Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].C([Sn](CCCC)(CCCC)[C:23]1[CH:27]=[CH:26][S:25][CH:24]=1)CCC>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>[S:25]1[CH:26]=[CH:27][C:23]([C:2]2[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=2)[O:5][CH2:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=[O:11])=[CH:24]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccsc1
Reactant: O=Cc1cccc(COc2cccc(Br)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: O=Cc1cccc(COc2cccc(-c3ccsc3)c2)c1
Yield: 76.7 %

Procedure:
1.4 g of 3-bromomethylbenzaldehyde was dissolved in 3 ml of dimethylformamide, and the solution was added to 5 ml of a tetrahydrofuran solution of phenolate, prepared from 1.5 g of 3-bromophenol and 0.36 g of 60% oily sodium hydride. The mixture was stirred for 2 hours at room temperature. The solvent was evaporated, and water and ethyl acetate were added to the residue to extract it. The extract was worked up in a customary manner to give crude 3-(3-bromophenoxymethyl)benzaldehyde. When the same reaction as in Referential Example 12 was performed using 440 mg of the resulting aldehyde compound, 747 mg of tributyl(3-thienyl)stannane and 10 mg of tetrakis(triphenylphosphine)palladium, 341 mg (yield 77%) of 3-[3-(3-thienyl)phenoxymethyl)benzaldehyde was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:26])=[CH:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([NH:19][CH3:20])=[CH:14][C:13]=3[C:12]3[CH2:21][N:22]([CH3:25])[CH2:23][CH2:24][C:11]2=3)=[CH:4][CH:3]=1.C(O[C:31](=[O:33])[CH3:32])(=O)C.[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH3:26])=[CH:9]/[N:10]2[C:18]3[CH:17]=[CH:16][C:15]([N:19]([CH3:20])[C:31](=[O:33])[CH3:32])=[CH:14][C:13]=3[C:12]3[CH2:21][N:22]([CH3:25])[CH2:23][CH2:24][C:11]2=3)=[CH:6][CH:7]=1
Reactant: CNc1ccc2c(c1)c1c(n2C=C(C)c2ccc(F)cc2)CCN(C)C1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N(C)c1ccc2c(c1)c1c(n2/C=C(\C)c2ccc(F)cc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-(2-(4-Fluorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-N,2-dimethyl-1H-pyrido[4,3-b]indol-8-amine (30 mg) was charged in a round bottom flask. Acetic anhydride (0.5 mL) was added and the contents stirred at RT for 30 min. The reaction mixture was then basified with 1N NaOH and extracted with EtOAc (2×25 mL). The organic layer was concentrated under vacuum and purified through reverse phase column chromatography to yield 19.38 mg of the desired compound. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.70 (m, 2H), 7.50 (s, 1H), 7.36 (d, 1H), 7.18 (m, 3H), 7.0 (s, 1H), 4.78 (d, 1H), 4.41 (d, 1H), 3.90 (m, 1H), 3.62 (m, 1H), 3.28 (s, 3H), 3.20 (m, 2H), 3.10 (s, 3H), 1.96 (s, 3H), 1.82 (s, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([NH:13][C:14]1[CH:15]=[C:16]([N:20]2[C:24]3[CH:25]=[CH:26][C:27]([C:29](O)=[O:30])=[CH:28][C:23]=3[N:22]=[CH:21]2)[CH:17]=[CH:18][CH:19]=1)(=[O:12])[CH3:11].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:46][CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1>CC(N(C)C)=O>[C:10]([NH:13][C:14]1[CH:15]=[C:16]([N:20]2[C:24]3[CH:25]=[CH:26][C:27]([C:29]([NH:46][CH2:47][C:48]4[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=4)=[O:30])=[CH:28][C:23]=3[N:22]=[CH:21]2)[CH:17]=[CH:18][CH:19]=1)(=[O:12])[CH3:11]
Reactant: NCc1cccnc1
Reactant: CC(=O)Nc1cccc(-n2cnc3cc(C(=O)O)ccc32)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(-n2cnc3cc(C(=O)NCc4cccnc4)ccc32)c1
Reaction time: 0.5 h

Procedure:
DIPEA (0.75 mL, 4.31 mmol) was added at rt to a mixture of 1-[3-(acetylamino)phenyl]-1H-benzimidazole-5-carboxylic acid (0.83 g, 2.8 mmol), EDC (0.81 g, 4.22 mmol), HOBt (0.57 g, 4.22 mmol) in anhydrous DMA (10 mL). The reaction mixture was stirred for 30 min prior to the dropwise addition of 3-aminomethylpyridine (0.57 mL, 5.62 mmol). After stirring for a further 25 h, the solvent was removed in vacuo and the crude material purified by column chromatography over silica gel eluting with 5-15% MeOH in DCM. The product was further purified by recrystallisation from acetone to afford 1-[3-(acetylamino)phenyl]-N-(pyridin-3-ylmethyl)-1H-benzimidazole-5-carboxamide. 1H NMR (400 MHz, DMSO-d6): δ 2.09 (3H, s), 4.54 (d, J=6.0 Hz, 2H), 7.35-7.4 (m, 2H), 7.56 (t, J=8.0 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.92 (dd, J=8.4 Hz, 1.2 Hz, 1H), 8.04 (t, J=2.0 Hz, 1H), 8.38 (d, J=1.2 Hz, 1H), 8.46 (dd, J=4.8 Hz, 1.6 Hz, 1H), 8.58 (1H, J=1.6 Hz, 1H), 8.68 (s, 1H), 9.21 (t, J=5.6 Hz, 1H), 10.33 (s, 1H); MS (ES+): m/z 386 [MH+]
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][CH2:46][CH2:47][NH2:48])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][CH2:46][CH2:47][NH:48][C:18]([C:14]2[CH2:15][CH2:16][O:17][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=4)=[CH:21][C:12]=3[CH:13]=2)=[O:19])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NCCCC2CCN(C(=O)OC(C)(C)C)CC2)CCO3)cc1
Yield: 99 %

Procedure:
To 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxylic acid (1402 mg, 5.00 mmol) dissolved in DMF (30 ml) were added at 0° C. 1-hydroxybenzotriazole (743 mg, 5.50 mmol), 3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propylamine (1333 mg, 5.50 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1438 mg, 7.50 mmol), and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (100 ml) was added to the residue and the resulting mixture was washed successively with water (10×3 ml), a 10% aqueous solution of potassium hydrogensulfate (10 ml×3), an aqueous saturated solution of sodium bicarbonate (10 ml×3) and an aqueous saturated solution of sodium chloride (10 ml). The organic layer was dried with anhydrous magnesium sulfate and was then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 80g, ethyl acetate/hexane=1/3→1/1)]. The objective fractions were concentrated under reduced pressure to obtain N-[3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (2498 mg, 4.95 mmol, 99%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccncc3)c1)=N2

Procedure:
The title compound was prepared from {5-ethoxy-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M32) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (184 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([CH:9]=1)[C:7]1[CH:10]=[C:11]([CH3:15])[C:12]([CH3:14])=[CH:13][C:6]=1[N:5]2[CH2:16][CH3:17].[CH2:18]=O.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>C(O)C>[CH2:20]([N:22]([CH2:18][C:9]1[N:8]2[C:4]([N:5]([CH2:16][CH3:17])[C:6]3[CH:13]=[C:12]([CH3:14])[C:11]([CH3:15])=[CH:10][C:7]=32)=[N:3][C:2]=1[CH3:1])[CH2:23][CH3:24])[CH3:21]
Reactant: C=O
Reactant: CCn1c2cc(C)c(C)cc2n2cc(C)nc12
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)Cc1c(C)nc2n(CC)c3cc(C)c(C)cc3n12
Temperature: 25 °C

Procedure:
A solution of 1.5 g (6.5 mmol) of 2,6,7-trimethyl-9-ethylimidazo[1,2-a]benzimidazole in 8 ml of ethanol is mixed with 0.6 ml (7.5 mmol) of 40% formaldehyde and diethylamine (0.76 ml, 7.5 mmol). Stir at room temperature. Once the reaction is complete (verified by thin- layer chromatographiy), evaporate, wash the residue with water, dry, and recrystallise from petroleum ether.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[CH2:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].[H-].[Na+].[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Br)[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:24]([O:31][C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=1)[CH2:38][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:10][O:11][C:12]3[CH:20]=[C:16]4[C:15](=[CH:14][C:13]2=3)[CH2:19][CH2:18][O:17]4)[C:2]1=[O:21])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: BrCc1cccc(OCc2ccccc2)c1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1N(Cc2cccc(OCc3ccccc3)c2)c2ccccc2C12COc1cc3c(cc12)CCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a stirred solution of 5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indolin]-2′-one (1.0 g, 3.6 mmol) in dry N,N-dimethylformamide (18 mL) was added sodium hydride (60% in mineral oil, 0.17 g, 4.3 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 1 h, cooled in an ice/water bath, and 1-(benzyloxy)-3-(bromomethyl)benzene (1.4 g, 5.0 mmol) in dry N,N-dimethylformamide (2 mL) was added dropwise. The mixture was stirred at ambient temperature for 16 h. Water (200 mL) and ethyl acetate (200 mL) were added to the mixture. The organic solution was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic solution was washed with brine (150 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (hexanes/ethyl acetate 3:1) to afford 1′-[3-(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (1.4 g, 82%) as a colorless solid: mp 66-68° C.; 1H NMR (300 MHz, CDCl3) δ 7.43-7.14 (m, 8H), 7.06-6.99 (m, 1H), 6.97-6.87 (m, 3H), 6.81-6.75 (m, 1H), 6.48 (s, 1H), 6.43 (s, 1H), 5.10-5.00 (m, 3H), 4.85-4.75 (m, 1H), 4.84 (ABq, 2H), 4.56-4.47 (m, 2H), 2.98-2.88 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.9, 161.8, 161.3, 159.2, 142.1, 137.4, 136.6, 132.7, 129.9, 128.7, 128.6, 128.0, 127.5, 123.8, 123.4, 120.2, 119.9 (2C), 118.8, 114.0, 113.9, 109.3, 93.2, 80.5, 72.3, 70.0, 57.7, 44.0, 29.0; MS (ES+) m/z 476.1 (M+1).
Reaction SMILES: O=[CH:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].Cl.[NH2:14][OH:15].N1C=CC=CC=1>CO>[OH:15][N:14]=[CH:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4]
Reactant: NO
Reactant: C[C@H](C=O)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: C[C@H](C=NO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 157.4 %

Procedure:
A mixture of (R)-tert-butyl 1-oxopropan-2-ylcarbamate (28.0 g, 81.0 mmol), hydroxylamine hydrochloride (11.2 g, 81.0 mmol), pyridine (60 mL), MeOH (100 mL) was stirred at rt overnight. The solvent was then evaporated. To the residue was added water (100 mL) and the mixture was extracted with DCM (3×200 mL). The combined organic phases were dried (Na2SO4) and concentrated. The crude residue was purified by flash column chromatography (petroleum ether:EtOAc, 4:1) to give (R)-tert-butyl 1-(hydroxyimino)propan-2-ylcarbamate (24.0 g, 79%). 1H NMR (DMSO-d6, 400 MHz) δ 10.63 (s, 1H), 7.20 (d, J=5.2 Hz, 1H), 4.12 (m, 1H), 1.38 (s, 9H), 1.15 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52][NH2:53])=[CH:50][CH:49]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:53][CH2:52][C:51]4[CH:54]=[CH:55][C:48]([Cl:47])=[CH:49][CH:50]=4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCc2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 4-chlorobenzylamine (Aldrich) to give the title product. LC-MS (ES+) 788 [(M+H)+].
Reaction SMILES: [NH:1]([C:8](=[O:28])[CH:9]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-:30]>C1COCC1.O.C(OCC)(=O)C>[NH:1]([C:8](=[O:28])[C:9]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=1)([C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[OH:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(C(O)(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 20 h
Yield: 25 %

Procedure:
To a solution of 4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoic acid in THF (5 mL) at room temperature was added a solution of LiOH (28 mg, 1.2 mmol) in water (2 mL). The reaction mixture was stirred open to air for 20 h then heated to 40° C. for 8 h. Additional LiOH (20 mg, 0.83 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate, washed with 1 M HCl (1×), brine (1×), dried over MgSO4, and concentrated. Purification by reverse phase HPLC (30% to 100% MeCN in water) gave 4-[2-anilino-1-(anilinocarbonyl)-1-hydroxy-2-oxoethyl]benzoic acid (31 mg, 25%) as a white solid: ESIMS calcd 391.1 (M++H), found 391.1 (M++H).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].OS(O)(=O)=O.[C:10]([CH2:13][C:14](=[O:16])[CH3:15])(=[O:12])[CH3:11]>O>[C:10]([C:13](=[N:1][OH:3])[C:14](=[O:16])[CH3:15])(=[O:12])[CH3:11]
Reactant: CC(=O)CC(C)=O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)C(=NO)C(C)=O
Reaction time: 1.75 h

Procedure:
A solution of 69.0 g (1 mol) of NaNO2 in 103 g water was adjusted to pH 4.0-4.6 using 50% by weight strength H2SO4. At about 15° C., a mixture of 100.0 g (1 mole) of acetylacetone and 475 g of water was metered in at constant pH over a period of 105 min. During the reaction, a product-containing organic phase was formed.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:34]=[CH:33][C:18]([O:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:12][N:4]1[CH:5]=[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]([O:1][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])=[CH:33][CH:34]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 59.3 %

Procedure:
A mixture of methyl 3-hydroxy-1-methyl-1H-pyrazol-4-ylacetate (245 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (452 mg), potassium carbonate (398 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 6 hrs. The reaction mixture was poured into water 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 silica gel column chromatography, and methyl 1-methyl-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-ylacetate (382 mg, yield 59%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12](=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])(OCC)=O)C.[Si:22]([O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O>C1COCC1>[Si:22]([O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1/[CH:32]=[CH:11]/[C:12](=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1C=O
Reactant: CCOP(=O)(CC(=O)CCCCC(=O)OC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCCCC(=O)/C=C/c1ccccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 0.26 g (10.87 mmol) of sodium hydride was added to a solution of 3.20 g (10.87 mmol) of methyl 7-(diethoxyphosphoryl)-6-oxoheptanoate from Ex. XIIb in 53 ml of THF. The mixture was stirred at room temperature for 30 min, a solution of 9.06 mmol of 2-{[tert-butyl(dimethyl)silyl]oxy}benzaldehyde from Ex. XIIa in 20 ml of THF was added and the mixture was stirred at room temperature for 18 h. Water was added, the mixture was extracted with ethyl acetate, the combined organic phases were dried over Na2SO4 and the solvent was removed. The product was purified chromatographically (silica gel, cyclohexane/EA 10:1). This gave 2.51 g (67.8%) of a colorless liquid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]1[O:28][C:27]2[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][C:19]=2[O:18]1.C(O)(=O)C1C=CC2OCOC=2C=1.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH2:17]1[O:28][C:27]2[CH:26]=[CH:25][C:21]([C:22]([NH:14][CH2:13][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:16][CH:15]=3)=[O:23])=[CH:20][C:19]=2[O:18]1
Reactant: NCc1ccc(OCCN2CCCC2)cc1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Agent: O=C(O)c1ccc2c(c1)OCO2
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(OCCN2CCCC2)cc1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.7 %

Procedure:
To a cooled solution of 20.0 g of 4-[2-(1-pyrrolidinyl)ethoxy]benzylamine in 30 ml of chloroform was added 17.7 g of 3,4-methylenedioxybenzoyl chloride (which was prepared with 15.9 g of piperonylic acid and 65.3 g of thionyl chloride in the usual manner). The mixture was stirred at room temperature for 20 minutes and the solvent was evaporated. 150 ml of water was added to the residue and the mixture was washed with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate and was extracted with ethyl acetate. The extract was washed with water, dried, and evaporated. The residue was washed with isopropyl ether to give 30.0 g of colorless crystals, which were recrystallized from ethyl acetate as colorless needles, m.p. 93.5°-94.5° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([F:15])([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([F:7])([F:6])[F:5].BrN1C(=[O:24])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[N+](C(C)C)([O-])=O.[Na]>ClC(Cl)(Cl)Cl.C(O)C>[F:15][C:3]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:24])=[CH:10][CH:9]=1)([C:4]([F:7])([F:6])[F:5])[C:2]([F:16])([F:17])[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)[N+](=O)[O-]
Solvent: CCO
Product: O=Cc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 29.9 %

Procedure:
A solution of 3.5 g of 4-(heptafluoroisopropyl)-toluene (13.4 mmol) in 100 ml tetrachloromethane was heated to reflux. Then 2.63 g of N-bromosuccinimide (14.8 mmol) and 326 mg of dibenzoyl peroxide (1.34 mmol) were added in small portions. After 5 h the mixture was cooled to 0° C., filtered and the solvent was evaporated. The remaining residue was dissolved in 15 ml ethanol and was added to a suspension that had been prepared by addition of 2-nitropropane (1.4 ml, 15.5 mmol) to a solution of 340 mg sodium (14.8 mmol) in ethanol. This mixture was stirred for 3 days. Then it was filtered, the solvent was removed and the remaining residue was dissolved in EtOAc and washed with 1 N sodium hydroxide solution, 1 N HCl solution, saturated NaHCO3 solution and with brine. The EtOAc layer was then dried with magnesium sulfate, filtered and concentrated. Purification of the residue (silica gel; c-hexane/EtOAc 10:1) gave 1.1 g (30%) of 4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzaldehyde as a light yellow oil. 1H-NMR (CDCl3, 300 MHz: δ 7.82 (d, J=8 Hz, 2H), 8.03 (d, J=8 Hz, 2H), 10.11 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: Cc1ccccc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of o-toluidine (1.07 ml, 10 mmol) and pyridine (0.86 ml, 10.6 mmol) in dichloromethane (2 mL) was added methanesulfonyl chloride (0.81 ml, 10.5 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by 1 N HCl aqueous solution and extracted with EtOAc. The organic layer was concentrated in vacuo to afford the title compound (1.84 g, 10 mmol, quant.) as an orange solid.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([O:28]CC)=[O:27])#[N:2].[OH-].[Na+].O.Cl>C(O)C.C1COCC1>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])#[N:2]
Reactant: CCOC(=O)/C=C/c1c(C#N)c2c(C)cc(C)nc2n1[C@@H]1CCCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@@H]3CCCc4ccccc43)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl (2E)-3-{3-cyano-4,6-dimethyl-1-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoate (4.25 g, 10.6 mmol) in ethanol (40 ml) and THF (30 ml) was added a 1 N aqueous sodium hydroxide solution (21 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water, neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give the objective product as a solid material. The resultant material was recrystallized from ethyl acetate and hexane.