Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[NH2:7][CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]1=[O:22].C(N(CC)CC)C.C(=O)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:48]([O:55][C:56]1[CH:63]=[CH:62][C:59]([CH2:60]Cl)=[CH:58][CH:57]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>ClCCl.O1CCCC1>[NH2:7][C:8]1([CH2:60][C:59]2[CH:62]=[CH:63][C:56]([O:55][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[CH:57][CH:58]=2)[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]1=[O:22]
Reactant: NC1CCCCN(Cc2ccccc2)C1=O
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Li+]
Solvent: ClCCl
Solvent: O=Cc1ccccc1
Solvent: C1CCOC1
Product: NC1(Cc2ccc(OCc3ccccc3)cc2)CCCCN(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Magnesium sulfate (5.0 g, 41.5 mmol) was added to a solution of commercially available 3-amino-1-benzylazepan-2-one (940 mg, 4.31 mmol), triethylamine (0.60 mL, 4.31 mmol) and benzaldehyde (0.46 mL, 4.52 mmol) in dichloromethane (20 mL). After 18 h, the mixture was filtered and concentrated to give the crude imine. Lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran; 1.42 mL, 1.42 mmol) was added to a solution of the crude imine (363 mg, 1.19 mmol) in tetrahydrofuran (4 mL). After 2 h, the mixture was cooled to 0° C. 4-benzyloxybenzyl chloride (290 mg, 1.24 mmol) was added and the mixture was allowed to warm to ambient temperature. After an additional 18 h, the mixture was quenched with 1N hydrochloric acid (10 mL). After 30 min, the mixture was extracted with ethyl acetate, and the organic layer was washed with aqueous saturated sodium carbonate, water, saturated brine, dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography [100% dichloromethane→90% dichloromethane/10% methanol (10% ammonium hydroxide/methanol)] gave the title compound. (109 mg) MS 415 (M+1). 1H NMR (500 MHz, CDCl3) δ 7.44–7.36 (m, 4H), 7.34–7.23 (m, 6H), 7.03 (d, J=8.6 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 5.29 (s, 2H), 4.64–4.52 (m, 2H), 3.31–3.26 (m, 1H), 3.22–3.18 (m, 1H), 3.02 (d, J=13.4 Hz, 1H), 2.86 (d, J=13.7 Hz, 1H), 1.90–1.75 (m, 4H), 1.72–1.60 (m, 2H), 1.49–1.42 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.[CH:12]1([C:15]#[C:16][CH2:17]O)[CH2:14][CH2:13]1>>[CH:12]1([C:15]#[C:16][CH2:17][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)[CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc(O)cn1
Reactant: OCC#CC1CC1
Product: O=C(O)c1ccc(OCC#CC2CC2)cn1

Procedure:
The title compound was synthesized analogously according to Method KS starting from methyl 5-hydroxypicolinate (Molbridge) and 3-cyclopropylprop-2-yn-1-ol. MS m/z: 218 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:7][C:6]=1[C:18]([F:21])([F:20])[F:19])C.O.[OH-].[Li+].Cl>O1CCCC1.O>[Br:11][C:9]1[C:8]([O:12][CH2:13][C:14]([F:15])([F:16])[F:17])=[N:7][C:6]([C:18]([F:21])([F:19])[F:20])=[C:5]([CH:10]=1)[C:4]([OH:22])=[O:3]
Reactant: CCOC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Temperature: 25 °C
Yield: 99.8 %

Procedure:
5-Bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid ethyl ester (244 g, 0.61 mol) was dissolved in a mixture of tetrahydrofuran (2100 mL) and water (700 mL). Lithiumhydroxid monohydrate (77 g, 1.85 mol) was added and the mixture was stirred and heated at reflux-temperature for 1.5 h. After cooling to room temperature the mixture was acidified with hydrochloric acid (2N, 750 mL). The mixture was extracted with diethylether (1×1500 mL, 1×1000 mL), and the organic phases were washed with brine (1000 mL). The organic phases were combined, dried with MgSO4 and the solvent was evaporated to give the title compound (224 g) as off-white solid; MS (ISP) 365.9, 367.9 (M−H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[H][H]>O1CCCC1.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:18])[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)CCc2ccc(N)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1ccc(C(O)CCc2ccc(N)cc2)cc1

Procedure:
60 g of the 1-(4-methylphenyl)-3-(4-aminophenyl)-n-propan-1-one prepared as described in Example A were hydrogenated, in 1 liter of tetrahydrofuran, in the presence of 5 g of 10% strength Pd on charcoal, under 1.1 bar, until 5.5 liters of hydrogen had been absorbed. The catalyst was separated off and the reaction solution was evaporated down, and the oil obtained crystallized on trituration with diisopropyl ether. After the white crystals had been dried, 53 g (88% of theory) of the carbinol of melting point 63°-65° C. were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]([NH:17][NH2:18])=[O:16])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(C)C(S(Cl)(=O)=O)=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]2[O:16][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)NN
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(-c2ccc(Br)cc2)c1Cc1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetic acid hydrazide (0.142 g, 0.46 mmol) in CH2Cl2 (2.3 mL) at 0° C. was added triethylamine (0.19 mL, 1.37 mmol) and benzoyl chloride (0.05 mL, 0.46 mmol), and the reaction was stirred at room temperature for 3 hours. Toluenesulfonyl chloride (0.088 g, 0.46 mmol) was added, and the reaction was stirred overnight. After aqueous workup, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([N:13]1[CH2:18][CH2:17][C:16]3([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[CH2:20][O:19]3)[CH2:15][CH2:14]1)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[CH3:1][C:2]1[N:3]([S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])[C:4]2[C:9]([C:10]=1[C:11]([N:13]1[CH2:14][CH2:15][C:16]3([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[CH2:20][O:19]3)[CH2:17][CH2:18]1)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1[nH]c2ccccc2c1C(=O)N1CCC2(CC1)OCc1ccccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N2CCC3(CC2)OCc2ccccc23)c2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a stirred solution of 40 mg (0.11 mmol) of 1′-[(2-methyl-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (the preparation of which has been described in example 43) in 3 ml DMF was added 5 mg (0.11 mmol) NaH (60% in oil). The mixture was stirred at RT for 30 min. and then 24 mg (0.14 mmol) of benzenesulfonyl chloride was added. The mixture was stirred an additional hour and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Re-crystallization in Et2O afforded 45 mg (80%) of 1′-{[2-methyl-1-(phenylsulfonyl)-1H-indol-3-yl]carbonyl}-3H-spiro[2-benzofuran-1,4′-piperidine] as white crystals. ES-MS m/e (%): 487.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:32]1[N:37]=[C:36]([NH2:38])[N:35]=[C:34]([NH2:39])[CH:33]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:32]4[N:37]=[C:36]([NH2:38])[N:35]=[C:34]([NH2:39])[CH:33]=4)=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: Oc1ccc(-c2nnc(Nc3ccc(Cl)cc3)o2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4ccc(Cl)cc4)o3)cc2)nc(N)n1
Temperature: 80 °C
Yield: 12.4 %

Procedure:
4-{5-[(4-chlorophenyl)amino]-1,3,4-oxadiazol-2-yl}phenol (144.0 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (100.0 mg, 0.5 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 6-chloro-2,4-diamino-pyrimidine (72.3 mg, 0.5 mmol) was added, followed by anhydrous K2CO3 (34.5 mg, 0.25 mmol). Then the vial was capped and microwaved at 200° C. for 15 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as a beige solid (24.5 mg).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[NH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>CC#N>[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=[C:5]([NH:25][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[N:10]=2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: NCc1cccnc1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NCc3cccnc3)n2)cc1
Yield: 94.2 %

Procedure:
To a stirred solution of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (0.10 g, 0.26 mmol) in MeCN (3 ml) was added 3-(aminomethyl)-pyridine (169 mg, 6 eq) and the resultant solution heated under reflux for 3 h. The cooled reaction mixture was concentrated in vacuo and the resulting oil purified by SPE chromatography with chloroform then chloroform:methanol (50:1) as eluant. This gave the title compound as a yellow solid (100 mg, 93%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:37]1[N:38]=[C:39]([NH:42]C=O)[S:40][CH:41]=1)[C:5]([NH:7][CH:8]1[C:35](=[O:36])[N:10]2[C:11]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:12]([CH:15]=[C:16]([Cl:18])[Cl:17])[CH2:13][S:14][C@H:9]12)=[O:6].Cl.O.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:37]1[N:38]=[C:39]([NH2:42])[S:40][CH:41]=1)[C:5]([NH:7][CH:8]1[C:35](=[O:36])[N:10]2[C:11]([C:19]([O:21][CH:22]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:12]([CH:15]=[C:16]([Cl:18])[Cl:17])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=C(Cl)Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=C(Cl)Cl)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
To a solution of benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(2,2-dichlorovinyl)-3-cephem-4-carboxylate (syn isomer) (2.2 g) in methanol (11 ml) was added conc. hydrochloric acid (0.72 ml) and the resulting mixture was stirred at ambient temperature for 3 hours. To the reaction mixture were added water and ethyl acetate, the mixture was adjusted to pH 7.0 with saturated aqueous sodium bicarbonate, the separated organic layer was washed with brine, dried over magnesium sulfate. The solution was evaporated in vacuo to give benzhydryl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(2,2-dichlorovinyl)-3-cephem-4-carboxylate (syn isomer) (1.98 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:40])[C:27]([C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[C:32]([F:39])[CH:31]=1)([CH3:29])[CH3:28].CCN(CC)CC>ClCCCl>[CH3:24][O:25][C:26](=[O:40])[C:27]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:38])=[C:32]([F:39])[CH:31]=1)([CH3:29])[CH3:28]
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: COC(=O)C(C)(C)c1ccc(N=C=O)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)C(C)(C)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 9.1) was reacted with 2-(3-fluoro-4-isocyanato-phenyl)-2-methyl-propionic acid methyl ester in 1,2-dichloroethane in the presence of Et3N for 3 days under reflux conditions to give the title compound as yellow solid. MS: m/e=563.5 [M+H+].
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]2[CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[C:12](=[O:13])[C:3]=12.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]3[CH2:10][N:11]([CH2:14][CH2:15][C:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:17]=4)[C:12](=[O:13])[C:3]=23)=[CH:29][CH:28]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Product: Cn1cc2c(c(-c3ccc(F)cc3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2

Procedure:
The title compound was prepared in analogy to the process of Example 13 starting from 7-chloro-5-methyl-2-(2-quinolin-2-yl-ethyl)-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (see Example c4)) and 4-fluorophenylboronic acid.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[O:16][CH:15]=[CH:14][C@@H:13]([OH:17])[C@@H:12]1[OH:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]([CH2:26][C:27](OC=C)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(COC)OC>[C:1]([O:9][CH2:10][C@H:11]1[O:16][CH:15]=[CH:14][C@@H:13]([O:17][C:27](=[O:28])[CH2:26][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:12]1[OH:18])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC[C@H]1OC=C[C@@H](O)[C@@H]1O)c1ccccc1
Reactant: C=COC(=O)COc1ccccc1
Solvent: COCCOC
Product: O=C(COc1ccccc1)O[C@@H]1C=CO[C@H](COC(=O)c2ccccc2)[C@H]1O
Yield: 88 %

Procedure:
226 mg (0.90 mmol) of 6-O-benzoylglucal are dissolved in 1 ml of dimethoxyethane and stirred with 1 ml of vinyl phenoxyacetate and 220 mg of lipase Fp at room temperature for 3 hours. Filtration and flash chromatography (silica gel; hexane and ether/hexane 1:1) result in 6-O-benzoyl-3-O-phenoxyacetylglucal in 88% yield (304.5 mg, 0.79 mmol).
Reaction SMILES: [BH4-].[Li+].C(O[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:10][CH:9]=1)(=O)C.[Cl-].[NH4+].[C:23](O)(=[O:25])C>O1CCCC1>[CH3:20][O:19][CH2:18][CH2:17][O:16][CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:23][OH:25])=[CH:13][CH:12]=1
Reactant: CC(=O)O
Reactant: COCCOCOc1ccc(COC(C)=O)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCOCOc1ccc(CCO)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
2.7 g (122.3 mmol) of lithium borohydride is added to a solution of 10 g (41 mmol) of [4-(2-methoxy-ethoxymethoxy)-phenyl]-methyl acetate in 100 ml of tetrahydrofuran. The reaction mixture is stirred at 60° C. for 4 h. After cooling, the reaction mixture is poured into a mixture of ice and saturated aqueous ammonium chloride solution, acidified with aqueous solution of acetic acid of concentration 1M and then extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, and dried over magnesium sulfate. After evaporation of the solvents, 8.9 g (97%) of 2-[4-(2-methoxy-ethoxymethoxy)-phenyl]-ethanol is obtained in the form of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].CO>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[O:22][CH3:21])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: COc1ccccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1C(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 77.7 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (660 mg, 2.4 mmol) and 2-methoxybenzoyl chloride (0.7 mL, 4.7 mmol) in THF (20 mL) was heated to reflux for 15 h. To the mixture was added methanol (5 mL) to give a suspension. The suspension was filtered and washed with methanol (20 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-methoxy-benzamide as a white solid (760 mg, 78% yield): mp, 286–287° C.; 1H NMR (DMSO-d6) (at 340K) δ 2.09–2.14 (m, 1H, CHH), 2.55–2.66 (m, 2H, CH2), 2.85–2.98 (m, 1H, CHH), 4.14 (s, 3H, OCH3), 5.19 (dd, J=5.5, 12.9 Hz, 1H, NCH), 7.17 (t, J=7.2 Hz, 1H, Ar), 7.30 (d, J=8.3 Hz, 1H, Ar), 7.61–7.68 (m, 2H, Ar), 7.89 (t, J=7.7 Hz, 1H, Ar), 8.12 (dd, J=1.8, 7.9 Hz, 1H Ar), 9.03 (d, J=8.5 Hz, 1H, Ar), 11.17 (s, 1H, NH), 11.64 (s, 1H, NH); 13C NMR (DMSO-d6) (at 340K) δ 22.09, 31.02, 49.29, 56.19, 112.65, 116.31, 117.93, 120.66, 121.14, 125.52, 131.59, 131.75, 134.34, 136.22, 137.00, 157.64, 163.82, 166.69, 168.15, 169.43, 172.32; Anal Calcd for C21H17N3O6: C, 61.92; H, 4.21; N, 10.31. Found: C, 62.05; H, 4.10; N, 10.38.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][N:15]1[C:27](=[O:28])[C:26]2[C:17](=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]([CH3:29])[NH:21][CH2:20][CH2:19]3)[CH2:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][CH:25]=[C:26]5[C:27](=[O:28])[N:15]([CH3:14])[CH2:16][C:17]5=4)[CH:22]3[CH3:29])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c1ccc1c2CN(C)C1=O
Product: CC1c2ccc3c(c2CCN1C(=O)c1cc2ncc(Br)cn2n1)CN(C)C3=O

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,6-Dimethyl-1,2,6,7,8,9-hexahydro-pyrrolo[3,4-f]isoquinolin-3-one to provide the title compound in moderate yield.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:22]([CH3:24])[CH3:23])[N:16]=[C:17]([CH2:19][O:20]C)[N:18]=1)[N:7]=3.C(=O)([O-])[O-].[Na+].[Na+]>Br>[Br:1][C:2]1[CH:26]=[CH:25][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:22]([CH3:24])[CH3:23])[N:16]=[C:17]([CH2:19][OH:20])[N:18]=1)[N:7]=3
Reactant: COCc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)n1nc(CO)nc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 25 °C
Yield: 59.8 %

Procedure:
A solution of 8-bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene 309 (280 mg, 0.67 mmol) in 48% aqueous HBr (4.19 mL) was heated at 100° C. for 4 h before cooling to RT. The solution was neutralized by the addition of 1M aqueous sodium carbonate and then extracted with DCM, the organic layer washed with water then dried (Na2SO4), filtered and concentrated in vacuo to give [5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-methanol as a cream solid (162 mg, 60%). LCMS RT=4.74 min, [M+H]+=404. 1H NMR 400 MHz (DMSO-d) δ: 8.30 (1H, d, J=8.65 Hz), 7.91 (1H, s), 7.33 (1H, dd, J=8.65, 2.06 Hz), 7.27 (1H, d, J=2.03 Hz), 5.82-5.75 (1H, m), 5.18 (1H, t, J=6.03 Hz), 4.51 (4H, s), 4.40 (2H, d, J=5.99 Hz), 1.44 (6H, d, J=6.60 Hz)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[CH:7]=1.[I:19]N1C(=O)CCC1=O>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[C:16]([I:19])[C:9]=23)[CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]ccc12
Solvent: CC#N
Product: COc1ccc(F)cc1-c1ccnc2[nH]cc(I)c12
Reaction time: 1 h

Procedure:
To a solution of Example 14A (22.4 g, 92 mmol) in acetonitrile (1 L) under nitrogen was added N-iodosuccinimide (21.84 g, 97 mmol) at ambient temperature. After stirring approximately 1 hour the reaction was complete. Solids started to crash out of the mixture and they were filtered off and washed with acetonitrile to provide the title compound as a solid. The filtrate was concentrated, mixed with 50 mL of dichloromethane, and sonicated for 30 minutes. Some solid did not dissolve and was filtered, washed with dichloromethane, and dried to give additional title compound. The filtrate was purified on an Analogix MPLC using a silica gel column eluting with 30-40% ethyl acetate/heptanes to give additional title compound. MS (ESI+) m/z 369.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]2=[N:17][OH:18])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc2c(c1)C(=O)CCC2(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)C(=NO)CCC2(C)C
Temperature: 70 °C

Procedure:
7-Methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (1.48 g, 7.24 mmol) (Winstein, S.; Heck, R. F, J. Org. Chem., 1972, 37, 825.) was dissolved in Ethanol (20 mL) then Hydroxylamine hydrochloride (0.61 g, 8.8 mmol) and Sodium acetate (1.20 g, 14.6 mmol) were added along with Water (20 mL). The mixture was warmed to 70° C. for 6 h, cooled and partitioned between 50 mL DCM, 10 mL satd. sodium bicarbonate and 40 mL water. The pH was 6-7. The phases were separated and the aq. extracted 2×50 mL DCM. The organic extracts were dried over sodium sulfate and concentrated in vacuo. 7-Methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one oxime was isolated as a yellow solid (1.55 g, 98%) and used without purification. 1H-NMR (CDCl3): 7.42 (d, 1H, J=2.4 Hz), 7.27 (d, 1H, J=8.5 Hz), 7.23 (s, 1H), 6.91 (dd, 1H, J=2.4, 8.5 Hz), 3.81 (s, 3H), 2.85 (t, 2H, J=6.8 Hz), 1.73 (t, 2H, J=6.8 Hz), 1.27 (s, 6H).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3B(O)O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1C=C1c2ccccc2CCc2ccccc21
Reactant: Clc1ccccn1
Product: C(=C1c2ccccc2CCc2ccccc21)c1ccccc1-c1ccccn1

Procedure:
Following procedures essentially as described in Example 225 and using 2-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylboronic acid (100 mg, 0.307 mmol) and 2-chloropyridine (52 mg, 0.460 mmol),provides the title compound. Purify further via silica gel chromatography to obtain 14.7 mg (13%) of material that is 84% pure by HPLC. MS (S) 360 (M+H).