Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:21]=[CH:20][C:8]2[N:9]=[C:10]([C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:19])[NH:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CO>[CH3:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=1[C:10]1[NH:11][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:21]=[CH:20][C:8]=2[N:9]=1
Reactant: COC(=O)c1ccc2nc(-c3c(C)cccc3C)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(C)c1-c1nc2ccc(C(=O)O)cc2[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a tan suspension of 7.23 g (25.8 mmol) of 2-(2,6-Dimethyl-phenyl)-3H-benzoimidazole-5-carboxylic acid methyl ester in 50 mL MeOH was added 80 mL of NaOH (1N). Allowed to stir at r.t. for 48 h. The reddish/brown solution was dried, and to the residue was added 50 mL water, and brought to pH 4. Solid was filtered off to give near quantitative yield of title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03 (s, 6H) 7.14 (d, J=7.58 Hz, 2H) 7.27 (t, J=7.64 Hz, 1H) 7.50 (d, J=8.46 Hz, 0.5H) 7.67 (d, J=8.46 Hz, 0.5H) 7.78 (dd, J=15.09, 8.40 Hz, 1H) 8.03 (s, 0.5H) 8.20 (s, 0.5H) 12.64 (br. s., 1H) 12.85 (d, J=16.29 Hz, 1H). MS (m/z) 267.1 M (+1), tR=0.87, Meth 10
Reaction SMILES: CO.[C:3]1(O)C=CC=CC=1.[C:10]1([CH3:17])[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][CH:11]=1>N#N>[CH3:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([CH3:3])[C:15]=1[OH:16]
Reactant: Cc1ccccc1O
Reactant: Oc1ccccc1
Agent: N#N
Solvent: CO
Product: Cc1cccc(C)c1O
Yield: 34 %

Procedure:
29.5 g of the catalyst is charged with a 5/1 moles methanol/mole phenol mixture with LHSV of 0.68 h-1. The gaseous mixture, diluted with N2 as the carrier gas after its vaporization at 140° C., is converted to an extent of 83% at 372° C. The yield is 34% of 2,6-dimethylphenol and 47% of o-cresol. After an operating period of 40 hours, the catalyst activity and selectivity decrease sharply.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]1[CH2:37][O:36][C:10]2([CH2:32][CH2:31][C@@:30]3([CH3:33])[C:12](=[CH:13][CH2:14][C@@H:15]4[C@:29]3([OH:34])[CH2:28][CH2:27][C@@:26]3([CH3:35])[C@H:16]4[CH2:17][CH:18]=[C:19]3[CH:20]([N+:23]([O-:25])=[O:24])[CH2:21][OH:22])[CH2:11]2)[O:9]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([O:22][CH2:21][CH:20]([N+:23]([O-:25])=[O:24])[C:19]1[C@:26]2([CH3:35])[C@H:16]([C@H:15]3[C@:29]([OH:34])([CH2:28][CH2:27]2)[C@:30]2([CH3:33])[C:12]([CH2:11][C:10]4([O:9][CH2:8][CH2:37][O:36]4)[CH2:32][CH2:31]2)=[CH:13][CH2:14]3)[CH2:17][CH:18]=1)(=[O:3])[CH3:2]
Reactant: C[C@]12CCC3(CC1=CC[C@H]1[C@@H]4CC=C(C(CO)[N+](=O)[O-])[C@@]4(C)CC[C@@]12O)OCCO3
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC(C1=CC[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]12C)OCCO5)[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
Acetic anhydride (1.5 ml) was added to a stirred suspension of 3,3-ethylenedioxy-20-nitropregna-5,16-diene-9α,21-diol (1.00 g of diastereomer II, prepared according to example 2), and 4-dimethylaminopyridine (100 mg) in methylene chloride (10 ml) to give a clear solution. The reaction mixture was stirred for an additional 30 minutes and concentrated under reduced pressure. The residue was dissolved in methylene chloride and filtered over a silica gel column. The filtrate was evaporated under reduced pressure to afford a white solid which was dried under reduced pressure at 50° C.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:9]=[C:8]([CH3:10])[N:7]([CH:11]([CH2:15][CH3:16])[C:12]([OH:14])=O)[N:6]=1)([CH3:4])[CH3:3].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32]3[CH2:31][CH2:30][CH2:29][NH:28][C:27]=3[CH:26]=[N:25]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:32]3[CH2:31][CH2:30][CH2:29][N:28]([C:12](=[O:14])[CH:11]([N:7]4[C:8]([CH3:10])=[CH:9][C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[N:6]4)[CH2:15][CH3:16])[C:27]=3[CH:26]=[N:25]2)=[CH:22][CH:23]=1
Reactant: CCC(C(=O)O)n1nc(C(C)(C)O)cc1C
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Product: CCC(C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1)n1nc(C(C)(C)O)cc1C

Procedure:
The title compound was prepared from 2-(3-(2-hydroxypropan-2-yl)-5-methyl-1H-pyrazol-1-yl)butanoic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method A. The reaction slurry was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to provide 3.7 mg of the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.44 (m, 2H), 7.15 (t, J=8.6 Hz, 2H), 5.92 (s, 1H), 5.17 (dd, J=7.4, 7.4 Hz, 1H), 3.73 (m, 1H), 3.48 (m, 1H), 2.75 (m, 2H), 2.33 (m, 1H), 2.23 (s, 3H), 2.17 (s, 1H), 2.14 (m, 1H), 1.87 (m, 1H), 1.73 (m, 1H), 1.52 (s, 6H), 0.96 (t, J=7.4 Hz, 3H); MS: (ES) m/z calculated for C23H29FN5O2 [M+H]+ 426.2, found 426.2.
Reaction SMILES: [I:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]=3[CH:12]=[CH:13][CH:14]=2.Cl.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C[Si](C)(C)N[Si](C)(C)C>[CH2:16]([N:23]=[C:6]1[C:5]2[CH:12]=[CH:13][CH:14]=[C:3]3[C:4]=2[C:8](=[CH:9][CH:10]=[C:2]3[I:1])[NH:7]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: O=C1Nc2ccc(I)c3cccc1c23
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Product: Ic1ccc2c3c(cccc13)C(=NCc1ccccc1)N2
Yield: 65.8 %

Procedure:
The product of the example was also prepared using the procedures of Method B as described in Example 21. 6-Iodo-1H-benzo[cd]indol-2-one (0.2 g, 0.68 mmol), benzylamine hydrochloride (0.195 g, 1.36 mmol) and p-toluenesulfonic acid monohydrate (0.01 g, 0.052 mmol) were stirred in hexamethyldisilazane (0.45 ml) for 3 h at 130°. Workup as before provided the crude product. Crystallization from EtOAc-ether gave 0.172 g (66%) of a dark yellow solid: mp 160-163°; NMR (CDCl3) δ 4.90 (s, 2H), 6.99 (d, J=7.3, 1H), 7.36 (m, 3H), 7.46 (m, 2H), 7.62 (m, 1H), 7.78 (m, 1H), 7.87 (m, 2H). MS (EI) m/z 385 (M+H calcd. for C18H14IN2 385).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].[Cl:6][C:7]1[C:15]2[CH:14]=[C:13]([C:16](N(OC)C)=[O:17])[S:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.O.Cl>O1CCCC1>[Cl:6][C:7]1[C:15]2[CH:14]=[C:13]([C:16](=[O:17])[CH2:1][CH2:2][CH3:3])[S:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CCC[Mg]Cl
Reactant: CON(C)C(=O)c1cc2c(Cl)cccc2s1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCC(=O)c1cc2c(Cl)cccc2s1
Temperature: 25 °C
Reaction time: 2.33 h

Procedure:
Propylmagnesium chloride (2M solution in ether; 4.3 ml) was added under nitrogen over 15 minutes to a stirred solution of 4-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide (2 g) in tetrahydrofuran (25 ml) then the mixture was stirred at ambient temperature for 2.33 hours. Further propylmagnesium chloride (2M solution in ether; 0.5 ml) was added, the mixture was stirred at ambient temperature for 0.5 hours, then water (150 ml) and 5M hydrochloric acid (15 ml) were added. The product was extracted into dichloromethane (3×40 ml), the combined extracts were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography over silica using dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to leave 1-(4-chlorobenzo[b]thiophen-2-yl)butan-1-one (0.95 g) which was used without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.CCN(CC)CC.[Br:29][C:30]1[CH:63]=[CH:62][C:33]([C:34]([NH:36][NH:37][C:38](=[O:61])[C@H:39]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[C:53]([Cl:59])[C:52]=2[CH3:60])[C@@H:40]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH3:41])=O)=[CH:32][CH:31]=1>C(Cl)Cl>[Br:29][C:30]1[CH:31]=[CH:32][C:33]([C:34]2[O:61][C:38]([C@H:39]([NH:50][C:51]3[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[C:53]([Cl:59])[C:52]=3[CH3:60])[C@@H:40]([O:42][Si:43]([C:46]([CH3:48])([CH3:49])[CH3:47])([CH3:44])[CH3:45])[CH3:41])=[N:37][N:36]=2)=[CH:62][CH:63]=1
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(Br)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(Br)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.5 %

Procedure:
To a solution of triphenylphosphine (4.23 g, 16.1 mmol) in DCM (200 mL) was added I2 (4.1 g, 16.2 mmol) at 0° C. After I2 was dissolved completely, Et3N (4.5 mL, 32.3 mmol) was added, followed by a solution of 4-bromo-N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-benzohydrazide (4.68 g, 8.1 mmol) in DCM (100 mL). The reaction mixture was allowed to warm to room temperature and stirred for additional 15 min. The reaction was quenched with saturated sodium thiosulfate (50 mL) and diluted with DCM (400 mL). The organic layer was separated and washed with water, brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash chromatography to provide the title compound (4.03 g, 89%), which was used directly in the next step
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=[O:8])=[C:4]([NH:10]C(OC(C)(C)C)=O)[CH:3]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:10][C:4]1[CH:3]=[C:2]([Br:1])[S:6][C:5]=1[C:7]([NH2:9])=[O:8]
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)sc1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1sc(Br)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
5-Bromo-3-(t-butyloxycarbonyl)aminothiophene-2-carboxamide (0.76 g) was stirred in dichloromethane (30 ml). Trifluoroacetic acid (51 ml) was added, the solution was stirred at room temperature for 1 h, poured into saturated aqueous sodium hydrogen carbonate solution (200 ml) and extracted with dichloromethane (3×100 ml). The combined extracts were washed with brine (150 ml), dried (magnesium sulphate), filtered and evaporated to give a yellow solid (0.511 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH2:7].[I:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>>[I:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:7][CH2:6][CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: NCC1CCCO1
Product: O=S(=O)(NCC1CCCO1)c1ccc(I)cc1

Procedure:
The title compound was prepared from (tetrahydro-2-furanylmethyl)amine and 4-iodobenzenesulfonyl chloride using a similar procedure to that described for Description 30.
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[Cl:17].[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[Cl:17]
Reactant: COC(=O)c1cc(-c2c(Cl)cnn2C)c(Cl)o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1cc(C(=O)O)oc1Cl
Yield: 93.9 %

Procedure:
A solution of methyl 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (224 mg, 0.82 mmol) in 6N sodium hydroxide (1.36 ml, 8.2 mmol) and tetrahydrofuran (5 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H2O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording the title compound (201 mg, 0.77 mmol, 94% yield) as a yellow oil: LCMS (ES) m/e 262 (M+H)+.
Reaction SMILES: [C:1]([CH:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([O:7]C)=O)(=O)[CH3:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([NH2:23])=[N:15]1>C1(C)C=CC=CC=1>[OH:7][C:5]1[N:15]2[N:14]=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]3)=[C:16]2[N:23]=[C:1]([CH3:2])[C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: Nc1n[nH]c2ccccc12
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)Cc1c(C)nc2c3ccccc3nn2c1O
Yield: 65.9 %

Procedure:
A mixture of a dimethyl acetylsuccinate (1.55 g; 8.27 mmol) and 1H-indazol-3-amine (1 g; 7.5 mmol) in toluene (7.5 mL) was heated to reflux under a Dean Stark system for 48 h. The precipitate was filtered-off, washed with toluene and diethylether to afford 1.34 g (67%) of methyl 2-(4-hydroxy-2-methylpyrimido[1,2-b]indazol-3-yl)acetate, which was used for the next step without any further purification. ESI/APCI(+): 272 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:16]O)([CH2:13][O:14][CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:16][N:41]2[C:37](=[O:47])[C:38]3[C:39](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:40]2=[O:42])([CH2:13][O:14][CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COCC1(CO)CCN(Cc2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCC1(CN2C(=O)c3ccccc3C2=O)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.9 %

Procedure:
A solution of (1-benzyl-3-methoxymethylpyrrolidin-3-yl)methanol (Example A19, 1.71 g, 7.27 mmol), triphenylphosphine (2.16 g, 8.22 mmol), phthalimide (1.14 g, 7.73 mmol), and anhydrous tetrahydrofuran is cooled to 0° C. and treated with diethyl azodicarboxylate (1.62 g, 9.31 mmol). The resulting mixture is stirred at room temperature for 18 hours and concentrated under vacuum. The residue is purified by flash column chromatography (1:5 ethyl acetate/hexanes) to afford the title compound, (0.58 g) as a solid. 1H NMR (200 MHz, CDCl3): δ 7.91-7.80 (m, 2H), 7.78-7.66 (m, 2H), 7.39-7.11 (m, 5H), 3.95-3.72 (m, 2H), 3.65-3.40 (m, 2H), 3.31 (s, 2H), 3.27 (s, 3H), 2.72-2.34 (m, 4H), 2.02-1.82 (m, 1H), 1.76-1.56 (m, 1H). MS ES: m/z 365 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:5]=[C:4]([Br:19])[CH:3]=1.[CH2:20]([O:22][C:23](=[O:34])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][C:27]=1[CH3:33])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:34])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[CH:5]=[C:4]([Br:19])[CH:3]=2)=[CH:28][C:27]=1[CH3:33])[CH3:21]
Reactant: CCOC(=O)COc1ccc(S)cc1C
Reactant: FC(F)(F)c1cccc(Oc2cc(Br)cc(Br)c2)c1
Product: CCOC(=O)COc1ccc(Sc2cc(Br)cc(Oc3cccc(C(F)(F)F)c3)c2)cc1C

Procedure:
1,3-Dibromo-5-(3-trifluoromethyl-phenoxy)-benzene (1.35 g; 3.4 mmol) and (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (0.7 g; 3.1 mmol) was condensed to give the title product applying the procedure described for {4-[3-Bromo-5-cyclopentylmethoxyphenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. The crude product was purified by preparative HPLC (Method A) followed by flash chromatography (dichloromethane:heptane 3:7). Yield 0.5 g. HPLC-MS: m/z: 541.3 (M)+; Rt: 3.03 min.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[CH3:15])[C:6]=2[CH:5]=[C:4]([CH3:16])[CH:3]=1.[Li][CH2:18][CH2:19]CC.ICC>>[CH3:1][C:2]1[C:14]2[CH:13]([CH2:18][CH3:19])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[CH3:15])[C:6]=2[CH:5]=[C:4]([CH3:16])[CH:3]=1
Reactant: [Li]CCCC
Reactant: Cc1cc(C)c2c(c1)-c1cccc(C)c1C2
Solvent: CCI
Product: CCC1c2c(C)cccc2-c2cc(C)cc(C)c21

Procedure:
The substitution reaction at the 9-position was performed according to the general procedure for the synthesis of 9-substituted fluorenes described above in item IV(i). 1,3,8-Trimethylfluorene (54) (1.2 g, 5.77 mmol) was used instead of fluorene, n-BuLi (3.0 ml, 2.5 M in hexane, 7.5 mmol), RX=1-iodoethane (1.35 g, 8.65 mmol). 55 was isolated to give a white solid (1.36 g, quant.).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:18][C:19]1[CH:24]=[C:23]([CH:25]=O)[CH:22]=[C:21]([CH3:27])[N:20]=1.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:18][C:19]1[CH:24]=[C:23]([C:25]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[C:8]([CH2:11][CH2:12][N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)[CH:7]=3)[N:1]=2)[CH:22]=[C:21]([CH3:27])[N:20]=1
Reactant: NC(=O)c1cc(CCN2CCCC2)ccc1N
Reactant: Cc1cc(C=O)cc(C)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3ccc(CCN4CCCC4)cc3c(=O)[nH]2)cc(C)n1
Temperature: 120 °C

Procedure:
To a solution of 2-amino-5-(2-pyrrolidin-1-yl-ethyl)-benzamide (0.16 g, 0.69 mmol) in N,N-dimethyl acetamide (7 mL) under a nitrogen atmosphere was added 2,6-dimethyl-pyridine-4-carbaldehyde (0.09 g, 0.68 mmol), followed by sodium hydrogensulfite (0.14 g, 1.36 mmol) and p-toluenesulfonic acid (0.32 g, 1.7 mmol). The resulting mixture was heated at 120° C. overnight. Then, the solvent was removed under reduced pressure, the residue was diluted with ethyl acetate, and was extracted with water. The pH of the water layer was made basic by adding sodium bicarbonate, then the layer was extracted with methylene chloride, dried over anhydrous sodium sulfate, and was evaporated under high vacuum. The crude yellow solid (0.09 g) was purified by column chromatography (silica gel 230-400 mesh; 95/5 methylene chloride/MeOH as eluent) to afford the title compound as a yellow solid. Yield: 54 mg (23%). MP 212.3-213.2° C. 1H NMR (400 MHz, CDCl3): δ 8.19 (s, 1H), 8.19 (br s, 1H), 7.83-7.77 (m, 1H), 7.76-7.70 (m, 3H), 3.0-3.15 (m, 2H), 2.78-2.88 (m, 2H), 2.7 (s, 6H), 2.58-2.68 (m, 4H), 1.8-1.95 (m, 4H). MS (ES+) m/z: 347.11 (M+1).
Reaction SMILES: [Cl:1][C:2](=[CH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:17]([Cl:18])=[C:16]([O:19][CH:20]([F:22])[F:21])[N:15]([CH3:23])[N:14]=2)[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])[C:3]([OH:5])=O.C(Cl)(=O)C([Cl:29])=O>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2](=[CH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:17]([Cl:18])=[C:16]([O:19][CH:20]([F:21])[F:22])[N:15]([CH3:23])[N:14]=2)[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])[C:3]([Cl:29])=[O:5]
Reactant: Cn1nc(-c2cc(C=C(Cl)C(=O)O)c(Cl)cc2F)c(Cl)c1OC(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cc(C=C(Cl)C(=O)Cl)c(Cl)cc2F)c(Cl)c1OC(F)F
Temperature: 90 °C

Procedure:
A solution of 27 g of 2-chloro-3-(2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorophenyl)acrylic acid (64 mmol) in 200 ml of toluene was treated with 3 drops of dimethylformamide and 33 g (0.26 mol) of oxalyl chloride. The mixture was subsequently stirred at 90° C. until the vigorous evolution of gas had ceased (after approximately 2.5 hours). The reaction mixture was then concentrated. Yield: 26 g of crude product which was further reacted without purification.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:16])O[C:10](C)(C)[O:11][C:12]=2[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=[N:18][C:19]([CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[CH3:20]>>[CH3:13][C:12]1[O:11][CH2:10][N:18]([C:19]([CH3:28])([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[CH3:20])[C:8](=[O:16])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1=C(c2ccccc2)C(=O)OC(C)(C)O1
Reactant: C=NC(C)(C)c1cccc(Cl)c1
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2cccc(Cl)c2)CO1
Temperature: 0 °C
Yield: 69.9 %

Procedure:
A mixture of 5-phenyl-2,2,6-trimethyl-2H,4H-1,3-dioxin-4-one (1.0 g) and N-methylene-1-methyl-1-(3-chlorophenyl)ethylamine (Compound of Example 3) (0.76 g) was heated at 15 0° C. for 30 minutes for reaction. The reaction mixture was purified by silica gel chromatography to obtain the captioned compound (1.0 g).
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:17]=[N:18][CH:19]=[C:20]([O:22][CH3:23])[CH:21]=2)[CH3:12])(=O)=O)=CC=1.[CH3:25][NH2:26]>C(O)C>[CH3:25][NH:26][CH:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[CH3:12]
Reactant: CN
Reactant: COc1cncc(/C=C/CC(C)OS(=O)(=O)c2ccc(C)cc2)c1
Solvent: CCO
Product: CNC(C)C/C=C/c1cncc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.8 %

Procedure:
A mixture of (4E)-5-(5-methoxy-3-pyridyl)-4-penten-2-ol p-toluenesulfonate (5.00 g, 14.41 mmol), methylamine (150 mL, 40% solution in water), and ethyl alcohol (10 mL) was stirred at ambient temperature for 18 h. The resulting solution was extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-methanol (7:3, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing an oil. Further purification by vacuum distillation furnished 1.25 g (41.8%) of a colorless oil, bp 90–100° C. at 0.5 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1.[C:26]1([CH3:35])[C:27]([N:32]=[C:33]=[O:34])=[CH:28][CH:29]=[CH:30][CH:31]=1>O1CCCC1>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:33]([NH:32][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[CH3:35])=[O:34])=[CH:18][CH:17]=3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1
Reactant: Cc1ccccc1N=C=O
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3cc(Cl)ccc32)cc1
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3cc(Cl)ccc32)cc1

Procedure:
As described for Example 122, a mixture of 0.348 g of 2-chloro-5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine and 0.175 g of o-tolylisocyanate in 15 ml of tetrahydrofuran is refluxed overnight and worked-up to give the product as a solid.
Reaction SMILES: CN(C)[S:3]([C:6]1[CH:7]=[C:8]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:9]([N:11]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]1[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:10])(=[O:5])=[O:4].[CH3:39]S(C1C=C(C=C(C(F)(F)F)C=1)C(O)=O)(=O)=O>>[CH3:30][O:29][C:27](=[O:28])[CH2:26][N:11]([C:9](=[O:10])[C:8]1[CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=[C:6]([S:3]([CH3:39])(=[O:5])=[O:4])[CH:7]=1)[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]1[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N(C)C)c1)c1cnccc1-c1cccnc1OC
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1cccnc1OC

Procedure:
The title compound was prepared in analogy to example 90, from (2-methoxy-[3,4′]bipyridinyl-3′-ylamino)-acetic acid methyl ester (example 178, intermediate) and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) after a reaction time of 72 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 20:80). The product-containing fractions were pooled and evaporated. The remaining solid was purified by preparative HPLC (Gemini NX column) with a gradient of methanol:water (containing 0.05% formic acid) (80:20 to 98:2). Light yellow foam (32%). MS (ESI): m/z=524.108 [M+H]+.