Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH2:2][O:3][CH:4]=[C:5]2[S:9][CH:8]=[CH:7][C:6]=12.[NH:10]([CH2:12]C(O)=O)[CH3:11].CS(C)=[O:18]>C(OCC)(=O)C>[CH3:11][N:10]1[C:4](=[O:3])[C:5]2[S:9][CH:8]=[CH:7][C:6]=2[NH:1][C:2](=[O:18])[CH2:12]1
Reactant: CNCC(=O)O
Reactant: CS(C)=O
Reactant: C1=c2sccc2=NCO1
Solvent: CCOC(C)=O
Product: CN1CC(=O)Nc2ccsc2C1=O
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A mixture of 30.0 g (177 mmol) of 2H-thieno[3,2-d][1,3]oxazine-2,4(1H-dione and 17.3 g (195 mmol) of sarcosine in 100 ml of dimethyl sulphoxide is stirred at 110° C. for 1.5 hours. The dark brown coloured solution is poured into ca 600 ml of ice/water. The separated oil is taken up in ca 200 ml of ethyl acetate and the aqueous phase is evaporated in vacuo until crystallisation begins. The mixture is cooled in an ice-bath for ca 3 hours and the separated material is filtered off under suction and washed with a small amount of water. After drying on a rotary evaporator, there is obtained 3,4-dihydro-4-methyl-2H-thieno[3,2-e][1,4]diazepine-2,5(1H)-dione of melting point 270°-272° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:4]2[C:9]([C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[N-:28]=[C:29]=[O:30].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[N:3]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:4]2[C:9]([C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])[NH2:28])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1c(C(=O)c2ccc(N)cc2)c2ccccc2n1CCN1CCOCC1
Reactant: [N-]=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(C(=O)c2ccc(NC(N)=O)cc2)c2ccccc2n1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a stirred suspension of 12.0 g. (0.03 mole) of 2-methyl-3-(4-aminobenzoyl)-1-[2-(4-morpholinyl)ethyl]- 1H-indole (Example 4B) in 15 ml of glacial acetic acid and 30 ml. of water was added a solution of 4.5 g. (0.06 mole) of sodium isocyanate in 30 ml of water. The mixture was stirred at room temperature for two hours, then diluted with water and made alkaline with 10% sodium hydroxide The solid which separated was collected and recrystallized from DMF to give 5.9 g (48%) of 2-methyl3-(4-carbamylaminobenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole, m p. 192°-202° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:48]=[CH:47][CH:46]=[CH:45][C:4]=1[C:5]([O:7][C@:8]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=1[F:44])([CH2:31][N:32]1[CH:36]=[N:35][CH:34]=[N:33]1)[C@H:9]([S:11][C@@H:12]1[CH2:17][O:16][C@@H:15](/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:23]=2[F:30])[O:14][CH2:13]1)[CH3:10])=[O:6].[CH3:49][N:50]([CH3:55])[CH2:51][C:52](O)=[O:53].[Cl-].ClC1N(C)CC[NH+]1C.CN1CCN(C)C1=O>ClCCl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:49][N:50]([CH2:51][C:52]([O:1][CH2:2][C:3]1[CH:48]=[CH:47][CH:46]=[CH:45][C:4]=1[C:5]([O:7][C@:8]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=1[F:44])([CH2:31][N:32]1[CH:36]=[N:35][CH:34]=[N:33]1)[C@H:9]([S:11][C@@H:12]1[CH2:17][O:16][C@@H:15](/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:23]=2[F:30])[O:14][CH2:13]1)[CH3:10])=[O:6])=[O:53])[CH3:55]
Reactant: CN(C)CC(=O)O
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)c1ccccc1CO)c1ccc(F)cc1F
Agent: CN(C)c1ccncc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)c1ccccc1COC(=O)CN(C)C)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (1R,2R)-2-[[trans-2-[(1E,3E)-4-(4-cyano-2-fluorophenyl)-1,3-butadienyl]-1,3-dioxan-5-yl]thio]-1-(2,4-difluorophenyl)-1-[(1H-1,2,4-triazol-1-yl)methyl]propyl 2-(hydroxymethyl)benzoate (640.7 mg, 0.95 mmol) obtained from Example 17-(4) in dichloromethane (20 ml) was cooled to 0° C., and then 4-(N,N-dimethylamino)pyridine (254.5 mg, 2.1 mmol), N,N-dimethylglycine (117.2 mg, 1.14 mmol), and 2-chloro-1,3-dimethylimidazolinium chloride (256.1 mg, 1.52 mmol) were added thereto. The reaction mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate, and then the organic layer was washed successively with a saturated aqueous solution of ammonium chloride and with a saturated aqueous solution of sodium chloride. The solvent was evaporated under reduced pressure, and then the residue was subjected to chromatography on a silica gel (40 g) column (eluent; ethyl acetate:methanol=100:3) to give a mixture of the title compound and 1,3-dimethyl-2-imidazolidinone. The mixture was purified by recycle preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm i.d. ×600 mm) and JAIGEL-2H (20 mm i.d. ×600 mm) connected in series for use; solvent, chloroform] to afford the title target compound (368.1 mg, 51% yield) as a colorless amorphous solid.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16](I)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].C1(C)C=CC=CC=1.[C:26]([NH:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:26]([NH:29][C:30]1[CH:35]=[C:34]([C:16]2[C:6]3[N:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:8]=[N:9][C:5]=3[CH:4]=[C:3]([C:1]#[N:2])[CH:17]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(-c2cc(C#N)cc3ncn(-c4ccccc4)c23)c1
Yield: 36.3 %

Procedure:
5-Cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), 3-acetamidophenylboronic acid (90 mg, 0.5 mmol), ethanol (3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) were combined and the mixture was stirred at reflux overnight. The solvent was removed under reduced pressure and the crude product was purified on a 2 g silica Isolute® SPE column, eluting with dichloromethane/methanol (98:2). The eluent from this column was evaporated under reduced pressure and the crude product was purified further by prep LCMS, then recrystallised from dichloromethane/diethyl ether to give the product as a white solid (64 mg, 36%) m/z, 353.0 (M+H)+.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH2:18])=[CH:13][C:12]=1[NH:19][C:20](=[O:38])[CH2:21][CH:22]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH3:10])([CH3:9])[CH3:8]>C(Cl)Cl.C(OCC)(=O)C>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:13][C:12]=1[NH:19][C:20](=[O:38])[CH2:21][CH:22]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH3:8])([CH3:9])[CH3:10]
Reactant: CCS(=O)(=O)Cl
Reactant: CCCCCC(CC(=O)Nc1cc(CN)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCC(CC(=O)Nc1cc(CNS(=O)(=O)CC)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Reaction time: 1 h
Yield: 42.5 %

Procedure:
180 μl (1.90 mmol) of ethanesulfonyl chloride and then 213 mg (1.75 mmol) of 4-N,N-dimethylaminopyridine were added to a solution of 700 mg (1.59 mmol) of N-[2-t-butyl-5-(aminomethyl)phenyl]-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Preparation 26A) in 15 ml of methylene chloride, whilst cooling in an ice-salt bath, and the resulting mixture was stirred at the same temperature for 1 hour. At the end of this time, the reaction mixture was diluted with ethyl acetate, and the diluted solution was washed with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 38 g of silica gel, using a 3:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 360 mg of the title compound as a foam-like substance.
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(OCC)=O)N=1)CC2)=O.OCC1C=CC(B(O)O)=CC=1.Cl[C:61]1[N:66]=[CH:65][C:64]([O:67][CH2:68][CH2:69][N:70]([CH3:72])[CH3:71])=[CH:63][CH:62]=1.CC1(C)C(C)(C)OB([C:81]2[CH:86]=[CH:85][C:84]([OH:87])=[CH:83][CH:82]=2)O1>>[CH3:71][N:70]([CH3:72])[CH2:69][CH2:68][O:67][C:64]1[CH:63]=[CH:62][C:61]([C:81]2[CH:86]=[CH:85][C:84]([OH:87])=[CH:83][CH:82]=2)=[N:66][CH:65]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: CN(C)CCOc1ccc(Cl)nc1
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: OCc1ccc(B(O)O)cc1
Product: CN(C)CCOc1ccc(-c2ccc(O)cc2)nc1

Procedure:
Compound 90B was prepared in a similar manner to the synthesis of compound 34D by substituting compound 34C and 4-(hydroxymethyl)phenylboronic acid with compound 90A and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, respectively: 1H NMR (DMSO-d6): δ 9.56 (s, 1H), 8.29 (d, J=2.76 Hz, 1H), 7.83 (d, J=8.59 Hz, 2H), 7.74 (d, J=8.59 Hz, 2H), 7.41 (dd, J=8.59, 2.76 Hz, 2H), 6.82 (d, J=8.29 Hz, 2H), 4.14 (t, J=5.68 Hz, 2H), 2.64 (t, J=5.68 Hz, 2H), 2.22 (s, 6H). ESI (+)/MS: 258 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:11][CH:12]([CH3:14])[CH3:13].Cl.[N:17]([O-])=[O:18].[Na+].[OH-].[Na+]>O>[N:17]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:11][CH:12]([CH3:13])[CH3:14])[C:2]([CH3:15])([CH3:1])[CH2:10]2)=[O:18]
Reactant: CC(C)CN1c2ccccc2CC1(C)C
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CN1c2ccc(N=O)cc2CC1(C)C
Temperature: 8 °C

Procedure:
A mixture of 2,2-dimethyl N-isobutylindoline (2.0 g) and concentrated hydrochloric acid (4.5 cm3) was cooled to 8° C. and sodium nitrite (0.8 g) in water (2 cm3) was added dropwise. The reaction mixture was allowed to warm to ambient temperature, made alkaline with sodium hydroxide solution an extracted with ethyl acetate. The ethyl acetate was dried over magnesium sulphate, filtered and evaporated to give 5-nitroso-2,2-dimethyl N-isobutyl indoline.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([Cl:32])=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:36]1([C:42](=[O:50])[CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[ClH:32].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][C:42]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[O:50])[CH2:45][CH2:46]3)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(F)cc2)[C@@H](c2ccc(F)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(F)cc2)[C@@H](c2ccc(F)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1
Product: Cl

Procedure:
2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-fluoro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-fluoro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12a) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 674.5 [(M+H)+]
Reaction SMILES: CCN(C(C)C)C(C)C.I[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[CH3:27][C@@H:28]([C:31]([N:33]1[C@H:37]([C:38]([OH:40])=[O:39])[CH2:36][CH2:35][CH2:34]1)=[O:32])[CH2:29][SH:30].C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH2:11]([S:30][CH2:29][C@@H:28]([CH3:27])[C:31]([N:33]1[CH2:34][CH2:35][CH2:36][C@H:37]1[C:38]([OH:40])=[O:39])=[O:32])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: C[C@H](CS)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCCCCCCCCCCCCCCCI
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCCCCCCCCCCCSC[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Yield: 47.5 %

Procedure:
DIEA (188 μl, 1.10 mmol) was added to a solution of 1-iodohexadecane (176 mg, 0.500 mmol), captopril (120 mg, 0.550 mmol) and DBU (165 μl, 1.10 mmol) in tetrahydrofuran (5 ml). The mixture was heated at 70° C. for 2h and then concentrated. The residue was poured onto water saturated with potassium hydrogensulphate and organic material was extracted into chloroform. The organic phase was washed with water and dried (MgSO4). The product purified by chromatography (silica, CHCl3/MeOH/AcOH 85:10:5) and lyophilised to give 105 mg (48%) of white solid material. The structure was verified by 1H (500 MHz) and 13C (125 MHz) analysis and further characterised by MALDI mass spectrometry, giving M-H in negative mode at m/z 440 as expected.
Reaction SMILES: OCC(N[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:35]=[CH:34][C:14]([CH2:15][C:16]2[CH:17]=[C:18]([C@H:23]3[C@H:28]([OH:29])[C@@H:27]([OH:30])[C@H:26]([OH:31])[C@@H:25]([S:32][CH3:33])[O:24]3)[CH:19]=[CH:20][C:21]=2[CH3:22])=[CH:13][CH:12]=1)(C)C.[NH2:36][C:37]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O)=O>>[CH3:22][C:21]1[CH:20]=[CH:19][C:18]([C@H:23]2[C@H:28]([OH:29])[C@@H:27]([OH:30])[C@H:26]([OH:31])[C@@H:25]([S:32][CH3:33])[O:24]2)=[CH:17][C:16]=1[CH2:15][C:14]1[CH:34]=[CH:35][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][NH:36][C:37]2([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:12][CH:13]=1
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCNC(C)(C)CO)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: NC(=O)C1(N)CCCC1
Solvent: O=CO
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCNC4(C(N)=O)CCCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The same procedure was employed as for amine 24, using 1-aminocyclopentanecarboxamide, to provide the product 26 with 0.5 equivalents of formic acid. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.52 (s, 0.5 H, formate), 6.98-7.22 (m, 7 H), 4.39 (d, J=9.6 Hz, 1 H), 4.13 (d, J=9.3 Hz, 1 H), 3.91-4.01 (m, 2 H), 3.34-3.51 (m, 3 H), 2.50-2.68 (m, 4 H), 2.21 (s, 3 H), 2.14 (s, 3 H), 2.10 (d, J=7.3 Hz, 2 H), 1.73-1.87 (m, 6 H), 1.63-1.72 (m, 2 H), 1.58 (d, J=7.1 Hz, 2 H). MS (ES+) [M+H]+=543.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:8]([Cl:11])=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>OS(O)(=O)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12]([F:15])([F:13])[F:14])[C:8]([Cl:11])=[CH:9][C:10]=1[N+:16]([O-:18])=[O:17])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To 3-acetamido-6-chlorobenzotrifluoride (908 mg, 3.82 mmol) in concentrated H2SO4 (4 mL) at 0° C. was added dropwise 70% HNO3 (0.5 mL, Baker). The mixture was stirred at 0° C. for 0.5 h, then at room temperature 3 h, and it was poured into ice water (15 g). The precipitate was collected by filtration, affording 990 mg (91%) of crude 3-acetamido-6-chloro-4-nitrobenzotrifluoride. It was crystallized from EtOH/H2O to give 770 mg of pure compound as yellow needles. 1H NMR (CDCl3): δ2.326 (s, 3H), 8.345 (s, 1H), 9.293 (s, 1H), 10.222 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]#[N:19])=[C:6]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:7]=1.[CH3:20][C:21]1[CH:29]=[C:28]([C:30]([F:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])[CH:27]=[C:26]([CH3:40])[C:22]=1[C:23](Cl)=[O:24]>O1CCCC1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[C:18]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:23](=[O:24])[C:22]2[C:21]([CH3:20])=[CH:29][C:28]([C:30]([F:39])([C:31]([F:32])([F:33])[F:34])[C:35]([F:36])([F:37])[F:38])=[CH:27][C:26]=2[CH3:40])=[CH:7][C:6]=1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)#[N:19]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1C(=O)Cl
Reactant: N#Cc1ccc(N)cc1NC(=O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1C(=O)Nc1ccc(C#N)c(NC(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 30.2 %

Procedure:
To a solution of N-(5-amino-2-cyano-phenyl)-4-fluoro-benzamide (0.20 g, 0.78 mmol) (Example I9) in anhydrous tetrahydrofuran (2.5 ml) under an atmosphere of nitrogen was added at room temperature a solution of 2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzoyl chloride (0.332 g, 1.04 mmol) (Example I4) in anhydrous tetrahydrofuran (2.5 ml). The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted with ethyl acetate and aqueous sodium hydrogen carbonate (saturated). The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 3:1) to give N-[4-cyano-3-(4-fluoro-benzoylamino)-phenyl]-2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzamide (131 mg, 66% yield). 1H-NMR (CDCl3, 400 MHz): 8.98 (s, 1H), 8.51 (d, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 8.21 (dd, 1H), 7.84 (m, 2H), 7.68 (d, 1H), 7.34 (s, 1H), 6.78 (t, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:18].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].CC(=O)CC.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CN(C)C=O>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][O:18][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[CH:9][S:8][C:7]=2[C:2]=1[Cl:1])[CH3:25]
Reactant: Oc1ccc2c(-c3ccccc3F)csc2c1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CCOC(=O)COc1ccc2c(-c3ccccc3F)csc2c1Cl
Yield: 78.2 %

Procedure:
A mixture of 8.3 g of 7-chloro-6-hydroxy-3-(2-fluorophenyl)benzo[b]thiophene, 6.0 g of ethyl bromoacetate, 60 ml of 2-butanone, 5 ml of dimethylformamide and 4 g of potassium carbonate is heated under reflux until the standing material completely dissolves. Methylene chloride is added to the cooled reaction mixture and the resultant precipitate is collected. Evaporation of the filtrate gives 8.5 g of ethyl{[7-chloro-3-(2-fluorophenyl)benzo[b]thien-6-yl]oxy}acetate.
Reaction SMILES: Cl[C:2]([Cl:13])([Cl:12])[C:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[C:14](#[N:17])[CH:15]=[CH2:16].[ClH:18].N1C=CC=CC=1>[Cu].S1(CCCC1)(=O)=O>[C:14]([CH:15]([Cl:18])[CH2:16][C:2]([Cl:12])([Cl:13])[C:3]([O:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:4])#[N:17]
Reactant: O=C(Oc1ccccc1)C(Cl)(Cl)Cl
Reactant: Cl
Reactant: C=CC#N
Agent: [Cu]
Solvent: c1ccncc1
Solvent: O=S1(=O)CCCC1
Product: N#CC(Cl)CC(Cl)(Cl)C(=O)Oc1ccccc1
Temperature: 125 °C
Reaction time: 10 h
Yield: 76 %

Procedure:
51 g of phenyl trichloroacetate, 17.5 ml of acrylonitrile, 0.88 g of cuprous chloride, 0.3 g of pyridine hydrochloride and 80 ml of anhydrous sulfolane were charged into a glass lined pressure reactor and heated with stirring at 125° C. for 10 hours. After cooling to ambient temperature, the brown reaction mixture was found to be homogeneous but for undissolved copper salts. GLC analysis indicated a yield of 76% (±1.5%) of the title compound based on phenyl trichloroacetate. The title compound was isolated by pouring the reaction mixture into water, extracting with several portions of methyl t-butyl ether and washing the organic phase with water. Drying (MgSO4) and subsequent removal of the combined organic extract by evaporation under reduced pressure yielded a light brown viscous oil which crystallized slowly on standing at ambient temperature. The resulting crystals were recrystallized from ether-petroleum ether (60-80) to give colorless needles of phenyl 4-cyano-2,2,4-trichlorobutyrate, m.p. 51.5°-52.5° C.;
Reaction SMILES: C[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:8][OH:9]>O>[CH:8]([OH:9])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCCCC
Reactant: CO
Solvent: O
Product: OC(c1ccccc1)c1ccccc1
Yield: 16.7 %

Procedure:
A procedure analogous to that described in Example 5 was used for obtaining a liquid mixture of 1,3-diketones, using CE-810 (Procter & Gamble) as the starting methyl ester. This ester had the following chain length distribution: C6: 4.1 weight %; C8: 52.8%; C10: 42.7%; and C12: 0.3%. For the preparation of potassium benzhydroxide, 103.36 g (0.561 mol) of benzhydrol was reacted with 0.55 mol of potassium hydroxide as described in Example 4. After addition of the ester (71.5 g; 0.425 mol), acetophenone (44.06 g; 0.367 mol) was added over a period of 12 minutes and the mixture was allowed to react for a total of 70 minutes. The mixture was allowed to cool to room temperature, and was acidified with 10% sulfuric acid. The cumene layer was washed with water until the washes were neutral, and then concentrated under vacuum in a rotary evaporator. The residue was treated with heptane, allowed to stand for a few minutes, and then filtered, affording pure benzhydrol (63.2 g; 61.1% yield). The heptane was removed under vacuum. More benzhydrol was obtained by adding 500 mL of heptane, 500 mL of methanol, and 250 mL of water, stirring, removing the lower layer, and repeating this extraction several times. Upon evaporation of the lower layer under vacuum in a rotary evaporator, and washing the resulting crystals with heptane, 17.3 g of benzhydrol (16.7% yield) was obtained. Evaporation of the solvents in the upper layer afforded 80.0 g (85% yield) of CBM with a purity of over 95% (GC).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN(C)C(=O)C.Br[C:21]1[C:22](Cl)=[N:23][CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1>[Pd].C(O)(=O)C.O>[N+:27]([C:25]1[CH:26]=[C:21]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:13][C:22]2=[N:23][CH:24]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Reactant: Oc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1cnc2oc3ccccc3c2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
Potassium carbonate (87 mg) and phenol (47 mg) were added to an N,N-dimethylacetamide (1 ml) solution containing 3-bromo-2-chloro-5-nitropyridine (100 mg), followed by stirring at 70° C. for 3 hours. Acetic acid palladium (20 mg) was added in a nitrogen atmosphere, followed by stirring at 100° C. for 3.5 hours. Water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, hexane and ethyl acetate were added to the obtained residue, an insoluble precipitate was collected by filtration, and a light yellow solid of 3-nitrobenzofuro[2,3-b]pyridine (47.1 mg) was thus obtained.