Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH2:7][NH:8][C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1)=O.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>C(O)C.O.C(OC)(C)(C)C>[OH:16][N:15]=[CH:1][C:3]1[CH:13]=[CH:12][C:6]([CH2:7][NH:8][C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1
Reactant: NO
Reactant: CC(=O)NCc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CCO
Solvent: O
Product: CC(=O)NCc1ccc(C=NO)cc1
Yield: 97.6 %

Procedure:
A solution of N-(4-formylbenzyl)acetamide (1.7 g), hydroxylamine hydrochloride (1.0 g) and sodium acetate (1.0 g) in ethanol (10 mL) and water (6 mL) was stirred for one hour at room temperature. After the reaction solution was diluted with t-butylmethylether, the solution was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to yield crude N-{4-[(hydroxyimino)methyl]-benzyl}acetamide (1.8 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[C:10]([CH3:21])([CH3:20])[CH2:9][N:8]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:7]=1)=[O:5])[CH3:2].[H][H]>C(O)(=O)C.O=[Pt]=O>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:11]=2[C:10]([CH3:21])([CH3:20])[CH2:9][N:8]([C:22](=[O:30])[C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1ccccc21
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1c2CCCC1

Procedure:
A solution of 3-(4-fluoro-benzoyl)-1,1-dimethyl-1,2,3,6-tetrahydro-azepino[4,5-b]indole-5-carboxylic acid ethyl ester (1.03 g) in 40 mL of glacial acetic acid containing 370 mg of Adams catalyst was subjected to hydrogenation under atmospheric pressure of hydrogen for 20 hours at room temperature. (Boekelheide, V. and Liu, C-T, J. Am. Chem. Soc. 1952, 74, 4920-4922). The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The crude product was purified first by column chromatography on silica gel eluting with hexane/DCM and then by preparative normal phase HPLC eluting with hexane/DCM. The title compound was obtained as yellow solid (64 mg). 1H-NMR(CDCl3):δ 10.18 (1H, s), 7.64-7.59 (2H, m), 7.41 (1H, s), 7.13-7.07 (2H, m), 4.18 (2H, q), 3.95 (2H, brs), 2.68-2.61 (4H, m), 1.78 (4H, m), 1.39 (6H, s), 1.18 (3H, t); MS (ES): 411 (MH+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[CH3:23][O:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[C:31]#[N:32]>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:32][CH2:31][C:30]3[CH:33]=[CH:34][CH:35]=[C:28]([O:27][CH2:26][CH2:25][O:24][CH3:23])[CH:29]=3)[CH:8]=2)[N:3]=1
Reactant: COCCOc1cccc(C#N)c1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: COc1ccccc1CN
Product: COCCOc1cccc(CNc2ccc3nc(NCc4ccccc4OC)ccc3c2)c1

Procedure:
The title compound, MS: m/e=444.4 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and 3-(2-methoxy-ethoxy)-benzonitrile (CAS 80407-67-6).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[O:10][CH3:11].[Cl:12][CH2:13][CH2:14][CH2:15][OH:16].[H-].[Na+]>CN(C)C=O>[Cl:12][CH2:13][CH2:14][CH2:15][O:16][CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[O:10][CH3:11]
Reactant: COc1ccc(F)cc1CCl
Reactant: OCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1COCCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.870 g (5.00 mmol) of 2-chloromethyl-4-fluoro-1-methoxy-benzene [B. Maziére, N. Dat-Xuong, Chim. Ther. (3), 1-9(1968)] and 0.83 ml of 3-chloro-1-propanol were dissolved in 4.8 ml of N,N-dimethylformamide. 0.267 g (6.23 mmol) of sodium hydride (55% dispersion in mineral oil) was added in small portions over 2 hours keeping the temperature at 10-15° C. After 1 hour stirring at room temperature, 0.032 g (0.75 mmol) of sodium hydride dispersion was added and the mixture stirred another 3 hours. Thereupon, the reaction mixture was poured into 50 ml of ice-water and extracted three times with 100 ml of ether. The combined ether phases were subsequently washed with water, dried over magnesium sulphate and evaporated on a rotary evaporator at a maximum 40° C. The residue (1.5 g) which was thereby obtained was chromatographed on silica gel with dichloromethane/hexane (1:1). There was thus obtained 0.928 g (3.99 mmol), 80%, 2-(3-chloro-propoxymethyl)-4-fluoro-1-methoxy-benzene as a colorless oil: MS: 232, 234 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:27]=[CH:28][C:29]=2[CH3:30])[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[C:26]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:27]=[CH:28][C:29]=3[CH3:30])[CH2:20][CH2:19]2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(C)(C)c2ccc(Cl)cc2)CC1

Procedure:
Example 91 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.41–7.27 (m, 7H), 7.09 (d, 1H, J=8.0 Hz), 6.59 (br s, 1H), 3.34 (dd, 2H, J=6.4, 12.0 Hz), 2.93 (d, 2H, J=11.6 Hz), 2.64 (m, 1H), 2.54 (m, 1H), 2.37 (t, 2H, J=6.4 Hz), 2.28 (s, 3H), 1.98 (t, 2H, J=12.4 Hz), 1.71–1.64 (m, 4H), 1.59 (s, 6H), 1.61–1.55 (m, 2H), 1.28 (d, 6H, J=6.8 Hz); ESMS m/e: 498.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)[CH2:4]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:32]=1[C:33](O)=[O:34]>C(#N)C.O.CN(C=O)C>[CH3:17][N:2]([CH3:1])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([C:10]3[O:12][C:33](=[O:34])[C:32]4[C:36]([CH3:40])=[CH:37][CH:38]=[CH:39][C:31]=4[N:30]=3)=[CH:13][CH:14]=[CH:15][N:16]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2ncccc2C(=O)O)C1
Reactant: Cc1cccc(N)c1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1cccc2nc(-c3cccnc3N3CCC(N(C)C)C3)oc(=O)c12
Temperature: 60 °C
Reaction time: 8 h
Yield: 11.6 %

Procedure:
A solution of compound C (133 mg, 0.56 mmol) and CDI (91 mg, 0.56 mmol) in anhydrous acetonitrile (1.0 mL) was stirred for 1 hour at ambient temperature. 2-Amino-6-methyl-benzoic acid (41 mg, 0.27 mmol) was added, and the mixture was stirred at 60° C. overnight. The reaction solution was diluted with water (2 mL) and DMF (2 mL), filtered, then purified by C18 reverse phase chromatography to afford compound 46 as an off-white powder (11 mg, 35% yield). 1H-NMR δ (CDCl3): 8.32 (dd, 1H, J=4.8 Hz, J=2.0 Hz), 8.09 (dd, 1H, J=8.0 Hz, J=1.6 Hz), 7.68 (t, 1H, J=15.6 Hz, J=0.8 Hz), 7.52 (t, 1H, J=4.0 Hz, J=7.6 Hz), 7.33 (d, 1H, J=7.2 Hz), 6.82 (dd, 1H, J=8 Hz, J=4.8 Hz), 3.95 (br s, 1H), 3.81 (br s, 1H), 3.57-3.64 (m, 2H), 3.48-3.53 (m, 2H), 2.83 (s, 3H), 2.64 (br s, 6H), 2.30 (br s, 1H). ESMS: 351.1 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([NH:12][C:13]1[CH:14]=[C:15]([C:21]#[N:22])[C:16](=[CH:19][CH:20]=1)[C:17]#[N:18])([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:6].C1(C)C=CC=CC=1>C(OCC)(=O)C>[C:5]([NH:12][C:13]1[CH:14]=[C:15]([C:21]#[N:22])[C:16](=[CH:19][C:20]=1[N+:1]([O-:4])=[O:2])[C:17]#[N:18])([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:6]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(=O)Nc1ccc(C#N)c(C#N)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)Nc1cc(C#N)c(C#N)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 48 h
Yield: 30 %

Procedure:
To 50 ml ice-cooled 100% nitric acid was added gradually 2.0 g (8.2 mmol) 4-ethoxalylaminophthalonitrile. Stirring was continued at 25° C. for 48 h. The reaction mixture was poured into 300 ml ice-water to give 1.6 g crude product. Column chromatography (200 g kiselgel; eluents: toluene containing ethyl acetate) gave 0.7 g (30%) 4-ethoxalylamino-5-nitrophthalonitrile. M.p. 140°-141° C. 1H-NMR (DMSO-d6): 11.7 (1H, s), 8.97 (1H, s), 8.70 (1H, s), 4.4 (2H, q), 1.4 (3H, t), and 0.75 g (32%) 4-ethoxalylamino-3-nitrophthalonitrile. M.p. 140-141° C. 1H-NMR (DMSO-d6) 11.7 (1H, s), 8.4 (2H, dd, J=9Hz), 4,4 (2H, q), 1.4 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([OH:11])[CH3:10].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([O:11][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:10]
Reactant: CC(O)c1c(F)cccc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)c1c(F)cccc1Cl
Yield: 94.6 %

Procedure:
1-(2-Chloro-6-fluorophenyl)ethanol (8.5 g), imidazole (8.1 g) and t-butyldimethylsilylchloride (8.71 g) were stirred in DMF for 24 hours. The mixture was diluted with ether and washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 1-(2-chloro-6-fluorophenyl)ethyl (t-butyldimethylsilyl)ether (13.3 g) as a dear oil, NMR (CDCl3) -0.1(s,3H), 0.05(s,3H), 0.85(s,9H), 1.S(d,3H), 5.4(q,1H), 6.9(m,1H), 7.05(m,2H).
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].Cl.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:20](=[CH:21][CH:22]=1)[NH:23][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[C:3]2[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: NNc1ccc(Cl)cc1
Reactant: O=C(O)CCCC(=O)c1ccccc1
Agent: Cl
Product: O=C(O)CCc1c(-c2ccccc2)[nH]c2ccc(Cl)cc12

Procedure:
Prepared from δ-oxobenzenepentanoic acid and (4-chlorophenyl)hydrazine hydrochloride according to the method of Description 7. 1H NMR (360 MHz, CDCl3) (Contains 20% δ-oxobenzenepentanoic acid) δ8.02 (1H, s), 7.52-7.33 (6H, m), 7.23-7.18 (1H, m), 7.10-7.07 (1H, m), 3.16-3.11 (2H, m), and 2.65-2.60 (2H, m).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].Cl[CH:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[OH-].[Na+].Cl>C(Cl)(Cl)Cl>[O:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH:12]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[OH:4])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:17]1
Reactant: ClC(CCN1CCOCC1)c1ccccc1
Reactant: NCC(O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: OC(CNC(CCN1CCOCC1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 46.5 %

Procedure:
2-Amino-1-phenylethanol (2.50 g, 18.2 mmol) and 4-(3-chloro-3-phenylpropyl)morpholine (4.37 g, 18.2 mmol) were mixed and heated to cause reaction at 110° C. for 40 minutes. The resulting mixture was cooled to room temperature, and then dissolved into chloroform (200 ml). After the solution was chilled with ice, 1N NaOH was added so that the hydrochloride was libereated. The chloroform portion was collected and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (chloroform/methanol=100/1) to obtain 2.88 g of the titled compound as a yellow oil (Yield: 46.5%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.Cl.[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.Cl.C1(C2N=NC(CN)=CC=2)C=CC=CC=1>>[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH:22][S:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:9])=[O:8])=[CH:23][CH:24]=1
Reactant: NCc1ccc(-c2nccs2)cc1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Agent: NCc1ccc(-c2ccccc2)nn1
Product: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1cccnc1
Yield: 79.7 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Reference Example 2-(d) except for using 3-pyridylsulfonyl chloride (495 mg, 2.79 mmol), and using 4-(thiazol-2-yl)benzylamine hydrochloride (687 mg, 2.61 mmol) obtained in Reference Example 4-(d) in place of (6-phenylpyridazin-3-ylmethyl)amine hydrochloride to afford the title compound (689 mg) as a white solid. (Yield: 80%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:10])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[F:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:10][S:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[CH:13]=2)(=[O:20])=[O:19])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: COc1nc(C)cnc1N
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccc(F)c1

Procedure:
Prepared by the method of Example 1 using 3-methoxy-5-methyl-2-pyrazinamine and 3-fluorobenzenesulphonyl chloride.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[CH:7]([S:13](Cl)(=[O:15])=[O:14])([S:9](Cl)(=[O:11])=[O:10])[CH3:8].C(N(CC)CC)C.[Cl-].[Cl-].[Ca+2]>C(COC)OC>[CH:7]1([S:13](=[O:15])(=[O:14])[O:6][CH2:1][CH2:2][CH2:3][CH2:4][O:5][S:9]1(=[O:11])=[O:10])[CH3:8]
Reactant: OCCCCO
Reactant: CC(S(=O)(=O)Cl)S(=O)(=O)Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CC1S(=O)(=O)OCCCCOS1(=O)=O
Yield: 9.2 %

Procedure:
1,4-Butanediol, obtained from Aldrich Chemical Co. (3.6 g, 0.04 mole) was dissolved in 75 ml of glyme in a 1 liter round bottom flask. A solution of 1,1-ethanedisulfonyl chloride (9.1 g, 0.04 mole) dissolved in 25 ml of glyme wa added to the flask through a dropping funnel. The reaction mixture was kept below -20° C. with a dowanol-dry ice bath. Triethylamine (8.08 g, 0.08 mole) dissolved in 100 ml of glyme was added to the mixture through a 125 ml dropping funnel over a period of 1 hour. Care was taken to maintain anhydrous conditions by covering the dropping funnels with drying tubes containing CaCl2. The reaction mixture was brought to 25° C. in a cold water bath. The glyme was removed by roto-evaporation, at a temperature below 37° C. The oily yellow residue that remained after removal of the glyme was washed once with 100 ml of 5% sodium bicarbonate and once with 50 ml of cold distilled water, the resulting emulsion being centrifuged immediately to separate the product, and aqueous material decanted. The remaining precipitate was dried under vacuum. The white, powdery solid which remained weighed 0.90 g, representing a 9.2% yield. Product identification was confirmed by characteristic IR and proton NMR spectral features. The product decomposed between 115 and 138° C. The product was soluble to less than about 0.01 gram in 1 ml of either methylene chloride or acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][N:11]2[N:39]=[C:15]3[CH2:16][C:17](=O)[C:18]4[CH2:19][S:20][N:21]=[C:22]([N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:13]([C:14]=43)=[N:12]2)[C:4]=1[CH3:40].ClC(Cl)C.[CH3:45][O:46][C:47]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[CH:51][C:48]=1[CH2:49][NH2:50].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(O)(=O)C>[CH3:45][O:46][C:47]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[CH:51][C:48]=1[CH2:49][NH:50][CH:17]1[C:18]2[CH2:19][S:20][N:21]=[C:22]([N:23]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C:13]3=[N:12][N:11]([CH2:10][C:5]4[C:4]([CH3:40])=[C:3]([O:2][CH3:1])[C:8]([CH3:9])=[CH:7][N:6]=4)[N:39]=[C:15]([C:14]=23)[CH2:16]1
Reactant: COc1c(C)cnc(CN2N=C3CC(=O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Reactant: COc1ccc(CN)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CNC2CC3=NN(Cc4ncc(C)c(OC)c4C)N=C4C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSCC2=C34)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A mixture composed of di-tert-butyl {2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-8-oxo-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 40 (170 mg), dichloroethane (2 mL), acetic acid (0.034 mL) and 2,4-dimethoxybenzylamine (0.073 mL) was stirred at room temperature for 10 minutes. Then, sodium triacetoxyborohydride (126 mg) was added and the mixture was stirred for two hours. Sodium triacetoxyborohydride (63 mg) was added to the reaction mixture, followed by further stirring for one hour. Methanol (three drops) was added dropwise to the reaction mixture, and then the mixture was separated with chloroform and a 0.5 N sodium hydroxide solution. The aqueous layer was extracted with chloroform, and then the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol-chloroform) to obtain the title compound (108 mg, 50%) as an oil.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[F:27][C:22]1[CH:21]=[C:20]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:25]=[CH:24][C:23]=1[OH:26]
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccc(O)c(F)c1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(O)c(F)c4)c3c2s1
Yield: 58 %

Procedure:
Prepared from VII and 4-amino-2-fluorophenol. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 58%; orange solid; mp>260° C.; IR (KBr) νmax/cm−1 3375, 2228, 1731, 1649, 1619, 1578, 1512, 1470, 1373, 1347, 1292, 1241, 1204, 1150, 1111, 978, 943, 856, 836; 19F NMR (282 MHz, DMSO-d6) δ −136.8; 1H NMR (300 MHz, DMSO-d6) δ 8.46 (d, 1H, J=9.0 Hz), 8.15 (s, 1H), 7.69 (d, 1H, J=9.0 Hz), 6.97-6.81 (m, 3H); HRMS calcd for C16H9N5OSF (M+H+): 338.0512, found 338.0516.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:13]1([C:5]([C:4]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([OH:1])[CH:3]=2)=[O:7])[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: COc1ccc(C(=O)O)cc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)cc1O
Yield: 45 %

Procedure:
The title compound is prepared from 3-hydroxy-4-methoxy-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 45% of theory; LC (method 4): tR=1.91 min; Mass spectrum (ESI+): m/z=324 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[CH2:11][CH2:12][OH:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl.O>[CH3:14][S:15]([O:13][CH2:12][CH2:11]/[CH:10]=[CH:9]/[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:17])=[O:16]
Reactant: OCC/C=C/c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCC/C=C/c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 97 %

Procedure:
To a solution of Intermediate 2B (986 mg, 4.54 mmol) in CH2Cl2 (20 mL) was added TEA (1.899 mL, 13.63 mmol). The mixture was cooled to 0° C. and methanesulfonyl chloride (0.531 mL, 6.81 mmol) was added dropwise. The reaction was stirred for 45 min at 0° C. then warmed to rt and diluted with water (20 ml) and CH2Cl2 (20 mL). The layers were separated, and the aqueous layer extracted with CH2Cl2. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated in vacuo to give Intermediate 2C (1.30 g, 97% yield). Intermediate 2C was carried onto the next reaction without further purification. HPLC/MS (Method D) RT=1.10 min, [M-MeSO3H+H]+199.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]1=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH:17](OCC)=[CH2:18]>>[CH:17]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]1=[O:10])=[CH2:18]
Reactant: C=COCC
Reactant: O=C1C=CC(=O)N1CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=COCCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A quantity of 1.18 g of N-(2-hydroxyethyl)maleimide was suspended in 25 ml ethyl vinyl ether and refluxed with stirring under an argon atmosphere, 70 mg mercuric acetate was added, and the reaction was continued at reflux for 24 hours. After 24 hours, the reaction mixture was allowed to cool to room temperature, and 1.50 mg of anhydrous potassium carbonate was added. After stirring for a few more minutes, the mixture was filtered and the precipitate was washed thoroughly with ethyl acetate. The washings were combined with the filtrate and evaporated to dryness in vacuo to yield an oily residue. This oily residue was chromatographed over 50 grams of neutral alumina, activity III, using methylene chloride-hexane (1:1) for elution. The initial fractions were collected and combined to yield 200 mg of crude 2-maleimidoethyl vinyl ether. The product was suitable for use in the next step in preparation of the crosslinker, but for analytical purposes could be purified by rechromatography over alumina or kugelrohr distillation.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl: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([CH2:42][CH2:43][C:44](=[O:46])[CH3:45])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:39]3[CH2:40][CH2:41][N:36]([CH2:42][CH2:43][C:44](=[O:46])[CH3:45])[CH2:37][CH2:38]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(=O)CCN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCC(C)=O)CC1
Product: Cl

Procedure:
4-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-butan-2-one hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 4-piperazin-1-yl-butan-2-one (example 18c) in an analogous manner as described in example 25. LR-MS: 649.4 [(M+H)+]