Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:6]([OH:7])[CH:5]=1.C(=O)([O-])[O-].O([CH2:26][C:27]([F:30])([F:29])[F:28])S(C(F)(F)F)(=O)=O>CN(C=O)C.C(Cl)Cl>[CH3:10][O:9][C:8]1[CH:11]=[CH:12][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:5][C:6]=1[O:7][CH2:26][C:27]([F:30])([F:29])[F:28]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
To a mixture of isovanillic acid methyl ester (33.0 g, 0.18 mol) and potassiuin carbonate (41.4 g, 0.30 mol) in DMF (100 ml) was added a solution of trifluoroethyl triflate [Burdon et al Tetrahedron 21, 1 (1965)] (65.0 g, 0.28 mol) in CH2Cl2. The mixture was stirred at room temperature for 18 h then evaporated to 50 ml, the mixture partitioned between ether and H2O, the organic layer washed with H2O and saturated brine, then dried over MgSO4 and evaporated. The resulting solid was triturated with hexane to give the subtitle compound as an off-white solid (42.55 g, 90%). Rf 0.47 (CH2Cl2). MS m/z 265 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.[F:14][C:15]([F:27])([F:26])[C:16]1[CH:17]=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1>>[CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH:13][S:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:14])([F:26])[F:27])[CH:17]=3)(=[O:24])=[O:23])=[N:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(COCC2CC2)cn1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: O=S(=O)(Nc1ccc(COCC2CC2)cn1)c1cccc(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 5-cyclopropylmethoxymethyl-pyridin-2-ylamine (0.051 g) and 3-(trifluromethyl)-benzenesulfonyl chloride (0.077 g) as a crystalline white solid (0.062 g). MS (ESI−): 385.0 ([M−H]−)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[C:6](N(OC)C)=[O:7])[CH3:2].Br[C:17]1[C:22]([N:23]([CH2:38][O:39][CH3:40])[S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=2)(=[O:26])=[O:25])=[CH:21][C:20]([Cl:41])=[CH:19][N:18]=1>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([S:24]([N:23]([C:22]2[C:17]([C:6](=[O:7])[C:5]3[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=3[O:3][CH2:1][CH3:2])=[N:18][CH:19]=[C:20]([Cl:41])[CH:21]=2)[CH2:38][O:39][CH3:40])(=[O:26])=[O:25])=[CH:28][C:29]=1[C:34]([F:35])([F:37])[F:36]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCOc1ccccc1C(=O)N(C)OC
Product: CCOc1ccccc1C(=O)c1ncc(Cl)cc1N(COC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
4-Chloro-N-[5-chloro-2-(2-ethoxy-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide was prepared from 2-ethoxy-N-methoxy-N-methyl-benzamide and N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide according to previously described procedure in example 29. The product was purified by flash column chromatography on silica gel using ethyl acetate-hexane. MS m/z: 562.4 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:19][CH2:20]O>>[CH2:19]([O:12][C:11]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:10][CH2:9]1)=[O:13])[CH3:20]
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(c2ccc(Br)cc2)CC1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid (5 g, 20.7 mmol) in EtOH (50 mL) was treated with sulfuric acid (2 mL), and the reaction was stirred at 75° C. for 1 hour. The mixture was worked up to give the title compound.
Reaction SMILES: CO[CH:3]([O:22]C)[C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH:9]([O:20][CH3:21])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.C([Li])CCC.CN(C)[CH:31]=[O:32].S(=O)(=O)(O)O>O1CCCC1.CCCCCC>[CH3:21][O:20][CH:9]([C:5]1[S:6][C:7]([CH:31]=[O:32])=[CH:8][C:4]=1[CH:3]=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(C(OC)c2sccc2C(OC)OC)cc1OC
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(OC)c2sc(C=O)cc2C=O)cc1OC
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
16.9 g of 3-dimethoxymethyl-2-(α-methoxy-3,4-dimethoxybenzyl)thiophene are dissolved in 200 ml of tetrahydrofuran. 37.5 ml of 1.6M n-butyl lithium in hexane are added dropwise thereto at -78° C., and the reaction mixture is warmed up to -30° C. gradually. After the mixture is chilled at -78° C., 4.3 ml of N,N-dimethylformamide are added thereto. The mixture is stirred for 30 minutes. The reaction mixture is warmed up to ambient temperature. The mixture is acidified with diluted sulfuric acid, stirred for one hour and extracted with chloroform. The extract is washed with aqueous sodium bicarbonate solution and water, dried and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography [solvent: hexane-ethyl acetate (2:1)], and the eluate is condensed. 14.6 g of 2-(α-methoxy-3,4-dimethoxybenzyl)thiophen-3,5-dicarbaldehyde are obtained as an oil.
Reaction SMILES: [CH2:1]([C:7](=[CH2:10])[CH:8]=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:11][O:12][C:13]([CH3:15])=[CH2:14]>[I-].[Zn+2].[I-]>[CH2:1]([C:7]1[CH2:10][CH2:14][C:13]([O:12][CH3:11])([CH3:15])[O:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=C(C=O)CCCCCC
Reactant: C=C(C)OC
Agent: [I-]
Agent: [Zn+2]
Product: CCCCCCC1=COC(C)(OC)CC1
Reaction time: 6 h
Yield: 15.4 %

Procedure:
To a zinc iodide suspension (0.21 g, 0.671 mmol) in 42 g (0.3 mol) of 2-hexyl-2-propenal there were added dropwise, at 60° C. and under nitrogen, 18.5 g (0.25 mol) of 2-methoxypropene. Once the introduction was completed (23 min), the reaction was allowed to continue for 6 h at 60° C. and the mixture was then distilled on a Vigreux column to give 8.16 g of 5-hexyl-3,4-dihydro-2-methoxy-2-methyl-2H-pyran (B.p. 73°-74°/3 Pa; yield 15.4%).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH2:9]([O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([C:27](O)=[O:28])[CH:21]=[CH:20]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl.C(N=C=NCCCN(C)C)C.O>C(Cl)Cl>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([C:27]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])=[O:28])[CH:21]=[CH:20]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCCCOc1ccc2cc(C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCCCCOc1ccc2cc(C(=O)ON3C(=O)CCC3=O)ccc2c1
Reaction time: 3 h
Yield: 79.5 %

Procedure:
To a susupension of N-hydroxysuccinimide (0.56 g) and 6-heptyloxy -2-naphthoic acid (1.39 g) in methylene chloride (42 ml) was added 1-ethyl -3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.21 g) and stirred for 3 hours at room temparature. The reaction mixture was added to water (100 ml). The organic layer was separated and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give succinimido 6-heptyloxy -2-naphthoate (1.48 g).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7].[Br:9]N1C(=O)CCC1=O>CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7]
Reactant: Cc1oc(=O)oc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1oc(=O)oc1CBr
Yield: 106.5 %

Procedure:
4,5-Dimethyl-1,3-dioxolene-2-one (11.4 g) was mixed with N-bromosuccinimide (19.6 g) and 2,2-azobis(2-methylpropionitrile) (0.5 g) in freshly distilled carbon tetrachloride (350 mL) and refluxed for 6 hours under an argon atmosphere. The reaction mixture was cooled in an ice bath after reflux and the precipitate formed was filtered off. The tiltrate was washed with water and brine, and dried over sodium sulfate. The solvent was evaporated to yield a yellow oil (20.54 g) which was distilled to obtain the pure monobromomethyl compound as a light yellow oil (11.86 g, 54%), bp 93° C. at 0.45 mm; 1H NMR (CDCl3) δ2.15 (s, 3H), 4.21 (S, 2H); IR (film) 1820, 1728, 1392, 1201, 1236, 768 cm-1.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C@@H:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1)[C:10]1[CH:22]=[CH:21][C:13]([C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1.[C:30]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O)([OH:32])=[O:31].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH2:17]([N:16]([CH2:19][CH3:20])[C:14]([C:13]1[CH:21]=[CH:22][C:10]([C@H:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[N:3]2[C@@H:2]([CH3:1])[CH2:7][N:6]([CH2:36][C:35]3[CH:34]=[C:33]([CH:40]=[CH:39][CH:38]=3)[C:30]([OH:32])=[O:31])[C@H:5]([CH3:8])[CH2:4]2)=[CH:11][CH:12]=1)=[O:15])[CH3:18]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)NC[C@@H]2C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)N(Cc3cccc(C(=O)O)c3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.3 %

Procedure:
The 4-[(R)-((2S,5R)-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide (2.50 g, 6.32 mmol) and 3-carboxybenzaldehyde (1.90 g, 12.64 mmol) were placed in a 250 mL flask with 60 mL of tetrahydrofuran and 0.80 mL (13.91 mmol) of acetic acid. The reaction was stirred at room temperature for 20 minutes, and sodium triacetoxyborohydride (2.68 g, 12.64 mmol) was added portionwise. The reaction solution became very turbid and was sealed under mntrogen and stirred overnight. The reaction mixture was evaporated to dryness and partitioned between ethyl acetate (60 mL) and 3M HCl (12 mL). The organic layer was extracted with a further 5×12 mL 3M HCl. The combined aqueous extracts were adjusted to pH 4.5-5 with 0.5 M NaOH solution and solid Na2CO3 The resulting gel was collected by filtration, dissolved in 30 mL of 0.5 M NaOH solution, and extracted with 20 mL of EtOAc/Et2O twice to remove impurities. 1M HCl was added dropwise to the aqueous solution to the precipitation point at pH 4.5-5. The resulting white gel was collected by filtration and washed with a small volume of cold water. The 3-{(2R,5S)-4-[(R)-(4-diethylcarbamoylphenyl)-(3-hydroxyphenyl)methyl]-2,5-dimethylpiperazin-1-ylmethyl}benzoic acid was dried in a vacuum oven (30 mmHg, 40° C.) to give 1.55 g of white solid. 1 H NMR (300 MHz, d6-DMSO): δ 0.99-1.20 (m, 12H); 1.89-2.05 (m, 2H); 2.48-2.65 (m, 5H); 3.06-3.57 (m, 5H); 3.78-3.83 (d, J=12.5 Hz, 1H); 4.94 (s, 1H); 6.63-6.84 (m, 3H); 7.09-7.91 (m, 9H); 9.36 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].CS(O[CH2:27][CH2:28][C:29]1[CH:33]=[CH:32][S:31][CH:30]=1)(=O)=O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[N:14]([CH2:27][CH2:28][C:29]3[CH:33]=[CH:32][S:31][CH:30]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3cc(F)ccc23)CC1
Reactant: CS(=O)(=O)OCCc1ccsc1
Product: CCOC(=O)N1CCC(c2cn(CCc3ccsc3)c3cc(F)ccc23)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 101.3 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) starting with 4 g (13.8 mmol) of 4-(6-fluoro-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester (example 24, part A) and 3.3 g (16 mmol) of 2-thiophen-3-yl-ethyl methansulfonate. The reaction mixture was stirred at 60° C. for 3 hours. After standard work-up, 5.6 g (100% of yield) of 4-[6-fluoro-1-(2-thiophen-3-yl-ethyl)-1H-indol-3-yl]-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:45])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:32](=[N:40][S:41](=[O:44])(=[O:43])[NH2:42])OC5C=CC=CC=5)[CH2:28][CH2:27]4)[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1.[NH3:46]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:45])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:32](=[NH:46])[NH:40][S:41](=[O:43])(=[O:44])[NH2:42])[CH2:28][CH2:27]4)[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1
Reactant: N
Reactant: NS(=O)(=O)N=C(Oc1ccccc1)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Solvent: C1CCOC1
Product: N=C(NS(N)(=O)=O)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 84 %

Procedure:
Phenyl 4-[2-[4-(3-bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperazinyl]-2-oxoethyl]-N-sulfamoyl-1-piperidinecarboximidate (Formula 6.0) (prepared as described in Example 5above) (0.089 g, 0.1 mmoles) was dissolved in anhydrous THF (1 ml). A saturated solution of ammonia in anhydrous THF (4 ml) was added and the mixture was stirred in a sealed reaction vessel at 25° C. for 19 h. The mixture was evaporated to dryness and chromatographed on silica gel using 2%-6% methanol in dichloromethane as the eluant to give the title compound (Formula 7.0) (0.0667 g, 84%), ESIMS: m/z 638.0 (MH+).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][CH:9]([C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([OH:23])=[C:15]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:14]=2)[C:10](O)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.ON1C2C=CC=CC=2N=N1.C>CO.C(Cl)Cl>[CH2:28]([NH:35][C:10](=[O:11])[CH:9]([NH:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:13]1[CH:18]=[C:17]([C:19]([CH3:21])([CH3:20])[CH3:22])[C:16]([OH:23])=[C:15]([C:24]([CH3:25])([CH3:27])[CH3:26])[CH:14]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)c1cc(C(NCC2CCCCC2)C(=O)O)cc(C(C)(C)C)c1O
Reactant: NCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1cc(C(NCC2CCCCC2)C(=O)NCc2ccccc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.4 %

Procedure:
To a methylene chloride (5 mL) solution of Example 22 (0.36 g, 0.96 mmol) was added benzyl amine (110 mg, 1.0 mmol), N,N1 -dicyclohexylcarbodiimide (DCC) (206 mg, 1.0 mmol), and 1-hydroxybenzotriazole (HOBT) (135 mg, 1.0 mmol). The solution was stirred at room temperature for 24 hours. The mixture was filtered free of insolubles and the filtrate evaporated to give an oil. The oil was dissolved in methanol (30 mL) treated with charcoal and evaporated to a foam. The foam was dissolved in ethyl acetate (75 mL) and washed with saturated sodium bicarbonate (50 mL) and then dried over magnesium sulfate. This was purified by chromatography (125 g silica gel, 2% methanol in methylene chloride). The appropriate fractions were combined and evaporated in vacuo to give 0.10 g (22%) of product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[I:16]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[C:7]([I:16])=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Nc1ncc(Br)cc1I
Temperature: 50 °C

Procedure:
To a solution of 2-amino-5-bromopyridine (2) in DMF was added trifluoroacetic acid (1.2 equiv). At room temperature, N-iodosuccinimide (1.1 equiv) was added and the reaction mixture was heated at 50° C. for 3 h. HPLC indicated complete conversion. After cooling to room temperature the product was precipitated by adding the reaction mixture to water. After neutralization with sodiumthiosulfate and 1N NaOH the title compound (11) was collected by filtration as a brown solid in 90% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH:8]([OH:22])[CH2:7]1)=[O:5])[CH3:2].[Na].[H-].[Na+].[CH3:26]I>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH:8]([O:22][CH3:26])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)N1CCc2c(nc3ccccc3c2C)C(O)C1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCc2c(nc3ccccc3c2C)C(OC)C1

Procedure:
2 gm (6.65 millimols) of 5-hydroxy-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester were converted into the sodium salt in 50 ml of absolute tetrahydrofuran with 0.32 gm (7 millimols) of 50% sodium hydride, and the salt was methylated with 0.43 ml (7 millimols) of methyl iodide.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14])=[O:5])#[N:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[C:1]([C:3](=[CH:17][N:18]([CH3:20])[CH3:19])[C:4]([NH:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14])=[O:5])#[N:2]
Reactant: N#CCC(=O)Nc1cc(F)ccc1F
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C#N)C(=O)Nc1cc(F)ccc1F

Procedure:
As for Example 1, 2-cyano-2',5'-difluoroacetanilide, colorless crystals, m.p. 165°-167° C. (prepared by the procedure described in U.S. Pat. No. 3,116,312), is heated with N,N-dimethylformamide dimethylacetal to give 2-cyano-3-dimethylamino-2',5'-difluoroacrylanilide as colorless needles, m.p. 175°-176° C.
Reaction SMILES: [NH3:1].[C:2]([NH:5][C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]([O:13]C)=O)[CH2:7]1)(=[O:4])[CH3:3]>CO>[C:2]([NH:5][C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]([NH2:1])=[O:13])[CH2:7]1)(=[O:4])[CH3:3]
Reactant: COC(=O)[C@@H]1CC[C@H](NC(C)=O)C1
Reactant: N
Solvent: CO
Product: CC(=O)N[C@H]1CC[C@@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ammonia gas was passed into a solution of (1R,3S)-methyl 3-acetamidocyclopentanecarboxylate (180 mg, 0.96 mmol) in MeOH (5 ml) at −78° C. in a pressure bomb. The reaction mixture was slowly warmed up to room temperature and stirred for 18 h at 100° C. The reaction mixture was concentrated under reduced pressure to afford 150 mg of (1R,3S)-3-acetamidocyclopentanecarboxamide as brown oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[N:15]1[C:19]([NH:20][C:21]([CH3:23])=[O:22])=[CH:18][CH:17]=[N:16]1.C(OC(=O)C)(=O)C.[N+:31]([O-])([OH:33])=[O:32]>C(O)(=O)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:10])[F:11])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[N:15]1[C:19]([NH:20][C:21]([CH3:23])=[O:22])=[C:18]([N+:31]([O-:33])=[O:32])[CH:17]=[N:16]1
Reactant: CC(=O)Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Temperature: 25 °C
Yield: 63.4 %

Procedure:
A stirred solution of 7.86 grams (0.0230 mole) of 1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-5-methylcarbonylaminopyrazole in 20 mL of glacial acetic acid was cooled in an ice-water bath. Acetic anhydride (2.9 mL, 0.031 mole) was added dropwise, and the mixture was stirred briefly. Concentrated nitric acid (1.05 mL, 0.0245 mole) was added dropwise, and the reaction mixture was allowed to warm to room temperature and was stirred for four hours. The mixture was poured into 60 mL of ice-water and stirred, forming a granular yellow solid. This solid was collected by filtration and washed with water. The solid was purified by recrystallization from ethanol and water to yield 5.63 grams of 1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl) -5-methylcarbonylamino-4-nitropyrazole, m.p. 136.5-138.5° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:22]2[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:21]=2[NH:20][C:19](=O)[CH2:18][N:17]=1>CC(C)=O>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:22]2[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:21]=2[N:20]([CH3:19])[C:1](=[O:4])[CH2:18][N:17]=1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN1C(=O)CN=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
42.4 g of potassium carbonate and 18.5 ml of methyl iodide are added to a solution of 50 g (0.158 mol) of 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one in 600 ml of acetone and the mixture is stirred at room temperature for 16 hours. After filtering-off insoluble material, the filtrate is evaporated and the residue is taken up in methylene chloride. The organic phase is washed once with water, dried and evaporated, there being obtained 5-(o-chlorophenyl)-1,3-dihydro-1-methyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 220°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21](=[O:22])[N:20]([CH3:23])[C:11]3[N:12]([CH3:19])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[Br:24][CH2:25][C:26](Cl)=[O:27]>>[Br:24][CH2:25][C:26]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:19])[C:11]1[N:20]([CH3:23])[C:21](=[O:22])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][C:10]2=1)=[O:27]
Reactant: O=C(Cl)CBr
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2)cc2c3ccccc3n(C)c21
Product: Cn1c(=O)c(-c2ccc(Cl)cc2)cc2c3cc(C(=O)CBr)ccc3n(C)c21

Procedure:
The process is carried out as in preparation 1.1 above, using compound from Example 104A, 3-(4-chlorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and bromoacetyl chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][C:28]=1[N+:29]([O-])=O)[CH2:12][CH:13]1[NH:19][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[NH:15][C:14]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CO.[Pt]=O>[NH2:29][C:28]1[CH:27]=[CH:26][C:11]([CH2:12][CH:13]2[NH:19][C:18](=[O:20])[C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[NH:15][C:14]2=[O:25])=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(Cc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)C(=O)Nc2ccccc21
Agent: O=[Pt]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(CC2NC(=O)c3ccccc3NC2=O)cc1OCc1ccccc1

Procedure:
A solution of the title J compound, 3-(3-benzyloxy-4-nitro-benzyl)-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dione (196 mg, 0.47 mmol) in EtOAc-methanol (1:1, 44 mL) is hydrogenated over platinum oxide (22 mg) at atmospheric pressure for 1 h. The catalyst is filtered off and the filtrate is evaporated to dryness to give 3-(4-amino-3-benzyloxy-benzyl)-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dione as a foam: [M+1]+=388.