(C)(C)O)CC3)cc2n1
Reactant: Brc1cccc2nccn12
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: CC(C)(O)C1CCN(Cc2cc3nc(-c4cccc5nccn45)nc(N4CCOCC4)c3o2)CC1
Yield: 42 %

Procedure:
A mixture of 2-[1-(4-morpholin-4-yl-2-tributylstannanylfuro[3,2-d]pyrimidin-6-ylmethyl)piperidin-4-yl]propan-2-ol (147 mg, 0.23 mmol), 5-bromoimidazo[1,2-a]pyridine (46 mg, 0.23 mmol), tetrakis(triphenylphosphine)palladium (22 mg, 8 mol %) and CuTC (9 mg, 20 mol %) in 1,4-dioxane (2.5 mL) was purged with argon gas then subjected to microwave irradiation at 140° C. for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), which was washed with MeOH/DCM before the desired product was eluted with 2 M NH3 in MeOH/DCM. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:NH3/MeOH (2 M); gradient from 100:0 to 96:4)), followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to afford 249 as a white foam (46 mg, 42%). LCMS (Method G): RT=3.47 min, M+H+=477. 1H NMR (CDCl3, 400 MHz) 9.14 (s, 1 H); δ 7.87 (dd, J=8.5, 1.19 Hz, 2 H); 7.76 (d, J=8.9 Hz, 1 H); 7.73 (d, J=1.3 Hz, 1 H); 7.30 (m, 1 H); 6.79 (s, 1 H); 4.11 (t, J=4.7 Hz, 4 H); 3.90 (t, J=4.7 Hz, 4 H); 3.75 (s, 2 H); 3.08 (d, J=11.0 Hz, 2 H); 2.12 (t, J=11.0 Hz, 2 H); 1.78 (m, 2 H); 1.52-1.38 (m, 3 H); 1.31 (m, 1 H) and 1.19 (s, 6 H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[C:12]([C:25]#[CH:26])[N:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C:15]=3[OH:17])[S:10][N:9]=2)=[CH:4][CH:3]=1.[OH:27]S(O)(=O)=O>O>[C:25]([C:12]1[N:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C:15]([OH:17])=[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9][S:10][C:11]=12)(=[O:27])[CH3:26]
Reactant: O=S(=O)(O)O
Reactant: C#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(-c3ccc(Cl)cc3)nsc12
Solvent: O
Product: CC(=O)c1nc(C(=O)NCC(=O)O)c(O)c2c(-c3ccc(Cl)cc3)nsc12
Temperature: 25 °C
Yield: 22.9 %

Procedure:
To the solution of {[3-(4-chloro-phenyl)-7-ethynyl-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid (0.28 mmol) in actone/water=4:1 (2.8 mL) was added conc. H2SO4 (36.2 mg, 0.37 mmol) and HgSO4 (84.3 mg, 0.28 mmol). The reaction mixture was refluxed for 2 h. After cooling to r.t. the mixture was concentrated in vacuo. The residue was dissolved in DMSO (2.5 mL) and purified by flash column chromatography on C18 (40 g), eluting with 30-80% CH3CN/H2O in 0.1% HCOOH to give the title compound (26 mg) as a brown solid: MS (m/z) 406.0 (M+1).
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[C:19]([C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28][NH2:29])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>C(O)C>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH2:28][NH:29][C:5]2[C:6](=[O:18])[C:7](=[O:17])[C:8]=2[C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[CH:30][CH:31]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Reactant: CC(C)(C)c1ccc(CCN)cc1
Solvent: CCO
Product: COc1ccc(-c2c(NCCc3ccc(C(C)(C)C)cc3)c(=O)c2=O)cc1
Yield: 81.3 %

Procedure:
In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) and 4-tert-butyl-phenethylamine (0.216 g, 1.22 mmol) in ethanol (2 mL) were converted to the title compound (0.180 g, 81%) m.p.: 258.1-260.2° C.; 1H NMR (DMSO-d6) δ9.07(br t,1H), 7.97(ABq,2H), 7.29(ABq,2H), 7.14(d,2H), 7.09(d,2H), 3.87(m,2H), 3.83(s,3H), 2.84(t,2H), 1.23(s,9H); IR(KBr) 3160, 2950, 1775, 1720, 1580, 1425, 1350, 1300, 1250, 1180, 1020, 840 cm−1; MS (m/z) 364 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([S:12]([F:17])([F:16])([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CC(=O)OCC>[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:2]2[CH:11]=[C:10]([S:12]([F:17])([F:16])([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:21][CH:20]=1
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)c1ccc(S(F)(F)(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(F)(F)(F)(F)F)cc1Oc1ccc(F)cc1
Temperature: 120 °C
Yield: 32 %

Procedure:
300 mg of methyl 2-chloro-4-pentafluorosulfanylbenzoate, 113 mg of 4-fluorophenol and 659 mg of Cs2CO3 were dissolved in 1.5 ml of DMF (anhydrous) and stirred at 120° C. The mixture was then allowed to cool and was diluted with 10 ml of EA and washed 3 times with 5 ml of water each time. Drying over MgSO4 was followed by removal of the solvent in vacuo. 120 mg of an amorphous solid were obtained and were chromatographed on reversed phase silica gel:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]#[N:14])=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:22][CH3:23]>C(C(C)=O)C.O>[CH2:22]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]#[N:14])=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1)[CH3:23]
Reactant: CCI
Reactant: CCn1cc(C#N)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCOc1ccc2c(C#N)cn(CC)c2c1
Reaction time: 8 h
Yield: 102 %

Procedure:
To a solution 6-hydoxy-1-ethyl-1H-indole-3-carbonitrile (80 mg, 0.43 mmol) in 5 mL of methyl ethyl ketone is added anhydrous K2CO3 (71 mg, 0.52 mmol) and iodoethane (0.05 mL, 0.60 mmol). After stirring overnight at reflux, the reaction mixture is cooled, diluted with H2O and extracted with EtOAc (3×). The combined organic phases are dried and concentrated. Flash chromatography (CH2Cl2) gives 94 mg (100%) of 6-ethoxy-1-ethyl-1H-indole-3-carbonitrile as a white wax.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[H-].[Na+].O([CH2:22][C:23]([F:26])([F:25])[F:24])S(C(F)(F)F)(=O)=O.O>CN(C)C=O.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A stirred solution of 3-fluoro-4-nitrophenol (200 mg, 1.3 mmol) in dimethylformamide (3 ml) at 0° C. under argon was treated portionwise with sodium hydride (60 mg of 60% oil dispersion, 1.5 mmol) and maintained for 20 minutes. The mixture was treated with trifluoroethyl triflate (325 mg, 1.4 mmol), then allowed to warm to room temperature and stir overnight. The yellow solution was treated with water (40 ml) and brine (5 ml) and extracted with ethyl acetate. The extract was washed with water, dried (Na2SO4) and concentrated under vacuum to leave the title compound as a yellow oil (280 mg, 92%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:13][CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16]>COCCO>[CH2:15]([CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH3:16]
Reactant: N#Cc1ccc(O)cc1
Reactant: CCCCC(CC)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: CCCCC(CC)COc1ccc(C#N)cc1
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
61.4 g (0.5 mol) of 4-hydroxybenzonitrile in 500 ml of methylcellosolve are placed in a 1 l sulfonating flask fitted with stirrer, condenser, dropping funnel and internal thermometer. The batch is heated to 80 C., and then 73.3 g of 30% NaOH (0.55 mol) are run in slowly with vigorous stirring. The mixture is stirred for 15 minutes before commencing the dropwise addition, over 30 minutes, of 116.8 g (0.575 mol) of 3-bromomethylheptane. The reaction is continued at 100 C. for about 12 hours. The thin-layer chromatogram indicates virtually quantitative conversion. Solvent and excess bromide are removed in vacuo and the residue (an oil) is taken up in 500 ml of toluene. The mixture is subjected three times to extraction by shaking with water and the extracts are dried over sodium sulfate and concentrated to dryness. High-vacuum distillation via a 10 cm Vigreux column (127-132 C., 0.15 mm) gives 97.5 g (84% of theory) of 4-(2-ethylhexyloxy)benzonitrile as a coloured oil.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:17][C:18](=[CH2:20])[CH3:19].O>C(Cl)(Cl)(Cl)Cl>[C:18]([C:9]1[CH:10]=[CH:11][C:6]([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)=[CH:7][CH:8]=1)([CH3:20])([CH3:19])[CH3:17]
Reactant: C=C(C)C
Reactant: c1ccc(C2CCNC2)cc1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(C)c1ccc(C2CCNC2)cc1
Reaction time: 0.25 h
Yield: 33 %

Procedure:
98 g (1 mole) of concentrated sulfuric acid were added dropwise to 29.4 g (0.2 mole) of 3-phenylpyrrolidine in 400 ml of carbon tetrachloride at 0°-5° C. After 15 minutes, 15.2 g (0.27 mole) of isobutylene were passed in gaseous form, the mixture was stirred for 1 hour at 0°-5° C. and hydrolysis was carried out with 400 ml of water at 20° C. The organic phase was separated off and the aqueous phase was extracted with twice 100 ml of dichloromethane. Working up of the organic phases gave 42 g of a crude product, which was fractionated under reduced pressure to give 13.4 g (33%) of a colorless oil of boiling point 84°-87° C./0.5 mbar.