Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:36][C:37]12[CH2:46][CH:41]3[CH2:42][CH:43]([CH2:45][C:39]([C:47]([O:49][CH3:50])=[O:48])([CH2:40]3)[CH2:38]1)[CH2:44]2.NC12CC3CC(CC(C(OC)=O)(C3)C1)C2>CN(C)C=O.O>[C:1]([NH:8][C@H:9]([C:17]([CH:38]1[C:37]2([NH2:36])[CH2:44][CH:43]3[CH2:42][CH:41]([CH2:40][C:39]1([C:47]([O:49][CH3:50])=[O:48])[CH2:45]3)[CH2:46]2)=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1)C2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C2
Temperature: -50 °C
Reaction time: 0.25 h

Procedure:
5.09 Grams of Boc-L-phenylalanine is dissolved in 25 ml of dry dimethylformamide and 2.13 ml of N-methylmorpholine is added. The reaction mixture is cooled to -50° C. and 2.51 ml of isobutylchloroformate is added. The reaction mixture is stirred for 15 minutes, then 1.77 ml of N-methylmorpholine and 3.93 g of methyl 3-amino-1-adamantanecarboxylate hydrochloride are added and the reaction mixture is stirred until all the methyl 3-amino-1-adamantanecarboxylate dissolves then stored for 3 days at 5° C. The reaction mixture is poured into 100 ml of water and extracted twice with 50 ml of ethyl acetate. The ethyl acetate fractions are washed twice with 50 ml of water, 50 ml of a 0.5 solution of potassium bisulfate, 50 ml of water, 50 ml of a 0.5 M solution of potassium bicarbonate, and 50 ml of water then dried over magnesium sulfate. The solvent is removed under reduced pressure, and the residue is dissolved in 150 ml of 10% chloroform in hexane and purified by low pressure chromatography on silica gel using a gradient of 10% to 50% solution of chloroform in hexane as eluent. Removal of the solvent under vacuum gives the product methyl Boc-L-phenylalanyl-3-amino-1-adamantanecarboxylate which is represented by the following formula ##STR23##
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4].[CH3:16]N(P(N(C)C)(N(C)C)=O)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1([CH3:16])[CH2:9][C:8]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4]
Reactant: COC(=O)C1Cc2cc(OC)ccc2O1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1(C)Cc2cc(OC)ccc2O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-methoxy-2,3-dihydro-benzofuran-2-carboxylic acid methyl ester (0.44 g, 2.0 mmol) and HMPA (0.20 mL) in THF (15 mL) at −78° C. was added LiHMDS (1M in THF, 3.0 mL, 3.0 mmol). After 15 min, methyl iodide (0.42 g, 3.0 mmol) was added and the reaction was gradually warmed to 25° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of NH4Cl. The organic phase was dried and concentrated. The residue was chromatographed on silica gel eluting with 8:2 hexane:ethyl acetate to give 0.32 g 5-methoxy-2-methyl-2,3-dihydro-benzofuran-2-carboxylic acid methyl ester.
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1/[CH:27]=[CH:28]/[CH:29]=[O:30]>>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:10]1[NH:11][C:12]2[O:13][C:29](=[O:30])[CH:28]([CH2:27][C:23]3[O:22][CH:26]=[CH:25][CH:24]=3)[CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]=2[N:9]=1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Reactant: O=C/C=C/c1ccco1
Product: O=C1Oc2[nH]c(-c3cc(F)ccc3F)nc2C(c2ccccc2)C1Cc1ccco1
Yield: 66 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-(furan-2-yl)acrylaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 16 as an off-white solid (80 mg, 66%). Analytical data for 16: 1H NMR (500 MHz, CDCl3) δ 9.45 (d, J=8.1 Hz, 1H), 7.90 (ddd, J=9.2, 6.1, 3.2 Hz, 1H), 7.37 (ap d, J=1.2 Hz, 1H), 7.37-7.27 (m, 3H), 7.11-7.01 (m, 3H), 7.01-6.94 (m, 1H), 6.34 (dd, J=3.2, 1.9 Hz, 1H), 6.02 (d, J=2.9 Hz, 1H), 4.20 (d, J=6.9 Hz, 1H), 3.70 (ddd, J=10.3, 6.8, 4.1 Hz, 1H), 3.30 (ddd, J=15.9, 4.2, 1.2 Hz, 1H), 2.48 (dd, J=15.8, 10.4 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 168.4, 159.1 (d, JCF=243.8 Hz), 155.4 (dd, JCF=241.2, 2.2 Hz), 151.8, 149.1, 141.6, 136.7, 136.5, 129.2, 128.3, 128.0, 118.4 (dd, JCF=12.8, 9.2 Hz), 117.1 (dd, JCF=25.6, 8.8 Hz), 116.6 (dd, JCF=24.9, 9.6 Hz), 114.5 (dd, JCF=26.9, 3.7 Hz), 110.7 (d, JCF=3.9 Hz), 110.4, 107.6, 44.9, 38.5, 25.6; IR (film) cm−1 1770, 1636, 1620, 1529, 1482, 1464, 1452, 1173, 1117, 1008, 919, 902, 885, 875, 814, 766, 736, 700; LRMS (ESI): Mass calcd for [M+H]+ C23H17F2N2O3: 407.1. found 407.3; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 5% IPA/3% MeOH/hexanes 0.5 mL/min, 280 nm), Rt1 (major)=32.4, Rt2 (minor)=36.4 min; er=98:2.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]=2[O:3]1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C(OCC)(=O)C>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]3[O:3][C:2]([CH3:21])([CH3:1])[CH:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:5]=3[C:13]=2[CH3:20])=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccccc1)C(C)(C)O2
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccccc1)C(C)(C)O2
Yield: 92 %

Procedure:
By using 2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 92%. Melting point: 156-158° C. (Ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.[CH2:25](OCC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10](=[O:16])[C:11](=[CH:25][NH:22][C:21]2[CH:23]=[CH:24][C:18]([F:17])=[CH:19][CH:20]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)CC(=O)C=Cc1ccc(Cl)cc1
Solvent: c1ccccc1
Product: COC(=O)C(=CNc1ccc(F)cc1)C(=O)C=Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
In 10 ml of benzene was dissolved 2.0 g of methyl 5-(4-chlorophenyl)-3-oxo-4-pentenoate, and to this solution was added 1.2 g of N,N-dimethylformamidodimethylacetal. The resulting mixture was subjected to reaction at 70° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and 1.12 g of p-fluoroaniline was then added thereto, after which the resulting mixture was further subjected to reaction for 1.5 hours. After completion of the reaction, 10 ml of diethyl ether was added to the reaction mixture, and the precipitated crystals were collected by filtration, and washed with 10 ml of diethyl ether to obtain 2.2 g of methyl 5-(4-chlorophenyl)-2-(4-fluorophenylaminomethylene)-3-oxo-4-pentenoate having a melting point of 166°-168° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([OH:31])=[C:25]([CH:30]=1)[C:26]([O:28][CH3:29])=[O:27].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([OH:31])=[C:25]([CH:30]=1)[C:26]([O:28][CH3:29])=[O:27])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)c1cc(N)ccc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NC(=O)C(CC(C)C)NC(=O)OCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.4 %

Procedure:
A mixture of 2-(benzyloxycarbonylamino)-4-methylpentanoic acid (1 g, 3.8 mmol), methyl 5-amino-2-hydroxybenzoate (0.66 g, 3.95 mmol) and Et3N (0.76 g, 7.6 mmol) were dissolved in CH3CN (10 mL) and HATU (1.503 g, 3.95 mmol) was added. The mixture was stirred (RT, 16 h). The solvent was removed under reduced pressure. Brine (50 mL) was added to the resulting residue, and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed successively with 2N aq. HCl (3×50 mL), brine (50 mL), 5% NaHCO3 (50 mL×3), brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica chromatography on (CH2Cl2) to give methyl 5-(2-(benzyloxycarbonylamino)-4-methylpentanamido)-2-hydroxybenzoate as a white solid (0.81 g, 51.8%).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O[CH2:16][CH2:17][O:18][C:19](=[O:31])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][CH2:16][CH2:17][O:18][C:19](=[O:31])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:11])=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Reactant: O=C(COc1ccc([N+](=O)[O-])cc1)OCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(COc1ccc([N+](=O)[O-])cc1)OCCOC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a mixture of (4-nitrophenoxy)acetic acid 22 (80 g, 406 mmol) and (4-nitrophen-oxy)-acetic acid-2-hydroxyethyl ester 23 (80 g, 332 mmol) in anhydrous dichloro-methane (2 L) under nitrogen atmosphere was added a solution of 1,3-di-cyclohexyl carbodiimide (128 g, 620 mmol) in anhydrous dichloromethane (750 ml) drop wise. The reaction mixture was stirred at room temperature for 8 hours. The solids were filtered off and dichloromethane distilled off to get crude 24. The crude 24 was purified by column chromatography on silica gel using hexane:ethyl acetate (95:5) to get pure 24 (75 grams, 54%) as a white powder with an m.p. between 138-139° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(N)ccc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(NS(C)(=O)=O)ccc1OC
Yield: 88.7 %

Procedure:
To a solution of methyl 2-methoxy-5-aminobenzoate (300 mg) and dry pyridine (3 ml), methanesulfonyl chloride (210 mg) is added dropwise with ice cooling and stirring, and the resultant mixture is stirred at room temperature for 1 hour. The reaction mixture is acidified with 6 N hydrochloric acid and shaken with methylene chloride. The organic layer is washed with water, dried over sodium sulfate, and evaporated under reduced pressure to remove the methylene chloride. The residue is chromatographed on a column of silica gel, which is eluted with methylene chloride--2% methanol/methylene chloride, and the eluate is evaporated to remove the solvent. The residue is recrystallized from ethyl acetate/isopropyl ether to give methyl 2-methoxy-5-methanesulfonamidobenzoate (381 mg) as colorless prisms melting at 84° to 86° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:62][CH2:63][CH2:64][C:65]1[CH:66]=[CH:67][C:68]2[C:72]([CH3:74])([CH3:73])[O:71][B:70]([OH:75])[C:69]=2[CH:76]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:26])([F:25])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:62][CH2:63][CH2:64][C:65]4[CH:66]=[CH:67][C:68]5[C:72]([CH3:73])([CH3:74])[O:71][B:70]([OH:75])[C:69]=5[CH:76]=4)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC1(C)OB(O)c2cc(CCN)ccc21
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCCc1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a solution of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (320 mg, 0.76 mmol) and HATU (456 mg, 1.2 mmol) in DMF (18 mL), DIPEA (310 mg, 2.4 mmol) was added. The reaction mixture was stirred at rt for 10 min and crude 6-(2-aminoethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (1 mmol) was added. The reaction mixture was continued to stir overnight. Water was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the final title compound 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)ethyl)-2-methylbenzamide (276 mg; yield 54.4%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.42 (t, J=6.0 Hz, 1H), 7.82 (t, J=2.0 Hz, 1H), 7.53-7.63 (m, 5H), 7.33-7.35 (m, 3H), 4.35 (d, J=18.5 Hz, 1 H), 4.30 (d, J=18.5 Hz, 1 H), 3.50 (q, J=7.5 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.23 (s, 3 H), 1.43 (s, 6H) ppm;
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][NH2:9])[CH:5]=[CH:4][CH:3]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])O.[Na+]>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(CN)n1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(CNc2ncccc2[N+](=O)[O-])n1
Reaction time: 3 h
Yield: 51 %

Procedure:
A mixture of 2.44 parts of 6-methyl-2-pyridinemethanamine, 3.2 parts of 2-chloro-3nitropyridine, 1.7 parts of sodium hydrogen carbonate and 120 parts of ethanol was stirred for 3 hours at reflux temperature. The reaction mixture was filtered while hot over diatomaceous earth. After cooling, the precipitate which formed in the tiltrate was filtered off and dried, yielding 2.5 parts (51%) of 6-methyl-N-(3-nitro-2-pyridinyl)-2pyridinemethanamine; mp. 131.7° C. (interm. 5).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C@H:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(C)C)(=O)C.C1(C)C=CC=CC=1.[C@:39]12([CH2:49][S:50]([OH:53])(=[O:52])=[O:51])[C:46]([CH3:48])([CH3:47])[CH:43]([CH2:44][CH2:45]1)[CH2:42][C:40]2=[O:41]>O>[CH3:47][C:46]1([CH3:48])[C@@H:43]2[CH2:44][CH2:45][C@@:39]1([CH2:49][S:50]([OH:53])(=[O:52])=[O:51])[C:40](=[O:41])[CH2:42]2.[CH3:23][N:20]1[CH2:19][CH2:18][N:17]([C@@H:13]2[CH2:14][CH2:15][CH2:16][C@H:11]([NH:10][C:9](=[O:24])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:12]2)[CH2:22][CH2:21]1
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: CN1CCN([C@@H]2CCC[C@H](NC(=O)OCc3ccccc3)C2)CC1
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)C
Solvent: O
Product: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A mixture of (cis)-benzyl-3-(4-methylpiperazin-1-yl)cyclohexylcarbamate (2.0 g, 6.04 mmol, 1.0 eq.), isopropyl acetate (12 ml) and toluene (2.5 ml) was heated for 15 minutes at 65° C. (1S)-(+) Camphorsulfonic acid (700 mg, 3.02 mmol, 0.5 eq.) and water (0.1 ml) were added at RT and the mixture was heated for 3 hours at 75° C. Stirring was then carried out for 3 hours at RT and the mixture was subsequently allowed to stand overnight at RT for crystallization. The resulting precipitate was filtered off and washed with isopropyl acetate (20 ml). For purification, the desired product was recrystallized from ethanol/isopropyl acetate. Yield: 14% (500 mg, 0.888 mmol)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Cl[C:10]1[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=1.[IH:17]>>[I:17][C:10]1[CH:15]=[C:14]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)[N:13]=[CH:12][N:11]=1
Reactant: OB(O)c1ccoc1
Reactant: Clc1cc(Cl)ncn1
Reactant: I
Product: Ic1cc(-c2ccoc2)ncn1

Procedure:
The compound was prepared according to Example 1 using furan-3-boronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CC=CC=1>ClCCl>[Br:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1c[nH]cn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Brc1cn(-c2ccccc2)cn1
Reaction time: 48 h
Yield: 26.4 %

Procedure:
4-Bromo-1H-imidazole (500 mg, 3.4 mmol, 1 eq), phenylboronic acid (830 mg, 6.8 mmol, 2 eq), anhydrous cupric acetate (926 mg, 5.1 mmol), activated 4 Å molecular sieves (2 g) and pyridine (0.3 ml) were combined in dichloromethane (20 ml) and stirred for 2 days in the presence of air. The reaction mass was then filtered through Celite, washed with methanol, and concentrated and purified by silica gel chromatography (eluent 15% ethyl acetate/hexane) to afforded yellowish sticky solid 4-bromo-1-phenyl-1H-imidazole (200 mg, 26%).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:11][C:12]([CH:14]2[CH2:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][CH:3]=1.Br[CH2:19][C:20]1[CH:39]=[CH:38][C:23]2/[C:24](=[C:34](/[CH3:37])\[C:35]#[N:36])/[C:25]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:26]=3[O:27][CH2:28][C:22]=2[CH:21]=1>>[C:35](/[C:34](=[C:24]1/[C:25]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:26]=2[O:27][CH2:28][C:22]2[CH:21]=[C:20]([CH2:19][N:11]([C:5]3[C:6]([N+:8]([O-:10])=[O:9])=[N:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]([CH:14]3[CH2:15][CH2:16][CH2:17]3)=[O:13])[CH:39]=[CH:38][C:23]/1=2)/[CH3:37])#[N:36]
Reactant: O=C(Nc1ccc(F)nc1[N+](=O)[O-])C1CCC1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(CN(C(=O)C3CCC3)c3ccc(F)nc3[N+](=O)[O-])cc2COc2cc(F)ccc21
Yield: 50 %

Procedure:
[step 3] Using N-(6-fluoro-2-nitropyridin-3-yl)cyclobutanecarboxamide (200 mg, 0.836 mmol) obtained in step 2 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (250 mg, 0.697 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, (E)-N-{[11-(1-cyanoethylidene)-3-fluoro-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl}-N-(6-fluoro-2-nitropyridin-3-yl)cyclobutanecarboxamide (180 mg, 50%) was obtained.
Reaction SMILES: [H][H].[CH3:3][C:4]1[NH:5][C:6](=[O:19])[S:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1.[OH2:20]>C(O)(=O)C>[CH3:3][C:4]1[NH:5][C:6](=[O:19])[S:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:11]=[CH:12][C:13]([S:16]([CH3:17])=[O:20])=[CH:14][CH:15]=1
Reactant: CSc1ccc(C(=O)c2sc(=O)[nH]c2C)cc1
Reactant: O
Reactant: [H][H]
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)sc1C(=O)c1ccc(S(C)=O)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Hydrogen peroxude (1 equivalent, 30%) is added to a solution of 4-methyl-5-[4-(methylthio)benzoyl)-2(3H)-thiazolone (2.7 g) in glacial acetic acid (80 ml). The mixture is stirred for 3 hours at 50° C. The precipatate obtained on addition of water is recrystallized from ethanol to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:19][S:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)(=[O:22])=[O:21])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[N+:33]([O-])=O.[CH:36](O)=O>[Pd]>[NH:1]1[C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:19][S:20]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)(=[O:22])=[O:21])[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]3)=[O:11])=[CH:4][C:3]=2[N:33]=[CH:36]1
Reactant: O=CO
Reactant: CC1CCN(C(=O)C(Cc2ccc(N)c([N+](=O)[O-])c2)NS(=O)(=O)c2ccc3ccccc3c2)CC1
Agent: [Pd]
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2ccc3ccccc3c2)CC1

Procedure:
Prepared from N-[1-((4-amino-3-nitro-phenyl)-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxo-ethyl]-naphthalene-2sulphonamide and cyclising with formic acid in the presence of palladium/charcoal analogously to Example 1.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH3:21])[CH:15]=[C:14]([O:22][CH2:23][O:24][CH3:25])[C:11]=1[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(=CC)C.Cl([O-])=[O:32].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[CH2:1]([O:8][CH2:9][C:10]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH3:21])[CH:15]=[C:14]([O:22][CH2:23][O:24][CH3:25])[C:11]=1[C:12]([OH:32])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: COCOc1cc(COCc2ccccc2)c(C=O)c(OCOC)c1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COCOc1cc(COCc2ccccc2)c(C(=O)O)c(OCOC)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 112.8 %

Procedure:
The above-obtained 2-(benzyloxymethyl)-4,6-bis(methoxymethoxy)benzaldehyde (0.80 g, 2.3 mmol) was dissolved in tert-butyl alcohol (20 mL) and the obtained solution was added with 2-methyl-2-butene (10 mL, 94 mmol), sodium chlorite (2.0 g, 22 mmol), sodium dihydrogen phosphate (2.0 g, 17 mmol) and water (5 mL), followed by stirring at a room temperature for 10 hours. The reaction mixture was extracted with chloroform 3 times. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure to obtain 2-(benzyloxymethyl)-4,6-bis(methoxymethoxy)benzoic acid (0.94 g, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:14][CH3:15])[N:8]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=1)[C:7]2=[O:53])([O-])=O>O1CCOCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:14][CH3:15])[N:8]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)=[CH:21][CH:22]=1)[C:7]2=[O:53]
Reactant: CCc1nc2ccc([N+](=O)[O-])cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ni]
Solvent: C1COCCO1
Product: CCc1nc2ccc(N)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
6-Nitro-2-ethyl-3-[(2'-(N-triphenylmethyltetrazol-5-yl)-biphen-4-yl)-methyl]-quinazolin-4(3H)-one (0.11 g) was hydrogenated in dioxane (2.0 ml) solution under 1 atm H2 for 1 hr in the presence of Raney nickel catalyst.