Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH2:21]([N:23](CC)[CH2:24][CH3:25])[CH3:22].N1CC=CC1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17]([N:23]2[CH2:24][CH:25]=[CH:22][CH2:21]2)(=[O:19])=[O:18])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CCN(CC)CC
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Agent: C1=CCNC1
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CC=CC3)sc2Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (500 mg; 1.2 mmol; 1 eq), is dissolved in anhydrous DCM (30 ml). The reaction is put under nitrogen. Triethylamine (0.34 ml; 2.41 mmol; 2 eq) and 3-pyrroline (166.2 mg; 2.41 mmol; 2 eq) are added successively and the reaction mixture is stirred overnight at room temperature. It is then washed with water, NH4Cl sat., brine and dried over MgSO4, affording the title compound (600 mg; 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[H-].[Na+].[CH2:12]([O:19][C:20]([N:22]1[CH2:26][CH:25]2[CH2:27][CH:28]([CH2:30][O:31][C:32]3[CH:41]=[C:40]4[C:35]([C:36](Cl)=[N:37][CH:38]=[N:39]4)=[CH:34][C:33]=3[O:43][CH3:44])[CH2:29][CH:24]2[CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.CCOC(C)=O>[CH2:12]([O:19][C:20]([N:22]1[CH2:23][CH:24]2[CH2:29][CH:28]([CH2:30][O:31][C:32]3[CH:41]=[C:40]4[C:35]([C:36]([O:8][C:5]5[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=5[F:9])=[N:37][CH:38]=[N:39]4)=[CH:34][C:33]=3[O:43][CH3:44])[CH2:27][CH:25]2[CH2:26]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(N)cc3F)ncnc2cc1OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Temperature: 25 °C
Yield: 149.6 %

Procedure:
4-Amino-2-fluoro-phenol (1.53 g, 12.0 mmol) was dissolved in dry DMF (30 ml) to which was added 60% NaH (774 mg, 19.3 mmol). After the mixture was stirred at room temperature for several minutes, a suspension of 5-(4-chloro-6-methoxy-quinazolin-7-yloxymethyl)-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (4.70 g, 6.7 mmol) in dry DMF (40 ml) was added. The reaction mixture was stirred at room temperature for 1-2 hrs, then diluted with EtOAc and washed with sat'd NaHCO3 (3×), H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give crude 5-[4-(4-amino-2-fluoro-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (5.6 g, 100%) which was used in the next reaction without further purification. 1H-NMR (400 MHz, DMSO): 8.50 (s, 1H), 7.48 (s, 1H), 7.34 (m, 5H), 7.28 (m, 1H), 7.02 (t, 1H), 6.48 (dd, 1H), 6.40 (dd, 1H), 5.40 (br s, 2H), 5.05 (s, 2H), 4.16 (d, 2H), 3.92 (s, 3H), 3.48 (m, 2H), 3.30 (m, 2H), 2.65 (m, 2H), 2.52 (m, 1H), 2.10 (m, 2H), 1.30 (m, 2H). LC/MS Calcd for [M+H]+ 559.2, found 559.4.
Reaction SMILES: O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+].[Si]([O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(C(C)(C)C)(C)C.Br[C:35]1[C:36]([NH2:41])=[N:37][CH:38]=[CH:39][CH:40]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:41][C:36]1[C:35]([C:28]2[CH:27]=[CH:26][C:25]([OH:24])=[CH:30][CH:29]=2)=[CH:40][CH:39]=[CH:38][N:37]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Reactant: Nc1ncccc1Br
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: O
Solvent: COCCOC
Product: Nc1ncccc1-c1ccc(O)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 86.3 %

Procedure:
A mixture of sodium carbonate decahydrate (86.0 g), tetrakis(triphenylphosphine)palladium(0) (7.76 g), (4-((tert-butyldimethylsilyl)oxy)phenyl)boronic acid (40 g) and 3-bromopyridin-2-amine (26.9 g) in DME (500 mL) and water (50 mL) was stirred at 90° C. for 24 hr. After cooling to room temperature, the aqueous layer was removed. The organic layer was filtered with NH-silica gel cartridge, and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was recrystallized from EtOAc-IPE to give the title compound (25.0 g) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:19][C:20]([OH:22])=[O:21]>O>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)CCl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)COc1ccc(C(=O)c2ccccc2)cc1
Temperature: 90 °C
Yield: 95 %

Procedure:
20.5 grams (103.4 mmol) of 4-hydroxybenzophenone were suspended in water and dissolved adding 3 equivalents of NaOH. The solution was heated up to 90° C. A solution of 15 grams of chloroacetic acid (1.6 eq.) in 40 mL of water was added dropwise to the reactor for 30 minutes. After that, the reactor was put on reflux at 100° C. for 14 hours or overnight. After that time the solution was cooled down to room temperature and acidified to pH 1-3. A white precipitate appeared. The solution was filtered and the solid dissolved in acetone. The acetone was filtered again and the acetone was evaporated to dryness. The product thus obtained was significantly contaminated with starting material. After crystallization in chloroform, 12 grams of a >95% (4-benzoylphenoxy)acetic acid was obtained (45% yield). FIG. 5 is the UPLC analysis of the compound after crystallization in CHCl3 at 264 nm, using the PCP_FAST method in a C18 column. This compound was used as an endcapping agent.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:30][C:29]([CH:31]=O)=[N:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:33][CH2:34][CH2:35][OH:36].[BH4-].[Na+].C(=O)([O-])O.[Na+]>CO>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:30][C:29]([CH2:31][NH:33][CH2:34][CH2:35][OH:36])=[N:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: NCCO
Reactant: O=Cc1nnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3nnc(CNCCO)s3)[nH]2)cc1)C1CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of 5-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3,4-thiadiazole-2-carbaldehyde (300 mg) in methanol (10 mL) was added 2-aminoethanol (250 μL) at room temperature, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was cooled to room temperature, sodium tetrahydroborate (72 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography to give a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-methanol (9:1, volume ratio). The pale-yellow amorphous solid was subjected to silica gel column chromatography, and the title compound (188 mg, yield 57%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-methanol (8:2, volume ratio). MS: 517 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16](Cl)(Cl)=[S:17]>O1CCOCC1.O>[CH3:9][S:8][C:6]1[CH:7]=[C:2]([N:1]=[C:16]=[S:17])[C:3]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:5]=1
Reactant: S=C(Cl)Cl
Reactant: CSc1ccc(-c2ccccc2)c(N)c1
Solvent: O
Solvent: C1COCCO1
Product: CSc1ccc(-c2ccccc2)c(N=C=S)c1

Procedure:
Reaction of 2-amino-4-methylthiobiphenyl (10.8 g) with thiophosgene (4.6 ml) in a mixture of dioxan (10 ml) and water (200 ml) at 10° C. and then at ambient temperature for 15 hours yielded 4-methylthio-2-biphenylylisothiocyanate as a yellow oil.
Reaction SMILES: [C:1](O)(=O)[CH3:2].[OH:5][N:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]([O:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:8][C:7]1([CH3:35])[CH3:34].OO.S([O-])([O-])=O.[Na+].[Na+]>O.C(O)(=O)C.C(#N)C.C1CCCCC1>[CH:2]1([O:5][N:6]2[C:11]([CH3:12])([CH3:13])[CH2:10][CH:9]([O:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:8][C:7]2([CH3:34])[CH3:35])[CH2:1][CH2:9][CH2:8][CH2:7][CH2:34]1
Reactant: CC(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(O)C(C)(C)C1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: C1CCCCC1
Product: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Yield: 511.4 %

Procedure:
A solution of 0.116 g (0.429 mmol) of ferric chloride hexahydrate and 0.096 g (1.60 mmol) of glacial acetic acid in 2 ml of water is added to a mixture of 5.08 g (11.6 mmol) of 1-oxyl-4-octadecanoyloxy-2,2,6,6-tetramethylpiperidine, 40 ml of cyclohexane, and 60 ml of acetonitrile that has been heated to 60°. A solution of 3.36 g (49.4 mmol) of aqueous 50% hydrogen peroxide is added to the reaction mixture dropwise over 2.5 hours at the reflux temperature of 60-62°. A solution of 0.033 g of ferric chloride hexahydrate and 0.040 g of glacial acetic acid in 1 ml of water is added to the reaction mixture 1.5 hours after the peroxide addition is begun. A solution of 0.031 g of ferric chloride and 0.028 g of glacial acetic acid in 1 ml of water is added to the reaction mixture 4 hours after the peroxide addition is begun. After being heated a total of 5 hours at reflux temperature, the reaction mixture is cooled and excess peroxide is decomposed by the addition of aqueous sodium sulfite solution. The organic layer is concentrated and purified by flash chromatography with 20:1 heptane-ethyl acetate to afford 4.27 g (71% yield) of the title compound, a white solid, mp 42-46. The assay is approximately 90% by NMR integration.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[NH:23][N:22]=3)[C:17]([CH2:29][OH:30])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.B(Cl)(Cl)Cl.O.CCOC(C)=O>C(Cl)Cl>[CH:26]1([C:24]2[NH:23][N:22]=[C:21]([NH:20][C:18]3[C:17]([CH2:29][OH:30])=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[N:19]=3)[CH:25]=2)[CH2:27][CH2:28]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(CO)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: ClB(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2ncc(CO)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Yield: 74.9 %

Procedure:
A solution of N-tert-butyl-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(hydroxymethyl) pyrimidin-2-yl) thiophene-2-sulfonamide (89 mg, 0.17 mmol, 1.0 eq) and BCl3 (1.0 ml, 1.0 mmol, 6.0 equiv.) in CH2Cl2 (5 mL) was stirred for 1 h at 0° C. After addition od water and extraction with EtOAc (3×50 ml), the combined organic phases were washed (brine), dried (Na2SO4), filtered and concentrated to produce 5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(hydroxymethyl)pyrimidin-2-yl)thiophene-2-sulfonamide (Compound 171) (50.0 mg, 74.8%) as white solid. LC-MS (m/z)=393.0 [M+H]+; 1H 1H NMR (400 MHz, DMSO-d6): δ 0.75-0.76 (m, 2H), 0.97-0.99 (m, 2H), 1.92-1.96 (m, 1H), 4.56 (d, J=5.2 Hz, 2H), 5.61 (t, J=5.2 Hz, 1H), 6.53 (d, J=10.4 Hz, 1H), 7.58 (d, J=3.6 Hz, 1H), 7.78 (s, 3H), 8.24 (s, 1H), 8.95 (s, 1H), 12.16 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1)=[O:3].C(N(C(C)C)C(C)C)C.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26]>C(Cl)Cl>[C:2]([C:4]1[CH:5]=[C:6]([NH:10][C:25]([C:21]2[O:20][CH:24]=[CH:23][CH:22]=2)=[O:26])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1cccc(N)c1
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cccc(NC(=O)c2ccco2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1 g of 3-aminoacetophenone in 20 mL of CH2Cl2 was added 5 mL of ethyl-di-iso-propylamine. To the stirred reaction mixture was then added 1 mL of 2-furoyl chloride which was allowed to stir at 25° C. for 8 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (CH2Cl2) to yield 900 mg of furan-2-carboxylic acid (3-acetyl-phenyl)-amide as a white solid. 1H NMR (CDCl3, 500 MHz) δ 8.11 (1 H, br s), 8.09 (1H, t, J=2 Hz), 7.93 (1 H, m), 7.66 (1H, m), 7.47 (1 H, m), 7.20 (1 H, m), 6.52 (1 H, m), 2.56 (3H, s) ppm.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[C:3]=1[OH:14].CCN(CC)CC>CCO.[Pd]>[CH3:12][C:11]1[CH:2]=[C:3]([OH:14])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:13])=[CH:6][CH:5]=2
Reactant: Cc1ccc2c(O)c(Br)c(C)cc2c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc2c(O)cc(C)cc2c1
Reaction time: 6 h

Procedure:
A solution of 2-bromo-3,6-dimethylnaphthalen-1-ol (31.9 g, 127 mmol) in EtOH (1.3 L) was treated with Et3N (26.6 mL, 191 mmol) at room temperature. Pd/C (13.5 g, 12.7 mmol, 10% wt on C) was added in one portion and the atmosphere replaced with H2. The reaction was left under balloon pressure of H2 for 6 hours. After replacing the atmosphere with air, Celite (20 g) was added and the slurry stirred for 15 minutes before filtering the solution through a pad of Celite. The volatiles were removed in vacuo, and the residue was taken up in EtOAc/water (250 mL each). The organics were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting residue was purified on Isco silica gel column chromatography (0-35% EtOAc/hex) to afford 3,6-dimethylnaphthalen-1-ol. LCMS-ESI+ (m/z): [M+H]+ calcd for C12H13O: 173.1. found: 173.4.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[NH:5][CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]1([CH3:24])[CH3:23].FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[CH3:23][C:3]1([CH3:24])[CH2:2][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[NH:5][CH:4]1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: CC1(C)C(O)c2cc(C#N)ccc2NC1c1cccc([N+](=O)[O-])c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Cc2cc(C#N)ccc2NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.9 %

Procedure:
To a mixture of 4-hydroxy-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (25 g, 77 mmol) and triethylsilane (50 mL) at 25° C. was added trifluoroacetic acid (25 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) to afford 3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (4 g, 16%) as a white solid: LC/MS m/e calcd for C18H17N3O2 (M+H)+: 308.36, observed: 308.1.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[CH3:17][O:18][C:19]1[N:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH:10][C:9]2[CH:11]=[CH:12][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=2)=[CH:23][N:24]=1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: COc1ccc(C#N)cn1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (1.8 g, 8.7 mmol) in toluene (50 ml) at 0° C., trimethylaluminum (2M solution in toluene, 5.2 ml, 10.4 mmol) was added over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 2 hours. A solution of 6-methoxy-3-cyanopyridine (1.75 g, 13 mmol) in toluene (100 ml) was added over 10 minutes and the mixture was heated to 85–90° C. After 24 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride and methanol and later with methanol. The combined filtrates were concentrated and the resulting yellowish solid was stirred with ethyl acetate (1000 ml) and filtered. The white solid (2 g, 75%) was used in the next reaction without further purification. Anal. Calc'd. for C14H16N3SClO3.0.5H2O: C, 47.93; H, 4.88; N, 11.98. Found: C, 48.01; H, 4.82; N, 11.32.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([N+:28]([O-:30])=[O:29])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].C(N(CC)CC)C>C(#N)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:20]([C:11]2[N:10]([CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:14]=[CH:13][N:12]=2)=[O:21])[CH:23]=[C:24]([N+:28]([O-:30])=[O:29])[C:25]=1[O:26][CH3:27]
Reactant: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Reactant: c1ccc(COCn2ccnc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(C(=O)c2nccn2COCc2ccccc2)cc([N+](=O)[O-])c1OC
Reaction time: 3 h

Procedure:
A solution of 10.0 g of 1-[(benzyloxy)- methyl]imidazole in 50 ml of acetonitrile is added dropwise within 10 minutes while cooling with ice to a solution of 13.0 g of 3,4-dimethoxy-5-nitrobenzoyl chloride and 5.4 g of triethylamine in 80 ml of acetonitrile so that the temperature does not exceed 25°. The mixture is subsequently stirred for an additional 3 hours, whereupon the solvent is distilled. After treatment with water, the mixture is extracted with ethyl acetate. After two-fold washing with water, the organic phase is dried over sodium sulfate and evaporated. The resulting oil is chromatographed on 600 g of silica gel with toluene/ethyl acetate (95:5). There is obtained 1-[(benzyloxy)methyl]imidazol-2-yl (3,4-dimethoxy-5-nitrophenyl) ketone as a yellowish oil.
Reaction SMILES: O.[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([O-:13])(=[O:12])=[O:11])=O.[Na+:14].C(=O)([O-])[O-].[K+].[K+].[CH3:21][O:22][C:23]([CH2:25]P(OC)(OC)=O)=[O:24]>O>[CH3:21][O:22][C:23]([CH:25]=[CH:2][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([O-:13])(=[O:12])=[O:11])=[O:24].[Na+:14]
Reactant: O=Cc1ccccc1S(=O)(=O)[O-]
Reactant: COC(=O)CP(=O)(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: COC(=O)C=Cc1ccccc1S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
A mixture of sodium 2-formylbenzenesulfonate hydrate (31) (tech., purity 75%; 1.33 g, 4.79 mmol), potassium carbonate (1.32 g, 9.56 mmol), and trimethyl phosphonoacetate (1.05 g, 5.77 mmol) in water (2.5 ml) was vigorously stirred at ambient temperature for 1 hour. The precipitate was filtered and carefully washed with methanol. The methanol extract was evaporated to give the title compound (0.66 g, 52%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 3.72 (3H, s); 6.43 (1H, d, J=16.0 Hz); 7.18-7.96 (4H, m); 8.83 (1H, d, J=16.0 Hz).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][C:37]([CH2:41][OH:42])([CH3:40])[CH2:38][OH:39])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[OH:39][CH2:38][C:37]([NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])([CH2:41][OH:42])[CH3:40]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(CO)(CO)NS(=O)(=O)c1cccc(N)c1
Product: CC(CO)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-benzenesulfonamide (example B.9) according to general procedure II. Yellow solid. MS (ISP) 600.4 [(M+H+]; mp 246° C.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.Br[CH2:32][C:33]([NH2:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:32][C:33]([NH2:35])=[O:34])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCC(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
N,N-Dimethylformamide (1.5 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (50 mg), bromoacetamide (62 mg), and potassium carbonate (62 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (49 mg, yield 83%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[CH3:20])[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]3([CH3:24])[CH3:23])=[CH2:9])[CH:5]=[CH:6][CH:7]=1.C(N(CCCC)CCCC)CCC.[C]=O.[C:40]([O:43][CH2:44]C)(=[O:42])C>CO.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:20][C:19]1[C:10]([C:8]([C:4]2[CH:3]=[C:2]([C:40]([O:43][CH3:44])=[O:42])[CH:7]=[CH:6][CH:5]=2)=[CH2:9])=[CH:11][C:12]2[C:13]([CH3:24])([CH3:23])[CH2:14][CH2:15][C:16]([CH3:22])([CH3:21])[C:17]=2[CH:18]=1
Reactant: CCOC(C)=O
Reactant: C=C(c1cccc(I)c1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CO
Solvent: CCCCN(CCCC)CCCC
Product: C=C(c1cccc(C(=O)OC)c1)c1cc2c(cc1C)C(C)(C)CCC2(C)C

Procedure:
A solution of 6-[1-(3-iodophenyl)vinyl]-1,1,4,4,7-pentamethyl-1,2,3,4-tetrahydronaphthalene (10.8 g, 25 mmol), palladium diacetate (650 mg, 2.9 mmol) and tributylamine (13.8 ml, 58 mmol) in methanol (300 ml) is heated for 3 h at 100° C. under a pressure of carbon monoxide (3 bar). After concentration on an evaporator under vacuum at 40° C., the oil obtained is diluted in ethyl acetate and washed three times with water. The product is purified by flash chromatography on a column of silica.