Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH:11]1[O:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:12]2[O:13][CH:11]2[CH3:10])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC1OC1Sc1ccc(Br)cc1

Procedure:
A suspension containing 9.45 g of 4-bromothiophenol, 14.45 g of 1-chloro-2,3-epoxypropane and 13.8 g of potassium carbonate in 100 ml of butanone is refluxed for 12 hours. The inorganic salts formed are filtered off and drained and the solvent and excess 1-chloro-2,3-epoxypropane are then evaporated off under vacuum. The residual oil is distilled at between 130° C. and 140° C. under 0.01 mm of mercury.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10](OCC)=[CH2:11]>C([O-])(=O)C.[Hg+]>[CH:10]([O:9][CH2:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH2:11]
Reactant: OCCC1CCCCC1
Reactant: C=COCC
Agent: CC(=O)[O-]
Agent: [Hg+]
Product: C=COCCC1CCCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Cyclohexylethyl alcohol was mixed with ethyl vinyl ether. Mercury acetate was added thereto and this mixture was stirred at room temperature for 12 hours. The resultant reaction mixture was extracted with ethyl acetate and water, and the extract was washed with water and then distilled under reduced pressure to obtain cyclohexylethyl vinyl ether (X-1) as the target compound.
Reaction SMILES: [CH3:1][NH2:2].O[CH:4]=[C:5]1[C:9]([CH3:11])([CH3:10])[O:8][C:7]([CH3:13])([CH3:12])[C:6]1=[O:14]>C(Cl)(Cl)Cl>[CH3:12][C:7]1([CH3:13])[C:6](=[O:14])[C:5](=[CH:4][NH:2][CH3:1])[C:9]([CH3:11])([CH3:10])[O:8]1
Reactant: CN
Reactant: CC1(C)OC(C)(C)C(=CO)C1=O
Solvent: ClC(Cl)Cl
Product: CNC=C1C(=O)C(C)(C)OC1(C)C
Yield: 74 %

Procedure:
Methylamine gas was bubbled through a solution of 4-hydroxymethylene-dihydro-2,2,5,5-tetramethyl-3(2H)furanone (5.0 g, 29 mmol) in 50 mL of chloroform for 30 min. The solvents were evaporated. The solid residue was recrystallized from hexanes to give 4.Og (74%) of dihydro-2,2,5,5-tetramethyl-4-methylaminomethylene-3(2H)furanone as a light yellow solid: mp 80°-82° C.; Anal Calc'd for C10H17NO2 : C, 65.57; H, 9.29; N, 7.65. Found: C, 65.47; H, 9.30; N, 7.60.
Reaction SMILES: [Li+].CCC[CH2-].C1C[O:9][CH2:8]C1.C(NC(C)C)(C)C.[Cl:18][C:19]1[N:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22]>CN(C=O)C>[Cl:18][C:19]1[C:20]2[C:21](=[O:23])[O:22][CH:8]([OH:9])[C:24]=2[CH:25]=[C:26]([Cl:28])[N:27]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: O=C1OC(O)c2cc(Cl)nc(Cl)c21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
N-Butyllithium (46.7 ml) was added to 100 ml of THF at −78° C., followed by the addition of diisopropylamine (16.65 ml) over 15 min. The mixture was stirred for 1 h at −78° C., then 2,6-dichloronicotinic acid (7.12 g) was added over 10 min. Stirring at −78° C. was continued for 2 h, then DMF (23.26 ml) was added dropwise maintaining the T<−70° C. The mixture was stirred for 1 h at −78° C., warmed to −50° C. for 30 min, and allowed to warm to RT. The mixture was quenched carefully by the addition of 2 N HCl (167 ml) until acidic pH was reached. The mixture was extracted with EtOAc, the organic layers were washed with brine and dried over MgSO4. After evaporation of the solvents the crude material was used without further purification: brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[N:3]=1.I[CH2:26][CH2:27][F:28]>>[NH2:1][C:2]1[N:3]=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH2:26][CH2:27][F:28])[CH:18]=2)=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: FCCI
Reactant: Nc1nc(-c2ccco2)c(-c2ccc(=O)[nH]c2)c(-c2ccco2)n1
Product: Nc1nc(-c2ccco2)c(-c2ccc(=O)n(CCF)c2)c(-c2ccco2)n1

Procedure:
The title compound was synthesized in a similar manner to Example 66 using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone and 1-iodo-2-fluoroethane.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18](=[O:20])[CH3:19])[CH:12]=[CH:11]2.[C:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>O.C1(C)C=CC=CC=1.C(O)C.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>[C:18]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:27]1[CH:28]=[CH:29][C:24]([C:21](=[O:23])[CH3:22])=[CH:25][CH:26]=1)[CH:17]=[CH:16]2)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: CC(=O)c1ccc2cc(Br)ccc2c1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(=O)c1ccc(-c2ccc3cc(C(C)=O)ccc3c2)cc1
Temperature: 95 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
A solution of sodium carbonate (5.43 g, 51.3 mmol) in water (35 mL) was added to a stirred solution of 1-(6-bromonaphthalen-2-yl)ethanone (2.554 g, 10.25 mmol) and 4-acetylphenylboronic acid (2.017 g, 12.30 mmol) in toluene (35.0 mL) and ethanol (35.0 mL) and nitrogen was bubbled through the reaction mixture for 15 min. Then Pd(PPh3)4 (0.237 g, 0.205 mmol) was added, and the reaction was flushed with nitrogen and heated at 95° C. under nitrogen for 8 h and then stirred overnight at rt. The reaction was concentrated to dryness under high vacuum and then partitioned between DCM (˜200 mL) and water (˜150 mL). The organic layer was then washed with brine (˜100 mL), dried (MsSO4), filtered and concentrated. The residue was triturated with MeOH (˜120 mL) and the remaining solids were redissolved into DCM and concentrated to dryness (˜2.7 g of orange solid). This material was dissolved into hot EtOAc (80 mL) and allowed to cool. The resulting solids were collected by filtration and rinsed with Et2O to yield 1-(4-(6-acetylnaphthalen-2-yl)phenyl)ethanone (1.84 g). LC-MS retention time 2.443 min; m/z 288.98 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, chloroform-d) δ ppm 8.51 (s, 1H), 8.05-8.16 (m, 5H), 7.98 (d, J=8.8 Hz, 1H), 7.81-7.88 (m, 3H), 2.76 (s, 3H), 2.68 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]=[CH2:16])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[C:23]([NH:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[C:32]([O:40][CH3:41])[CH:31]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[C:23]([NH:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([N:11]2[C:10](=[O:13])[N:9]([CH2:14][CH:15]=[CH2:16])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:12]2)(=[O:37])=[O:38])=[C:32]([O:40][CH3:41])[CH:31]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: C=CCn1c(-c2ccc(Cl)cc2)n[nH]c1=O
Reactant: COc1cc(C(=O)NC(C)(C)C)ccc1S(=O)(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCn1c(-c2ccc(Cl)cc2)nn(S(=O)(=O)c2ccc(C(=O)NC(C)(C)C)cc2OC)c1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
An amount of 231 mg (0.24 mmol) of the compound from Example 3A was suspended in 4 ml of tetrahydrofuran and cooled to −78° C. This suspension was admixed with stirring with 110 mg (0.981 mmol) of potassium tert-butylate. The mixture was allowed to warm to room temperature, and the solid dissolved. The reaction solution was stirred at room temperature for 10 minutes thereafter. Subsequently it was cooled again to −78° C. It was admixed with 300 mg (0.981 mmol) of 4-(tert-butylcarbamoyl)-2-methoxybenzenesulphonyl chloride (illustration as per Liotta et al., J. Org. Chem., 2001, 66, 3653-3661), the cooling bath was removed, and the solution was left with further stirring at room temperature overnight. The residue was admixed with water. It was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue was purified by preparative HPLC (Method 6). This gave 275 mg (55% of theory) of the target compound.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6]/[C:7]/2=[CH:12]\[C:13]([O:15][CH2:16][CH3:17])=[O:14].C([O-])=O.[NH4+]>CCO>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)/C=C1\CCc2c(OC)cccc21
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CC1CCc2c(O)cccc21
Temperature: 65 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
A round bottomed flask was flushed with argon and then charged with Pd(OH)2 (316 mg, 10 wt %). The flask was evacuated and back-filled with argon, and then EtOH (5 mL) was added to the catalyst. Ethyl (2E)-(4-methoxy-2,3-dihydro-1H-inden-1-ylidene)ethanoate (Example 8, 3.2 g, 13.6 mmol) was added as a solution in EtOH (63 mL). Ammonium formate (4.3 g, 68 mmol) was added, and the reaction mixture was heated to 65° C. After 2 h, the reaction mixture was cooled and filtered through a pad of Celite®, and concentrated under reduced pressure. The reaction mixture was used without further purification according to the method outlined in Example 6 to give the title compound (2.3 g, 78%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.14 (t, 1H), 6.76 (d, 1H), 6.67 (d, 1H), 4.91 (br s, 1H), 4.19 (q, 2H), 3.60 (m, 1H), 2.85-2.88 (m, 1H), 2.76-2.80 (m, 2H), 2.19-2.26 (m, 2H), 1.76-1.82 (m, 1H), 1.26 (t, 3H); GC-MS m/z[M+H]+ 221.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:50])[C:23]([CH3:49])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)=[C:35]([CH:39]=2)[C:36](O)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:50])[C:23]([CH3:49])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)=[C:35]([CH:39]=2)[C:36]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: C1COCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(Oc3cccc(OC)c3)c(C(=O)O)c2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3cccc(OC)c3)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.6 %

Procedure:
Morpholine (0.106 g, 1.225 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.352 g, 1.838 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-methoxyphenoxy)benzoic acid (0.250 g, 0.613 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.173 g, 0.341 mmol, 51%).
Reaction SMILES: [OH-].[K+].[C:3]([C:7]1[CH:39]=[CH:38][C:10]2=[N:11][N:12]([C:14]3[CH:19]=[C:18]([C:20]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:21])[CH:17]=[C:16]([C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([CH3:30])[CH3:29])[C:15]=3[OH:37])[N:13]=[C:9]2[CH:8]=1)([O:5]C)=[O:4].Cl.CCOCC>CO.C(OCC)(=O)C>[C:3]([C:7]1[CH:39]=[CH:38][C:10]2=[N:11][N:12]([C:14]3[CH:19]=[C:18]([C:20]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:21])[CH3:22])[CH:17]=[C:16]([C:28]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)([CH3:29])[CH3:30])[C:15]=3[OH:37])[N:13]=[C:9]2[CH:8]=1)([OH:5])=[O:4]
Reactant: COC(=O)c1ccc2nn(-c3cc(C(C)(C)CC(C)(C)C)cc(C(C)(C)c4ccccc4)c3O)nc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(C(=O)O)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Temperature: 40 °C
Yield: 95.3 %

Procedure:
To a 250 mL 3-necked flask equipped with a mechanical stirrer, thermometer, condenser and nitrogen inlet is added 1.8 g of potassium hydroxide and 40 mL of methanol. The mixture is warmed to 40° C. to dissolve the potassium hydroxide. To this solution is added 2.7 g of 5-carbomethoxy-2-(2-hydroxy-3-α-cumyl-5-tert-octylphenyl)-2H -benzotriazole, prepared in Example 36, in 40 mL of methanol. The reaction mixture is refluxed for six hours. The mixture is then cooled and acidified with hydrochloric acid. Ether and ethyl acetate are added, and the organic layer is separated and dried over anhydrous sodium sulfate. After vacuum stripping of the solvent, 2.5 g of 5-carboxy-2-(2-hydroxy-3-α-cumyl-5-tert-octylphenyl)-2H-benzotriazole is isolated.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28](=[O:52])[CH:29]([C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:38]=1)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:52])[CH:29]([C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:39][CH:38]=1)[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1
Reactant: CCOC(=O)C(Cc1ccccc1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)C(Cc1ccccc1)c1ccc(-c2ccc(-c3onc(C)c3C(O)CCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-ol and 3-phenyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid ethyl ester.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[C:6]=1[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.[H-].[Na+].CS([C:31]1[N:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][N:32]=1)(=O)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:38][O:37][C:34]1[CH:33]=[N:32][C:31]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:13])=[O:14])[C:6]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:36][CH:35]=1
Reactant: CCCS(=O)(=O)Nc1ncnc(OCCO)c1-c1ccc(C)cc1
Reactant: COc1cnc(S(C)(=O)=O)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ncnc(OCCOc2ncc(OC)cn2)c1-c1ccc(C)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 40.4 %

Procedure:
n-Propanesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (115.5 mg) was dissolved in THF (10 ml) and sodium hydride (60 mg) was added followed by stirring for 15 min at 50° C. Then 2-methanesulfonyl-5-methoxy-pyrimidine (138 mg) was added and stirring was continued for 8 h at 75° C. The reaction mixture was poured onto ice water, acidified with solid citric acid and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and the solvent was evaporated. The crude material was purified by plate chromatography with diethyl ether to give propane-1-sulfonic acid {6-[2-(5-methoxy-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide (61 mg) as a white powder. LC-MS: tR: 4.51, [M+H]+: 460.27.
Reaction SMILES: O=[CH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[C:14](=[O:23])[NH:15][C:16]3[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7]2.[CH3:24][S:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])=[O:26].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:24][S:25]([N:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8]([C:13]2[C:14](=[O:23])[NH:15][C:16]4[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7]3)[CH2:30][CH2:29]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=CCc1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CS(=O)(=O)N1CCN(CCc2ccc3[nH]c(-c4cc5ccccc5[nH]c4=O)cc3c2)CC1
Reaction time: 18 h

Procedure:
A slurry of the 3-{5-[2-oxoethyl]-1H-indol-2-yl}quinolin-2(1H)-one (10-2, 75 mg, 0.25 mmol, 1 equiv) and 1-(methylsulfonyl)piperazine (163 mg, 1.0 mmol, 4 equiv) in 1,2-dichloroethane(100 mL) was treated with acetic acid (0.67 mg, 1.12 mmol, 4.5 equiv) and sodium triacetoxyborohydride (156 mg, 0.75 mmol, 3 equiv) and the reaction was stirred under ambient conditions for 18 hours. The reaction was concentrated and the residue was partitioned between EtOAc and sat. NaHCO3 solution. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on a silica column. Elution with EtOAc to 5% NH3-EtOH/EtOAc gave 3-(5-{2-[4-(methyl-sulfonyl)piperazin-1-yl]ethyl}-1H-indol-2-yl)quinolin-2(1H)-one (10-3) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 12.2 (s, 1H), 11.4 (s, 1H), 8.52 (s, 1H), 7.72 (d, J=8 Hz, 1H), 7.51 (t, J=8 Hz, 1 H), 7.42 (d, J=8 Hz, 1 H), 7.38 (m, 2 H), 7.25 (m, 2H), 6.99 (d, J=8 Hz, 1H), 3.11 (m, 4 H), 3.87 (s, 3H), 2.81 (br t, J=8 Hz, 2 H), 2.61 (br t, J=8 Hz, 2H), 2.56 (m, 4 H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([CH3:17])[CH:6]=1)=[O:4].[OH-].[Na+]>CO.O>[CH3:17][C:7]1[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)O)ccc1-c1ccccc1
Yield: 77.1 %

Procedure:
A solution of 2-methyl-biphenyl-4-carboxylic acid methyl ester (0.10 g, 0.44 mmol) in CH3OH (5 mL) and H2O (0.5 mL) is reacted with NaOH (88 mg, 2.2 mmol) at reflux for 2 h. Organic solvent is removed in vacuo, the residue is diluted with H2O, and extracted with Et2O. The aqueous layer is acidified with 5 M HCl, extracted with Et2O, dried with MgSO4, filtered and concentrated to give the title compound as a white solid (72 mg, 77%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:39]([CH:40]([OH:52])[C:41]3[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=3)=[C:38]([CH:53]([CH3:55])[CH3:54])[CH:37]=[C:36]3[C:31]=2[C:32](=[O:58])[CH2:33][C:34]([CH3:57])([CH3:56])[O:35]3)=[CH:26][CH:25]=1>ClCCl>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:39]([C:40](=[O:52])[C:41]3[CH:42]=[CH:43][C:44]([O:47][C:48]([F:50])([F:51])[F:49])=[CH:45][CH:46]=3)=[C:38]([CH:53]([CH3:54])[CH3:55])[CH:37]=[C:36]3[C:31]=2[C:32](=[O:58])[CH2:33][C:34]([CH3:56])([CH3:57])[O:35]3)=[CH:26][CH:25]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(OC(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(=O)c1ccc(OC(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reaction time: 4 h

Procedure:
At 0° C., 185 mg (439 μmol) of 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-one are added to a solution of 110 mg (220 μmol) of 5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethoxy)-phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 24A) in 4.5 ml of dichloromethane, and the mixture is stirred at this temperature for 4 h. The mixture is then diluted with dichloromethane and washed three times with 1 M aqueous sodium hydroxide solution. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure, and the residue is purified by column chromatography on silica gel (mobile phase: gradient cyclohexane→eyclohexane/ethyl acetate 10:1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N+:13]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23](Cl)(=[O:25])=[O:24])([O-:15])=[O:14]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:23]([C:17]2[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])(=[O:24])=[O:25])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1ccc(Cl)c2cccnc12
Reactant: Cc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)c3cccnc23)c([N+](=O)[O-])c1
Yield: 53.6 %

Procedure:
In a similar fashion using route 14 general procedure 26, 5-chloro-8-aminoquinoline (Intermediate 27) (150 mg, 0.84 mmol), 2-nitro-4-methylbenzenesulfonyl chloride (Intermediate 20) (228 mg, 1.26 mmol) gave the title compound (170 mg, 54%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Na+].[CH3:7][C:8]1([CH3:21])[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[C:14]2[CH:13]=[C:12]([OH:20])[CH:11]=[CH:10][C:9]1=2.[OH-].[Na+].[I-:24].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>CO>[I:24][C:11]1[C:12]([OH:20])=[CH:13][C:14]2[C:15]([CH3:19])([CH3:18])[CH2:16][CH2:17][C:8]([CH3:21])([CH3:7])[C:9]=2[CH:10]=1
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Reactant: [I-]
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(I)c(O)cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 3.6% sodium perchlorate solution was added dropwise to a mixture of 5,5,8,8-tetramethyl-5,6,7,8tetrahydronaphthalen-2-ol(6.35 g, 31.1 mmol), sodium hydroxide (1.23 g, 34.2 mmol) and sodium iodide (4.6 g, 31.1 mmol) in methanol (115 ml), at 0° C. The mixture was maintained under stirring for two hours at 0° C. 33 ml of a 10% sodium thiosulfate solution were added. After stirring, the mixture was acidified with hydrochloric acid to pH 1. It was extracted with 200 ml of ethyl ether. The organic phase was washed twice with 400 ml of water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40° C.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH:31]([S:34](Cl)(=[O:36])=[O:35])([CH3:33])[CH3:32]>N1C=CC=CC=1>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:34]([CH:31]([CH3:33])[CH3:32])(=[O:36])=[O:35])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)C(C)C)ccc3N2)c(O)c2cccnc21
Temperature: 120 °C
Yield: 7.5 %

Procedure:
To the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added isopropylsulfonyl chloride (22 μl, 0.2 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 120 minutes. The reaction was cooled to 25° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered, and washed with 1:1 hexane:ethyl acetate. The crude product was chromatographed on silica gel eluting with 199:1 dichloromethane:methanol to give the title compound (2 mg, 7%). 1H NMR (300 MHz, DMSO-d6): δ 0.98 (d, J=6.62 Hz, 6 H) 1.28 (d, J=6.99 Hz, 6 H) 1.57 (m, 2 H) 1.71 (m, 1 H) 3.29 (m, 1 H) 4.49 (m, 2 H) 7.50 (dd, J=7.91, 4.60 Hz, 1 H) 7.59 (dd, J=8.82, 2.57 Hz, 1 H) 7.67 (d, J=2.57 Hz, 1 H) 7.74 (d, J=9.18 Hz, 1 H) 8.56 (dd, J=8.09, 1.84 Hz, 1 H) 8.89 (dd, J=4.60, 1.65 Hz, 1 H) 10.33 (s, 1 H) 14.11 (s, 1 H). MS (ESI−) m/z 532 (M−H)−.