Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:15]([C:16]([O:18]C)=[O:17])C3C=C(C=CC(OC)=O)C=C(OC)C=3O2)[CH:6]=[CH:7][C:8]=1[O:9]C.CC(C)=O.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[OH:9])[CH:11]=[CH:15][C:16]([OH:18])=[O:17]
Reactant: COC(=O)C=Cc1cc(OC)c2c(c1)C(C(=O)OC)C(c1ccc(OC)c(OC)c1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C=CC(=O)O)ccc1O
Yield: 330.9 %

Procedure:
1 g of methyl 3-[2-(3,4-dimetoxyphenyl)-7-methoxy-3-methoxycarbonyl-2,3-dihydro -1-benzofuran-5-yl]prop-2-enoate, 10 mL of acetone and 2.5 mL of water were mixed and stirred to dissolve. Then, 3% NaOH (6 mL) was added to the mixture and stirred for 0.5 hr. After reaction completed, the mixture was acidified and purified by chromatography on silica gel column with a 1:2:0.8 V/V mixture of petroleum ether, ethyl acetate and acetic acid as eluent. After removing solvent, it gave 1.5 g yellow solid of 5-[(E)-2-carboxyethenyl]-2-(3,4-dimetoxyphenyl)-2,3-dihydro-7-methoxy-3-benzofurancarboxylic acid (IM2).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([F:28])[C:26]=1[F:27]>>[CH3:17][C:7]1[C:6]2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=[C:2]([C:23]3[CH:22]=[C:21]([F:20])[C:26]([F:27])=[C:25]([F:28])[CH:24]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]=12
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4cc(F)c(F)c(F)c4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, off-white solid (37 mg, 40%), MS (ISP) m/z=370.4 [(M+H)+], mp 306° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 3,4,5-trifluoro-phenylboronic acid (57.2 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[CH:11]12[C:20](=O)[O:19][C:17](=[O:18])[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]2>C(O)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[N:4]1[C:17](=[O:18])[CH:12]2[CH:11]([CH2:16][CH2:15][CH2:14][CH2:13]2)[C:20]1=[O:19]
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: Nc1c(F)cc(F)cc1F
Solvent: CC(=O)O
Product: O=C1C2CCCCC2C(=O)N1c1c(F)cc(F)cc1F

Procedure:
9.54 Parts of 2,4,6-trifluoroaniline were added to a solution of 10 parts of cyclohexane-1,2-dicarboxylic anhydride in 100 parts of glacial acetic acid. The mixture was refluxed for 20 hours and the resulting mixture was poured into 200 parts of ice. The resulting crystals were filtered, dried and recrystallized twice from 70 parts of methanol at -40° C to yield 8.3 parts of white crystals of 2-(2,4,6-trifluorophenyl)-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)-dione melting at 129°-131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:3]=1.[Cl-].[NH4+].C(OCC)(=O)C>C(O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Oc1ccc(F)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)cc1Oc1ccc(F)cc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a solution of 4-chloro-2-(4-fluorophenoxy)-1-nitrobenzene (4.56 g, 17.0 mmol) and iron powder (3.07 g, 55.0 mmol) in ethanol (20 mL), a saturated aqueous ammonium chloride solution (aq., 8.0 mL) was added, and the mixture was stirred at 90° C. for 30 minutes. After the reaction, the reaction mixture was cooled to room temperature, and ethyl acetate (30 mL) was added. After the organic phase was washed with water (30 mL), 1N sodium hydroxide (aq., 30 mL) and saturated brine (20 mL), it was dried with sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound (3.62 g, 90%). The obtained compound was used for the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([Cl:15])[CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:16])[CH:2]=CC.C[OH:18]>ClCCl>[Cl:15][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6](=[O:16])[CH:5]([CH2:1][CH:2]=[O:18])[CH2:14][CH2:13]2
Reactant: CC=CCC1CCc2cccc(Cl)c2C1=O
Reactant: CO
Solvent: ClCCl
Product: O=CCC1CCc2cccc(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 83 %

Procedure:
7.7 g of 2-(2-buten-1-yl)-8-chloro-1-tetralone were dissolved in a mixture of 220 ml of dichloromethane and 60 ml of methanol, cooled to -75° and the double bond was ozonized in the usual manner. After flushing the reaction mixture with oxygen and argon, 4.8 ml of dimethyl sulfide were added dropwise. The mixture was left to warm slowly to room temperature and was stirred for an additional 15 hours. The crude product (10.8 g) was dissolved in about 100 ml of dichloromethane and added to a mixture of 12 ml of 10% aqueous oxalic acid, 120 g of silica gel and 300 ml of dichloromethane. The mixture was stirred at room temperature for 2 hours. 6.4 g (83%) of 8-chloro-2-(2-oxoethyl)-1-tetralone were obtained as a pale brown oil by extraction with dichloromethane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([O:14][CH2:15][CH3:16])[C:11]([OH:13])=O.Cl.Cl.[CH2:19]([O:26][C:27](=[O:39])[NH:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33][CH:32]=1)=[NH:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCN(CC)CC>[CH2:19]([O:26][C:27](=[O:39])[NH:28][C:29]([C:31]1[CH:32]=[CH:33][C:34]([CH2:37][NH:38][C:11](=[O:13])[CH:10]([C:3]2[C:4]([F:9])=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[F:1])[O:14][CH2:15][CH3:16])=[CH:35][CH:36]=1)=[NH:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(C(=O)O)c1c(F)cc(O)cc1F
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(C(=O)NCc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1)c1c(F)cc(O)cc1F
Temperature: 25 °C
Yield: 67.6 %

Procedure:
(RS)-(2,6-Difluoro-4-hydroxy-phenyl)-ethoxy-acetic acid (2.3 g) was dissolved in DMF (75 ml) and [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid benzyl ester dihydrochloride [Prepared according to Ch. Lila, Ph. Gloanec, L. Cadet, Y. Hervé, J. Fournier, F. Leborgne, T. J. Verbeuren, G. De Nanteuil, Synthetic Communications 1998, 28, 23, 4419–4429] (3.18 g) and HOBt (2.15 g) were successively added. The slurry was cooled in an ice bath and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.05 g) was added. Et3N (8.0 ml) was slowly added. The resulting mixture was left to stir over night warming up to rt. After removing the solvent precipitation from CH2Cl2/MeOH 19:1 yielded the product. Drying over night on the high vacuum afforded 3.0 g (60 g) of pure (RS)-[(4-{[2-(2,6-difluoro-4-hydroxy-phenyl)-2-ethoxy-acetylamino]-methyl}-phenyl)-imino-methyl]-carbamic acid benzyl ester. White solid. MS 498.3 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1.C1(O)C=CC=CC=1>O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[CH:3]=[C:2]([N:20]3[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Cc1ccc2nc(-c3ccc(Cl)cc3)cc(Cl)c2c1
Solvent: O
Solvent: Oc1ccccc1
Product: Cc1ccc2nc(-c3ccc(Cl)cc3)cc(N3CCC(C(N)=O)CC3)c2c1

Procedure:
A mixture of 10 g (35 mmol) of 4-chloro-2-(4-chlorophenyl)-6-methylquinoline, 8.9 g (70 mmol) of isonipecotamide, and 20 g of phenol was stirred and heated in an oil bath at 165°-170° for 3.5 hr. It was then cooled and diluted with water. Crystallization was induced by the addition of ethanol and scratching. The solid was collected and washed with ether to give 11.9 g of crude product. Recrystallization from pyridine gave the named compound as off-white prisms, mp 261°-265° dec.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:11]([S:14]CC1C=CC(OC)=CC=1)[CH:12]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C@H:32]([C:34]([N:36]1[CH2:47][CH2:46][CH2:45][C@H:37]1[C:38]([O:40]C(C)(C)C)=[O:39])=[O:35])[CH3:33].C(O)C.C([BH3-])#N.[Na+]>O1CCCC1>[C:1]([NH:9][C@@H:10]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:11]([SH:14])[CH2:12][NH:31][C@H:32]([C:34]([N:36]1[CH2:47][CH2:46][CH2:45][C@H:37]1[C:38]([OH:40])=[O:39])=[O:35])[CH3:33])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: COc1ccc(CS[C@H](C=O)C(Cc2ccccc2)NC(=O)c2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@H](NCC(S)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 2.5 h

Procedure:
A mixture of (S)-β-(benzoylamino)-α-[[(4-methoxyphenyl)methyl]thio]-benzenebutanal (isomer A) (0.45 g., 1.07 mmole), L-alanyl-L-proline, 1,1-dimethylethyl ester (0.78 g., 3.21 mmole), and crushed 3A° molecular sieves (2 g.) in tetrahydrofuran (5 ml.) and absolute ethanol (5 ml.) is stirred at room temperature under argon. After 2.5 hours, sodium cyanoborohydride (0.20 g., 3 eq.) is added and stirring continued for 15 hours. The reaction mixture is filtered to remove the sieves and the filtrate is diluted with ethyl acetate and washed with water, 1N hydrochloric acid (twice), 1N sodium bicarbonate, and brine. After drying over anhydrous MgSO4, the solvent is removed to give the desired product, as a mixture of diastereomers, as a pale yellow oil. TLC (silica gel, benzene:acetone, 4:1) isomer A at Rf =0.30 and isomer B at Rf =0.13. Flash chromatography (silica gel LPS-1; benzene:acetone, 7:3) affords impure product (isomer A). Repeated flash chromatography (silica gel LPS-1; ethyl acetate:benzene, 6:4) gives 0.20 g. of 1-[N-[(3S)-3-(benzoylamino)- 2-[[(4-methoxyphenyl)methyl]thio]-4-phenylbutyl]L-alanyl]-L-proline, 1,1-dimethylethyl ester (isomer A) as a nearly colorless oil.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl.Cl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:9][CH2:8][CH2:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: OCCCC1CCCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(OCCCC1CCCC1)c1ccc(Br)cc1
Reaction time: 16 h
Yield: 83.1 %

Procedure:
To a solution of 3-cyclopentyl-1-propanol (2.0 g, 15.6 mmol) in triethylamine (3.25 ml, 23.4 mmol) and dichloromethane (50 ml) was added 4-bromobenzenesulfonyl chloride (4.4 g, 17.6 mmol). The solution was stirred for 16 h, diluted with 2 N aqueous hydrochloric acid (100 ml) and extracted with dichloromethane (100 ml). The extract was washed with saturated aqueous sodium hydrogen carbonate solution (100 ml) and brine (100 ml), dried (MgSO4) and concentrated in vacuo to give the title compound as a white crystalline solid (4.50 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][N:7]([CH2:15][C@@H:16]([OH:48])[C@@H:17]([NH:27][C:28](=[O:47])[C:29]1[CH:34]=[C:33]([NH:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:32]=[C:31]([C:44](=O)[CH3:45])[CH:30]=1)[CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].Cl.[OH:53][NH2:54]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][N:7]([CH2:15][C@@H:16]([OH:48])[C@@H:17]([NH:27][C:28](=[O:47])[C:29]1[CH:30]=[C:31](/[C:44](=[N:54]/[OH:53])/[CH3:45])[CH:32]=[C:33]([NH:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=1)[CH2:18][C:19]1[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=1)[C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:11])[CH3:13]
Reactant: COc1cccc(CN(C[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(NC(=O)c3ccccc3)cc(C(C)=O)c2)C(=O)OC(C)(C)C)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: COc1cccc(CN(C[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(NC(=O)c3ccccc3)cc(/C(C)=N/O)c2)C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Yield: 49.5 %

Procedure:
A mixture of tert-butyl 3-methoxybenzyl((2R,3S)-3-(3-acetyl-5-(benzamido)benzamido)-4-(3,5-difluorophenyl)-2-hydroxybutyl)carbamate (20 mg, 0.0282 mmol) and hydroxyamine hydrochloride (0.0564 mmol) in ethanol (0.14 mL) was heated at 80° C. for 2 h. The reaction mixture was purified by reverse phase prep HPLC to give the title compound (10 mg): HPLC retention time: 2.255 min (method A). MS (ESI) (M+H)+ 725.53.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](O)=[O:22])[NH:3]1.[C:24]1([CH:30]([NH2:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH:30]([NH:38][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)=[O:22])[CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NC(Cc1ccccc1)c1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(Cc1ccccc1)c1ccccc1
Yield: 68 %

Procedure:
The title compound was prepared in a yield of 68% in a similar manner to that described in Example 1 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and 1,2-diphenylethylamine.
Reaction SMILES: C([CH2:5][C:6]([C@@H:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:12]([O:11][C:9](=[O:10])[C@@H:8]([C:6](=[O:7])[CH3:5])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)CC(=O)[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Yield: 105.3 %

Procedure:
The product from Example 94 (0.52 g, 1.47 mmol) was dissolved in a 1:1 (v:v) solution (6 mL). of trifluoroacetic acid and dichloromethane and stirred at room temperature for 1 h. The volatiles were removed in vacuo to provide the title compound (0.437 g, 100%) as an oil which crystallized on standing. The unpurified material was of sufficient purity to employ in subsequent steps. Mass spectrum: (M)+=298.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)COC)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f49) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([CH3:34])([CH3:33])[CH2:11][C:12]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[O:25])[O:23][N:22]=[C:21]([CH3:26])[C:20]=2[CH:27]=1)=[O:14]>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([CH3:34])([CH3:33])[CH2:11][C:12]([OH:32])([C:28]([F:29])([F:30])[F:31])[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[O:25])[O:23][N:22]=[C:21]([CH3:26])[C:20]=2[CH:27]=1)=[O:14]
Reactant: COc1cccc(C(C)(C)CC(O)(C(=O)Nc2ccc3c(=O)onc(C)c3c2)C(F)(F)F)c1Br
Solvent: ClC(Cl)Cl
Product: Cc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cccc(O)c3Br)C(F)(F)F)cc12

Procedure:
Example 25 is produced analogously to Example 24 starting from the corresponding (−)-6-[4-(2-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one. Flash point 227–231° C., [α]D=−94.3° (c=0.5 in chloroform).
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](OC)=[C:6]([N+:16]([O-:18])=[O:17])[CH:5]=1>CN(C)C=O>[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([NH:2][CH3:1])=[C:6]([N+:16]([O-:18])=[O:17])[CH:5]=1
Reactant: COc1c([N+](=O)[O-])cc(Br)c2ccccc12
Reactant: CN
Solvent: CN(C)C=O
Product: CNc1c([N+](=O)[O-])cc(Br)c2ccccc12
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
1.1 cc (0.012 mole) of a 35% aqueous solution of CH3NH2 is gradually dripped into a stirred solution of 2.82 g (0.01 mole) of 4-bromo-1-methoxy-2-nitronaphthalene in 20 cc of dimethylformamide heated to 60° C. The reaction mixture is stirred at 60° C. for 10 minutes then cooled to 0° C. and filtered, yielding 1.81 g of 4-bromo-N-methyl-2-nitro-1-naphthylamine. Further, an addtional 0.79 g of this compound is obtained from the mother liquors by dilution with water. Overall yield 92%. M.p. 187°-188° C. (from Ethanol). A mixture of 35.3 g (0.1255 mole) of 4-bromo-N-methyl-2-nitro-1-naphthylamine, 1.8 g of 10% Pd-C catalyst, and 600 cc of methanol containing 17.6 cc (0.1255 mole) of triethylamine is shaken in a Paar hydrogenator under about 5 atm. of hydrogen pressure for 11/2 hours, until the theoretical amount of hydrogen is adsorbed, then the catalyst is filtered off under argon atmosphere and the mother liquor is concentrated to dryness. The residue is taken up with 250 cc of benzene and filtered again under argon over celite and bleaching earth FF. By evaporating the solvent, 19.73 g (0.115 mole) of N1 -methyl-1,2-naphthyldiamine is obtained as a dark oil. To a mixture of this compound and 16.1 cc (0.115 mole) of triethylamine in 500 cc of methylene chloride cooled to 0°-5° C. and kept under argon atmosphere, a solution of 14.55 g (0.115 mole) of 3-chloropropanoyl chloride in 140 cc of anhydrous methylene chloride is added dropwise. When the addition is terminated, the reaction mixture is allowed to stand at room temperature for a few hours and then it is heated at reflux temperature for 1/2 hour. The pH is brought to 7 by the addition of 2 cc of triethylamine and the reaction mixture is warmed to 35° C. for two hours, washed with water and dried. The raw product (25.5 g) which is obtained by evaporating the solvent is taken up with 160 cc of 5% HCl and stirred at 60° C. for 3 hours. The solids which are insoluble at this temperature are separated by filtration and discarded while the solution is decolorized with activated carbon. The clear solution is cooled to 0° C. and made alkaline with NH4OH. The product which precipitates is separated by filtration and recrystallized from 95% Ethanol. Yield 57.6%. M.p. 251° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([N:16]=[C:17](N)[CH3:18])=[S:15])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24](=[O:27])[CH2:25]Br.CCN(CC)CC>C(O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[S:15][C:25]([C:24](=[O:27])[C:23]2[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=2[CH3:21])=[C:17]([CH3:18])[N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1C(=O)CBr
Reactant: CC(N)=NC(=S)NCCCCCNC(=O)OC(C)(C)C
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)c1sc(NCCCCCNC(=O)OC(C)(C)C)nc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.9 %

Procedure:
To a solution of 290 mg (0.96 mmol) {5-[3-(1-Amino-ethylidene)-thioureido]-pentyl}-carbamic acid tert-butyl ester in 5 ml ethanol was added 213 mg (1 mmol) o-Methylphenacyl bromide and 139 μl NEt3 and allowed to stir for 5 h at room temperature. Afterwards the mixture was directly applied to preparative HPLC on reversed phase eluting with an acetonitrile/water gradient. The evaporation of the product fractions yielded 180 mg (45%) of the title compound.
Reaction SMILES: [F:1][C:2]([CH3:10])([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C1C=CC=CC=1.CCCCC>[Br:30][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([CH3:10])[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(F)CCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: c1ccccc1
Product: CC(C)(F)CCCCCBr
Temperature: 0 °C
Yield: 72.4 %

Procedure:
A stirred solution of the product from Step IV (0.427 g, 0.00288 mol) in benzene (5.2 ml) was mixed with triphenylphosphine (0.83 g, 0.00317 mol) cooled in an ice bath and treated, portion-wise, during 26 minutes with N-bromosuccinimide (0.56 g, 0.00317 mol). The mixture was kept in the ice bath for 30 minutes and at ambient temperature for 3.5 hours; it was then diluted with pentane (20 ml), cooled in an ice bath for a few minutes and filtered. The solid was washed with pentane and the filtrate was concentrated. A mixture of the residue and pentane was cooled in an ice bath for a few minutes and again filtered. The filtrate was mixed with Et2O and washed successively with cold 5% aqueous sodium thiosulfate, 0.5 N NaOH and brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with 1-3% EtOAc-hexane to give 0.440 g of 1-bromo-6-fluoro-6-methylheptane.
Reaction SMILES: C[OH:2].O.[Si]([O:11][CH2:12][CH2:13][O:14][C:15]1[C:16]([F:50])=[C:17]([CH:23]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]3[N:48]=[C:47]([CH3:49])[O:46][N:45]=3)=[CH:40][CH:39]=2)[C:24]2[NH:28][C:27](=[O:29])[N:26]([C:30]3[C:31](=[O:36])[NH:32][CH:33]=[CH:34][N:35]=3)[N:25]=2)[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)(C(C)(C)C)(C)C>[Fe].C(O)(=O)C>[C:47]([OH:2])(=[O:46])[CH3:49].[F:50][C:16]1[C:15]([O:14][CH2:13][CH2:12][OH:11])=[CH:20][C:19]([O:21][CH3:22])=[CH:18][C:17]=1[CH:23]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([NH2:48])=[NH:45])=[CH:40][CH:39]=1)[C:24]1[NH:28][C:27](=[O:29])[N:26]([C:30]2[C:31](=[O:36])[NH:32][CH:33]=[CH:34][N:35]=2)[N:25]=1
Reactant: COc1cc(OCCO[Si](C)(C)C(C)(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncc[nH]c3=O)c(=O)[nH]2)c1
Reactant: CO
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncc[nH]c3=O)c(=O)[nH]2)c1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
Iron powder (55 mg) was added to 4.5 ml of a methanol:water:acetic acid=1:1:1 mixed solvent solution containing 34 mg of 3-(3-{{3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-1-yl)-1H-pyrazin-2-one. The mixture was stirred at 65° C. for 24 hours under a nitrogen atmosphere. The reaction mixture was filtered and then purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-[5-oxo-1-(3-oxo-3,4-dihydropyrazin-2-yl)-4,5-dihydro-1H-[1,2,4]triazol-3-yl]methyl}amino)benzamidine acetate (5.9 mg).