Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].C(OO)(=[O:18])C>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:18])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(=O)OO
Reactant: CC(C)COc1ncc(B(O)O)cc1Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)COc1ncc(O)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 138.6 %

Procedure:
To a suspension of 5-chloro-6-isobutoxypyridin-3-ylboronic acid (3.02 g, 13.1 mmol) in acetic acid/water (1:1 20 mL) cooled to 0° C. was slowly added peracetic acid (3.9 mL, 20.0 mmol) and the reaction mixture was maintained at 0° C. for 1.5 hours and then at room temperature for 1 hour. Additional peracetic acid (3.9 mL, 20.0 mmol) was added and the reaction stirred at room temperature for 40 minutes after which time the suspension dissolved. The reaction mixture was quenched with sodium thiosulphate solution (15 mL) and stirred for 5 minutes. The mixture was extracted with ethyl acetate (2×30 mL) and the combined organic extracts washed with brine (30 mL), dried over magnesium sulphate and filtered. The solvent was removed under reduced pressure to give a yellow oil (3.66 g). Purification by flash column chromatography (Biotage™ 50 g silica cartridge) eluting with a gradient of dichloromethane/methanol (100% to 90% to 80%) gave the title compound (1.94 g, 73%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][CH:16]=2)=[O:10])=[C:4](I)[CH:3]=1.[C:24](=[O:26])=[O:25]>C1COCC1.C(OCC)(=O)C>[C:13]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=[C:11]([C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[C:24]([OH:26])=[O:25])=[O:10])[CH:12]=1
Reactant: O=C(Nc1ccc(Cl)cc1I)c1cccc(-c2ccccc2)c1
Reactant: O=C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1C(=O)O)c1cccc(-c2ccccc2)c1
Reaction time: 0.5 h
Yield: 14 %

Procedure:
433 mg (1.0 mmol) of N-(4-chloro-2-iodophenyl)biphenyl-3-carboxamide was dissolved in 5 mL of THF solution, and 1.6M n-butyllithium(n-BuLi)hexane solution (1.25 mL) was added dropwise under an Ar atmosphere at −78° C. The mixture was stirred for 0.5 hours. Dry ice was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated saline, and dried over anhydrous sodium sulfate. The resultant was separated and purified by silica gel column chromatography, thereby giving 48.2 mg of the target 2-[(biphenyl-3-ylcarbonyl)amino]-5-chlorobenzoic acid (yield: 14%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:52])[C:7]([S:25][C@@H:26]1[CH2:30][N:29](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H:28]([CH2:44][O:45][CH2:46][CH2:47][NH:48][C:49]([NH2:51])=[O:50])[CH2:27]1)=[C:8]2[C:12]([O:14]CC1C=CC([N+]([O-])=O)=CC=1)=[O:13])[CH3:3].P([O-])([O-])([O-])=O.[H][H]>[OH-].[OH-].[Pd+2].O1CCCC1>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:52])[C:7]([S:25][C@@H:26]1[CH2:30][NH:29][C@H:28]([CH2:44][O:45][CH2:46][CH2:47][NH:48][C:49]([NH2:51])=[O:50])[CH2:27]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3]
Reactant: [H][H]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](COCCNC(N)=O)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](COCCNC(N)=O)C3)[C@H](C)[C@H]12
Yield: 46.2 %

Procedure:
A mixture of 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-{(2-ureidoethyl)oxylmethyl}pyrrolidin-4-yl]thio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.75 g), tetrahydrofuran (40 ml), 0.1M phosphate buffer (pH 6.5) (20 ml) and 20% palladium hydroxide on carbon (0.20 g) was stirred at ambient temperature for 5 hours under atmospheric pressure of hydrogen. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to remove tetrahydrofuran. The residual solution was washed with ethyl acetate (40 ml×2) and the organic solvent was removed by evaporation. The residual solution was subjected to a column chromatography on nonionic adsorption resin "Diaion HP-20" (40 ml) eluting with a mixture of acetone and water (5:95 V/V), and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(2S,4S)-2-{(2-ureidoethyl)oxymethyl}pyrrolidin-4-yl]thio-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.20 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:30]3[CH2:31][CH2:32][CH:28]([CH2:27][O:26][CH3:25])[CH2:29]3)=[O:21])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: COCC1CCNC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: COCC1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)C1

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-(methoxymethyl)pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ 1.51-1.66 (m, 1 H) 1.83-1.99 (m, 1 H) 2.36 (s, 3 H) 3.14 (s, 1 H) 3.22 (s, 2 H) 3.37-3.62 (m, 4 H) 7.56-7.61 (m, 1H) 7.65 (s, 1 H) 7.74 (d, J=8.1 Hz, 1 H) 8.03-8.15 (m, 2 H) 8.31 (d, J=8.3 Hz, 1 H) 8.55-8.62 (m, 1 H) 13.07 (br. s., 1 H). MS m/z [M+H]+ 418.4.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[CH:11][C:10]=2[CH3:17])[CH2:5][CH2:4][N:3]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][N:27]=1>>[Cl:25][C:26]1[N:27]=[CH:28][C:29]([S:32]([N:15]([CH3:16])[C:12]2[CH:13]=[CH:14][C:9]([CH2:8][N:6]3[CH2:5][CH2:4][N:3]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C@@H:2]([CH3:1])[CH2:7]3)=[C:10]([CH3:17])[CH:11]=2)(=[O:34])=[O:33])=[CH:30][CH:31]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c(C)c1
Product: Cc1cc(N(C)S(=O)(=O)c2ccc(Cl)nc2)ccc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Reaction time: 8 h

Procedure:
The title compound was prepared from D8 and 2-chloropyridine-5-sulfonyl chloride using a method similar to that described for D15 except that the reaction time was overnight. The work-up involved concentration of the reaction mixture and purification by elution through an SCX cartridge (MeOH then 0.2M NH3 in MeOH), followed by column chromatography eluting with 0-20% EtOAc/petroleum ether. δH (CDCl3, 400 MHz) 8.55 (1H, dd), 7.76 (1H, dd), 7.42 (1H, d), 7.21 (1H, d), 6.96 (1H, d), 6.80 (1H, dd), 6.86 (1H, dd), 4.20 (1H, br.s), 3.79 (1H, m), 3.38 (2H, AB), 3.20 (3H, s), 3.05 (1H, m), 2.69 (1H, m), 2.56 (1H, m), 2.32 (3H, s), 2.19 (1H, m), 1.99 (1H, m), 1.46 (9H, s), 1.21 (3H, d). MS (ES+): MH+ 509/511.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([NH2:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH3:13][O:14][CH2:15][N:16]=[C:17]=[O:18]>C1(C)C=CC=CC=1>[CH3:13][O:14][CH2:15][NH:16][C:17]([NH:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)=[O:18]
Reactant: COCN=C=O
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Solvent: Cc1ccccc1
Product: COCNC(=O)NC1CC(C)(C)N(C)C(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
34 parts of 1,2,2,6,6-pentamethyl-4-aminopiperidine were dissolved in 100 parts of toluene, followed by the dropwise addition of 25° C. of 18.8 parts of 93% methoxymethyl isocyanate. After stirring for 1 hour at 25° C., the toluene was evaporated in vacuo and the residue was crystallised from cleaning spirit, giving 42.5 g of colourless crystals melting at 105° C.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH3:22][C:23]1[C:28]([CH2:29][OH:30])=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH:26]=[C:25]([CH3:38])[N:24]=1>ClCCl>[CH3:22][C:23]1[C:28]([CH:29]=[O:30])=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH:26]=[C:25]([CH3:38])[N:24]=1
Reactant: Cc1cc(-c2ccc(F)cc2)c(CO)c(C)n1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1cc(-c2ccc(F)cc2)c(C=O)c(C)n1
Temperature: 250 °C
Reaction time: 2 h

Procedure:
1.5 g (7 mmol) of pyridinium dichromate are added in portions to 1.0 g (4.3 mmol) of the compound from Example 29 in 20 ml of dichloromethane, the mixture is stirred for 2 h at 250° C., after concentrating chromatographed over 150 g of silica gel using dichloromethane/methanol 10:1 and 0.71 g of product are obtained.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:24])[CH:8]=2)[N:3]=1.[CH3:25][O-:26].[Na+]>C1(C)C=CC=CC=1>[Cl:23][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:24])[CH:8]=2)[N:3]=[C:2]([O:26][CH3:25])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1
Reactant: C[O-]
Reactant: FC(F)(F)c1cccc(Cc2c(Cl)nc3ccc(I)cc3c2Cl)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1nc2ccc(I)cc2c(Cl)c1Cc1cccc(C(F)(F)F)c1
Temperature: 90 °C

Procedure:
A suspension of 2,4-dichloro-6-iodo-3-(3-(trifluoromethyl)benzyl)quinoline (1.551 g, 3.217 mmol, Intermediate 7: step b) and sodium methoxide (1.738 g, 32.174 mmol) in dry toluene (16 mL) was heated at 90° C. for 16 hours. The reaction was cooled to room temperature and quenched by the addition of saturated aqueous NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified (FCC, 80 g SiO2, 0-20% CH2Cl2/hexanes over 20 minutes) to afford the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:37][C@@:36]2([CH3:38])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:39])[C:17](=[O:35])[CH:18]([O:20][C:21](=[O:34])[C@@H:22]([NH:26]C(OC(C)(C)C)=O)[CH:23]([CH3:25])[CH3:24])[OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:41])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:40])[CH2:6][CH2:5]1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[OH:1][C@H:2]1[CH2:37][C@@:36]2([CH3:38])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:39])[C:17](=[O:35])[CH:18]([O:20][C:21](=[O:34])[C@@H:22]([NH2:26])[CH:23]([CH3:25])[CH3:24])[OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:41])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:40])[CH2:6][CH2:5]1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC(O)C(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](N)C(=O)OC(O)C(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
500 mg (0.89 mmol) of (2S)-2-((1,1-dimethylethoxycarbonyl) -amino)-3-methyl-butyric acid [11β,17,21-trihydroxy-3,20-dioxo -pregn-4-en-21-yl] ester (Example 27) is mixed with 1 ml of trifluoroacetic acid and stirred for 10 minutes at room temperature. Then, the trifluoroacetic acid is evaporated in a vacuum. The residue is mixed with stirring with a little diethyl ether, the white precipitate that is produced is suctioned off and dried. 385 mg (76%) of (2S)-2-amino-3-methyl-butyric acid [11β,17,21-trihydroxy-3,20-dioxo-pregn-4-en-21-yl] ester trifluoroacetate is obtained.
Reaction SMILES: C(Cl)(=O)C.[CH3:5][C:6]1([CH3:34])[C:10]([CH3:12])([CH3:11])[O:9][B:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23]C3CCCCO3)=[C:15]([C:30]([F:33])([F:32])[F:31])[CH:14]=2)[O:7]1>CO>[CH3:11][C:10]1([CH3:12])[C:6]([CH3:5])([CH3:34])[O:7][B:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][OH:23])=[C:15]([C:30]([F:32])([F:33])[F:31])[CH:14]=2)[O:9]1
Reactant: CC1(C)OB(c2ccc(OCCCOC3CCCCO3)c(C(F)(F)F)c2)OC1(C)C
Solvent: CC(=O)Cl
Solvent: CO
Product: CC1(C)OB(c2ccc(OCCCO)c(C(F)(F)F)c2)OC1(C)C
Reaction time: 0.17 h
Yield: 101.2 %

Procedure:
Acetyl chloride (14.26 ml) was added to MeOH (150 ml) at 0° C. and stirred for 10 minutes. The above mixture was added to 4,4,5,5-tetramethyl-2-(4-(3-(tetrahydro-2H-pyran-2-yloxy)propoxy)-3-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (43 g) in MeOH (300 ml) and stirred at 50° C. for 1.5 hours. The solvent was removed under reduced pressure, DCM was added to the residue and it was basified with sodium bicarbonate, washed with water, and the DCM was removed under reduced pressure to give expected compound (35 g). 1H NMR (CDCl3) δ: 8.00 (s, 1H), 7.92 (d, 1H), 6.98 (d, 1H), 4.21 (t, 2H), 3.86 (t, 2H), 2.07 (quin, 2H), 1.34 (s, 12H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32]>O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:30](=[O:33])[CH:31]=[CH2:32])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: C=CC(=O)Cl
Reactant: N#Cc1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCCCCCOc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a solution of 1.26 g (4.27 mmol) of the resulting compound (9) and 1.8 ml (24.8 mmol) of anhydrous triethylamine dissolved in 20 ml of tetrahydrofuran under argon atmosphere was added dropwise 5 ml of an tetrahydrofuran solution containing 0.38 ml (4.08 mmol) of acryloyl chloride. The whole was stirred at room temperature overnight, thereby a salt precipitated. After addition of water to the reaction mixture, the whole was extracted with diethyl ether. The extract was purified by silica gel column chromatography. The resulting pale yellow solid was recrystallized from methanol to obtain 1.01 g of 4-cyano-4'-(6-acryloxyhexyloxy)biphenyl (10) (yield: 67.7%).
Reaction SMILES: FC(F)(F)S([C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:25]3[CH:30]=[CH:29][C:28](S(C(F)(F)F)(=O)=O)=[CH:27][CH:26]=3)[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][CH:7]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[Cl:46][C:47]1[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][CH:48]=1>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.O1CCCC1>[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3([C:25]4[CH:30]=[CH:29][C:28]([C:50]5[CH:51]=[CH:52][C:47]([Cl:46])=[CH:48][CH:49]=5)=[CH:27][CH:26]=4)[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:18]4[C:13]3=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:8][CH:7]=2)=[CH:49][CH:48]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=S(=O)(c1ccc(C2(c3ccc(S(=O)(=O)C(F)(F)F)cc3)c3ccccc3-c3ccccc32)cc1)C(F)(F)F
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: C1CCOC1
Product: Clc1ccc(-c2ccc(C3(c4ccc(-c5ccc(Cl)cc5)cc4)c4ccccc4-c4ccccc43)cc2)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 77.4 %

Procedure:
16 g of 9,9-bis[4-(trifluoromethylsulfonyl)phenyl]fluorene, 100 ml of tetrahydrofuran, 62 g of a 20% sodium carbonate aqueous solution, 8.54 g of 4-chlorophenylboronic acid, and 0.6 g of tetrakis(triphenylphosphine)palladium were placed in a 300 ml four-necked flask, and the mixture was heated at 70° C. The resulting mixture was aged at the same temperature for 18 hours, and the reaction mixture was then cooled to room temperature and subjected to liquid separation. An organic phase was washed with a saturated ammonium chloride aqueous solution and saturated salt water, and the resulting organic phase was concentrated and recrystallized from tetrahydrofuran to obtain 11.4 g of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:19])[C:8]=1[O:9][CH:10]([CH3:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[NH2:5].[F:20][C:21]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:22]=1[C:23]([N:25]=[C:26]=[O:27])=[O:24]>ClCCCl>[F:20][C:21]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:22]=1[C:23]([NH:25][C:26]([NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[C:8]([O:9][CH:10]([CH3:18])[C:11]([F:16])([F:17])[C:12]([F:14])([F:15])[F:13])=[C:7]([Cl:19])[CH:6]=1)=[O:27])=[O:24]
Reactant: CC(Oc1c(Cl)cc(N)cc1Cl)C(F)(F)C(F)(F)F
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: ClCCCl
Product: CC(Oc1c(Cl)cc(NC(=O)NC(=O)c2c(F)cccc2F)cc1Cl)C(F)(F)C(F)(F)F
Temperature: 25 °C

Procedure:
1.0 of 3,5-Dichloro-4-(1-methyl-2,2,3,3,3-pentafluoropropoxy)aniline was placed in a flask to which was added 15 mL of 1,2-dichloroethane. With stirring, 0.62 g 2.6-difluorobenzoyl isocyanate was added all at once to the mixture. The mixture was warmed to near reflux for one hour then cooled to room temperature and stirred overnight. It was then concentrated under vacuum to give 2.30 g crude product. The product was recrystallized from toluene, giving 208 mg of 1-(2,6-difluorobenzoyl)-3-[3,5-dichloro-4-(1-methyl-2,2,3,3,3-pentafluoropropoxy)phenyl]urea. 1H NMR: 10.59 (s, 1H) 9.58 (s, 1H), 7.34 (m, 3H), 7.07 (t, J=8.4 Hz,2H), 5.09 (m, 1H). MS: 506 m/z. IR:1746(s), 1710(s), 1539(s), 1470(m).
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[NH:10][C:9]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19]I>CN(C=O)C>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[N:10]([CH3:19])[C:9]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cc1[nH]c2ccc(Br)cc2c1Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(Cc2ccccc2)c2cc(Br)ccc2n1C

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 3-benzyl-5-bromo-2-methyl-1H-indole (1.530 g, 5.097 mmol) was reacted with k-t-butoxide (0.601 g, 5.352 mmol) and methyl iodide (0.760 g, 5.352 mmol) in DMF (15 ml) to give the product (1.453 g, 4.624 mmol, 91%) as a yellow solid, mp 104-106° C. 1H NMR (DMSO-d6) δ 2.39 (s, 3H), 3.65 (s, 3H), 3.99 (s, 2H), 7.10-7.14 (m, 2H), 7.18 (d, J=6.7 Hz, 2H), 7.22 (t, J=7.6 Hz, 2H), 7.34 (d, J=8.6 Hz, 1H), 7.49 (d, J=1.8 Hz, 1H); [ESI(+)], m/z 314/316 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:11])=[O:10])[CH:6]=[CH:5][CH:4]=1.[Br:12]Br>O1CCOCC1>[Br:12][CH2:11][C:9]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][CH3:1])[CH:8]=1)=[O:10]
Reactant: BrBr
Reactant: CCc1cccc(C(C)=O)c1
Solvent: C1COCCO1
Product: CCc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To a stirred solution of 3-ethylacetophenone (Maybridge Chemical; 1.103 g, 7.44 mmol) in dry 1,4-dioxane (15 mL) was added bromine (383 μL, 7.44 mmol). The solution was stirred at room temperature for 30 min. and then the solvent was removed on a rotary evaporator. The residue was chromatographed on a Foxy 200 machine (Isco, Inc., P.O. Box 82531, Lincoln, Nebr. 68501, USA.; eluent, 5%CH2Cl2/Hexane, 0-2 min. then 20-30% CH2Cl2/Hexane, 2-20 min.) to give 2-bromo-1-(3-ethylphenyl)ethanone (1.15 g, 68%) as a clear oil.
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:51]([O:58][C:59](=[O:62])[CH2:60][NH2:61])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:51]([O:58][C:59](=[O:62])[CH2:60][NH:61][C:24](=[O:25])[C@@H:23]1[CH2:27][CH2:28][CH2:29][N:22]1[C:20](=[O:21])[C@H:18]([CH3:19])[NH:17][P:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCC(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
Dibenzylphosphoryl-L-alanyl-L-proline (1.2 g, 2.5 m mole), HOBt (338 mg, 2.5 m mole) and glycine benzylester p-toluene sulfonic acid salt (1.0 g, 3 m mole) were suspended in DMF (10 ml), and WSC (0.5 ml) was dropwise added thereto while cooling to -15° C. and stirring. The reaction was carried out for 3 hours under cooling, and next, overnight at room temperature. To the reaction solution ethyl acetate (100 ml) was added and the mixture was washed with 1N hydrochloric acid and water in order, and dried with anhydrous sodium sulfate. The thus dried solution was distilled off an under reduced pressure to give an oily dibenzylphosphoryl-L-alanyl-L-prolyl-glycine benzylester material (1.5 g). The oily material gave a single spot with Rf 0.7 by thin layer chromatography (developing solvent; chloroform:methanol:acetic acid=95:5:3, colour forming method: spraying of 25% hydrobromic acid and 0.1% ninhydrine and heating).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[Cl:14][CH2:15][Si:16]([CH3:19])([CH3:18])Cl.C(OCC)C>O1CCCC1>[Cl:14][CH2:15][Si:16]([CH3:19])([CH3:18])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: C[Si](C)(Cl)CCl
Reactant: Fc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Si](C)(CCl)c1ccc(F)cc1
Temperature: -70 °C

Procedure:
250 ml of n-butyl lithium (1.6M in hexane) are added to 39 ml of 4-bromo-fluoro-benzene in 400 ml of tetrahydrofuran within a period of 45 minutes with stirring at −70° C. The mixture is stirred for a further 30 minutes and then 53 ml of chloromethyl-dimethyl-chlorosilane dissolved in 50 ml of tetrahydrofuran are added dropwise. The mixture is stirred at −70° C. for a further 30 minutes and the temperature of the reaction mixture is then allowed to rise to 0° C. The reaction mixture is poured onto 200 ml of ice, and 300 ml of diethyl ether are added; the mixture is washed with water and saturated sodium chloride solution and dried over sodium sulfate; the solvent is evaporated off in vacuo. Distillation of the residue at 97-105° C. (21 mbar) yields the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[CH3:33][S:34]([CH2:37][CH2:38][NH2:39])(=O)=[O:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[CH:17]3[C:12]([C:13]4[CH:28]=[CH:27][C:26]([C:29]([NH:39][CH2:38][CH2:37][S:34]([CH3:33])=[O:35])=[O:31])=[CH:25][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCOCC2)cc1Cl
Reactant: CS(=O)(=O)CCN
Agent: Cl
Product: CS(=O)CCNC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCOCC1

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(tetrahydro-2H-pyran-4-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 36 and 2-(methylsulfonyl)ethanamine hydrochloride according to Method F. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25-1.32 (m, 2H), 1.41 (ddd, J=24.50, 12.42, 4.43 Hz, 1H), 1.51-1.57 (m, 1H), 1.87-1.99 (m, 2H), 2.25-2.33 (m, 1H), 2.87-3.00 (m, 1H), 3.04 (s, 3H), 3.08-3.21 (m, 3H), 3.38 (t, J=6.85 Hz, 2H), 3.61-3.79 (m, 5H), 4.82 (dd, J=9.80, 3.63 Hz, 1H), 7.18-7.23 (m, 1H), 7.44 (s, 1H), 7.71 (d, J=8.59 Hz, 1H), 7.73-7.77 (m, 1H), 7.78 (s, 1H), 8.08 (d, J=8.06 Hz, 1H), 8.79 (t, J=5.50 Hz, 1H); HRMS m/z 541.1702 (M+H).