Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[O:11]=[C:12]1[CH2:21][CH2:20][C@@:19]2([C:22]([O:24][CH3:25])=[O:23])[C:14]([CH2:15][CH2:16][N:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:18]2)=[CH:13]1.[CH:33](OCC(F)(F)F)=[O:34].Cl>CCOCC.C(OCC)(=O)C.O>[OH:34]/[CH:33]=[C:21]1\[C:12](=[O:11])[CH:13]=[C:14]2[C@:19]([C:22]([O:24][CH3:25])=[O:23])([CH2:20]\1)[CH2:18][N:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:16][CH2:15]2
Reactant: O=COCC(F)(F)F
Reactant: COC(=O)[C@]12CCC(=O)C=C1CCN(C(=O)OC(C)(C)C)C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@]12C/C(=C/O)C(=O)C=C1CCN(C(=O)OC(C)(C)C)C2
Temperature: -78 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Lithium hexamethyldisilazide (12.93 ml, 12.93 mmol) was added to diethyl ether (20 mL) at −78° C. (R)-2-tert-butyl 8a-methyl 6-oxo-3,4,6,7,8,8a-hexahydroisoquinoline-2,8a(1H)-dicarboxylate (WO2005087769) (1.0 g, 3.23 mmol) in ether (5 mL) was added followed by the addition of 2,2,2-trifluoroethyl formate (2.51 ml, 25.9 mmol) after 20 minutes. The reaction was stirred at −78° C. for 2 hours then allowed to slowly warm to room temperature. 1M hydrochloric acid (8 mL) was added, followed by water (10 mL) and ethyl acetate (10 mL). The organic phase was separated, washed with brine, dried (magnesium sulfate) and solvent removed to give (R,Z)-2-tert-butyl 8a-methyl 7-(hydroxymethylene)-6-oxo-3,4,6,7,8,8a-hexahydroisoquinoline-2,8a(1H)-dicarboxylate (1.09 g) as a yellow oil. LCMS (Method F, ES-API): RT 1.99 min, m−H=336.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11](I)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH2:40]([N:43]1[CH:47]=[CH:46][N:45]=[CH:44]1)[CH:41]=[CH2:42]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([CH:42]=[CH:41][CH2:40][N:43]2[CH:47]=[CH:46][N:45]=[CH:44]2)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccc(I)cc1Cl
Reactant: C=CCn1ccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C=CCn2ccnc2)cc1Cl

Procedure:
A mixture of ethyl 2-chloro-4-iodobenzoate (0.92 g, 2.96 mmol), triphenylphosphine (0.014 g, 0.0534 mmol), triethylamine (0.58 g, 5.73 mmol), 1-allylimidazole (1.2 g, 11.1 mmol), and palladium acetate (0.007 g) in acetonitrile (0.6 ml) was stirred and heated at 120° for 6 h in a steel bomb. The reaction mixture was cooled and concentrated to give an oily solid. The solid was purified by `flash` chromatography to give 1-[3-(3-chloro-4-ethoxycarbonylphenyl)prop-2-enyl]imidazole as a white solid.
Reaction SMILES: O=C[C@H]([C@@H:5]([C@@H:7]([CH2:9][OH:10])O)O)O.N[C@H](C(O)=O)C[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(O)[C:25]([NH2:30])(CO)CO>>[CH3:18][CH2:19][CH2:14][CH2:15][CH2:16][CH2:17][O:20][C:9]([C:7]([C:25]#[N:30])=[CH2:5])=[O:10]
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: NC(CO)(CO)CO
Product: C=C(C#N)C(=O)OCCCCCC
Reaction time: 0.08 h

Procedure:
Overnight arabinose-induced cultures were harvested by centrifugation. The cells were resuspended in 50 mM Tris, pH 8.5. Four repeating cycles of 30 seconds sonicatation and 60 seconds rest were used to break open the cells. These samples were centrifuged to separate the soluble and insoluble fractions. The pellets were resuspended in 50 mM Tris, pH 8.5. The enzyme assay was then performed using UV grade cuvettes in a final volume of 1 mL. The assay buffer was the same 50 mM Tris at pH 8.5 used throughout the sample preparation. The substrate used was 1 mM tyrosine and the sample was 40 μg of crude cell free extract. The assay was performed at 25° C. and was run for 5 mins.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1B(O)O.Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:35]=[C:34]3[C:29]([CH:30]=[CH:31][CH:32]=[N:33]3)=[CH:28][CH:27]=2)[CH:20]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:35]=[C:34]3[C:29]([CH:30]=[CH:31][CH:32]=[N:33]3)=[CH:28][CH:27]=2)[CH:20]=1
Reactant: COCOc1cc(C(F)(F)F)ccc1B(O)O
Reactant: Clc1cc(Oc2ccc3cccnc3c2)ncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COCOc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Temperature: 140 °C

Procedure:
To a suspension of 2-methoxymethoxy-4-trifluoromethylphenyl-boronic acid, (Example 135(b)), (220 mg, 0.87 mmol) and 7-(6-chloro-pyrimidin-4-yloxy)-quinoline, (Example 102(a)), (150 mg, 0.58 mmol) in toluene/EtOH (1:4, 3.8 mL) was added 2 M K2CO3 (1.2 mL, 2.3 mmol) and Pd(PPh3)4 (34 mg, 0.030 mmol, Strem). The reaction mixture was stirred and heated by microwave synthesizer at 140° C. for 10 min. The mixture was partitioned between CH2Cl2 and 1 N NaOH. The organic phase was separated, and the aqueous phase was extracted with CH2Cl2. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuum. Purification by silica gel chromatography (MeOH/CH2Cl2 1:125 and then 1:100) afforded a light-yellow gum. The title compound was obtained as a white solid after recrystallization from MeOH. MP: 98.8–99.4° C. MS (ESI, pos. ion) m/z: 428 (M+1). Anal. Calcd for C22H16F3N3O3: C, 61.83; H, 3.77; N, 9.83. Found: C, 62.13; H, 3.87; N, 9.52.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5](=[N:7][N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH2:4][CH:3]=1.Cl[Si](C)(C)C.[C:19](Cl)([Cl:21])=[O:20]>C(N(CC)CC)C>[Cl:21][C:19]([N:10]1[CH2:11][CH2:12][N:8]([N:7]=[C:5]2[CH2:4][CH:3]=[C:2]([CH3:1])[O:6]2)[C:9]1=[O:13])=[O:20]
Reactant: O=C(Cl)Cl
Reactant: CC1=CCC(=NN2CCNC2=O)O1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: CC1=CCC(=NN2CCN(C(=O)Cl)C2=O)O1

Procedure:
50.0 pts. by wt. of 1-(5-methylfurylideneamino)-2-oxo-imidazolidine, 84.3 pts. by wt. of triethylamine, 84.0 pts. by wt. of chlorotrimethylsilane and 51.4 pts. by wt. of phosgene are reacted as in Example 1.2. After recrystallisation from acetonitrile, 50.7 pts. by wt. of 1-chlorocarbonyl-2-oxo-3-(5-methylfurylideneamino)-imidazolidine of dec. pt. 180°-186° C. are obtained.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]([CH3:20])[C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=1)[CH2:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1.CN(CCN(C)C)C.[CH:29]12[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[C:30]1=[O:39])[CH2:36]2>CCCCCC.C1COCC1.O>[CH3:20][N:7]([CH3:6])[C:8]1[CH:9]=[C:10]([CH:11]([C:30]2([OH:39])[CH:31]3[CH2:37][CH:35]4[CH2:34][CH:33]([CH2:38][CH:29]2[CH2:36]4)[CH2:32]3)[C:12]2[NH:16][CH:15]=[CH:14][N:13]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CN(C)c1cccc(Cc2ncc[nH]2)c1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)c1cccc(C(c2ncc[nH]2)C2(O)C3CC4CC(C3)CC2C4)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
20 ml (31 mmol) of a 1.55 molar solution of n-butyllithium in hexane were added dropwise to a solution of 3.03 g (15 mmol) of (3-dimethylaminobenzyl)-imidazole and 1.75 g (15 mmol) of TMEDA in 30 ml of absolute THF. Stirring was carried out for 1 hour at -70° C., after which a solution of 2.26 g of adamantanone in 40 ml of absolute THF was added dropwise at -30° to -15° C. The mixture was allowed to warm up to room temperature in the course of about 45 minutes and was stirred for a further 2 hours at room temperature, 400 ml of water were added at 10° C., while cooling, and stirring was continued for 15 minutes at 0°-5° C., a crystalline precipitate being formed. This was filtered off under suction, rinsed with hexane and diisopropyl ether and dried in vacuo. 2.20 g (= 41.7% yield) of pure (3-dimethylaminophenyl)-(2-hydroxy-2-adamantyl)-1-imidazolylmethane of melting point 185° C. were obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S(Cl)([Cl:28])=O>ClCCl>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[N:14][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][Cl:28])=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(CCc3ccc(CO)cc3)nc2)CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(CCl)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a solution of (4-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}phenyl)methanol (227.0 mg, 0.669 mmol) in dichloromethane (5 ml) was added thionyl chloride (0.096 ml, 1.331 mmol). After stirring at room temperature for 2 hrs, the reaction mixture was concentrated. To the residue was added aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness to give 1-acetyl-4-(6-{2-[4-(chloromethyl)phenyl]ethyl}pyridin-3-yl)piperazine (234.8 mg, yield 98.1%) as a silghtly yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=1)=[CH2:2].[CH3:11][N:12]([CH3:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[Cl-:8].[CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N+:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:11])[CH3:23])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: CCCCCCCCCCN(C)C
Reactant: C=Cc1ccc(CCl)cc1
Product: C=Cc1ccc(C[N+](C)(C)CCCCCCCCCC)cc1
Product: [Cl-]
Reaction time: 8 h

Procedure:
4-Vinylbenzyl chloride (18.60 g, 100 mmol) and N,N-dimethyl-N-decylamine (15.26 g, 100 mmol) were mixed in a 100 mL round bottomed flask. The mixture was allowed to sit overnight. The crystalline product was crushed and washed with ether. The product was collected by filtration (30.3 g, 90%)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](Cl)=[N:18][CH:19]=[N:20]3)=[CH:15][C:14]=2[O:24][CH3:25])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:26][C:27]1[C:35]([OH:36])=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[C:30]([CH3:37])[NH:31]2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.CC(C)=O.FC1C(O)=CC=C2C=1C=C(C)N2.C(=O)([O-])[O-].[K+].[K+]>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([O:36][C:35]4[C:27]([F:26])=[C:28]5[C:32](=[CH:33][CH:34]=4)[NH:31][C:30]([CH3:37])=[CH:29]5)=[N:18][CH:19]=[N:20]3)=[CH:15][C:14]=2[O:24][CH3:25])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCN1CCN(C(C)=O)CC1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CC(C)=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCN1CCN(C(C)=O)CC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
A mixture of 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-chloro-6-methoxyquinazoline (12.24 g, 33.5 mmol), 4-fluoro-5-hydroxy-2-methylindole (5.54 g, 33.5 mmol), (prepared as described for the starting material in Example 1), and potassium carbonate (4.64 g, 33.5 mmol) was heated in N,N-dimethylacetamide (150 ml) at 85° C. for 4 hours. 4-Fluoro-5-hydroxy-2-methylindole (33 mg, 0.2 mmol) and potassium carbonate (108 mg, 57%) were added and the mixture heated for a further 1 hour at 85° C. and then stirred at ambient temperature overnight. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give a white solid which was suspended in acetone (150 ml) and heated at reflux for 1 hour. After cooling the mixture was filtered and the solid dried in air to give 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (10 g, 60%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N-:4][N:3]=1.[CH2:8]([O:15][C:16]([NH:18][C@@H:19]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH:20]([OH:24])[C:21]([OH:23])=[O:22])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)(Cl)Cl>ClCCl>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N-:4][N:3]=1.[CH2:8]([O:15][C:16]([NH:18][C@@H:19]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH:20]([O:24][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][O:29]1)[C:21]([OH:23])=[O:22])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(O)C(=O)O
Reactant: C1=COCCC1
Agent: Cc1cc(C)[n-]n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(OC1CCCCO1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
162 mg of (2RS,3S)-3-benzyloxycarbonylamino-2-hydroxy-5-methylhexanoic acid 3,5-dimethylpyrazolide was dissolved in 1 ml of dry dichloromethane, and 102 μl of dihydropyran and 0.8 mg of p-toluenesulfonic acid monohydrate were added thereto. The mixture was stirred at room temperature for 1.5 hours. Then, 10 ml of chloroform was added to the mixture, and the mixture was washed with a 4% sodium hydrogencarbonate and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 207 mg of (2RS,3S)-3-benzyloxycarbonylamino-2-(2-tetrahydropyranyloxy)-5-methylhexanoic acid 3,5-dimethylpyrazolide as a colorless oily substance.
Reaction SMILES: [H-].[K+].[CH3:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[H][H].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:25])=[C:20]([N:22]=[C:23]=[S:24])[CH:21]=1>C1COCC1.CCOCC.CCCCCC>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:25])=[C:20]([NH:22][C:23]([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[C:4]2[CH3:3])=[S:24])[CH:21]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: [H][H]
Reactant: Cc1cc2ccccc2[nH]1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1ccc(Cl)cc1NC(=S)n1c(C)cc2ccccc21
Reaction time: 16 h

Procedure:
A stirred slurry of hexane washed potassium hydride (1.51 g, 38 mmol) in 10 mL of dry THF was treated dropwise with a solution of 2-methylindole (5.0 g, 38 mmol) in 30 mL THF. The mixture was stirred until hydrogen evolution ceased. To the dark red solution was slowly added 5-chloro-2-methylphenylisothiocyanate (7 g, 38 mmol) and stirring was continued for 16 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc and 1N HCl. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give 11.5 g of rose colored solids. The solids were dissolved in Et2O and clarified with Norite-A. Hexane was added to the filtered solution and the precipitate was collected and dried to give 7.0 of the title compound as a light yellow solid, m.p. 121-122° C. (53% of theory).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].[H][H].Cl[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([S:20]([NH2:23])(=[O:22])=[O:21])=[C:16]([CH2:18][CH3:19])[N:17]=2)[N:14]=1.Cl>CN(C=O)C.O>[CH2:18]([C:16]1[N:17]=[C:12]2[CH:11]=[CH:10][C:9]([S:5][CH2:3][CH3:4])=[N:14][N:13]2[C:15]=1[S:20]([NH2:23])(=[O:22])=[O:21])[CH3:19]
Reactant: [H][H]
Reactant: CCc1nc2ccc(Cl)nn2c1S(N)(=O)=O
Reactant: CCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1ccc2nc(CC)c(S(N)(=O)=O)n2n1

Procedure:
60% sodium hydride (0.19 g, 4.75 mmol) was suspended in DMF (5.0 ml) and ethanethiol (0.29 g, 4.6 mmol) was added thereto with stirring. After evolution of hydrogen was ceased, 6-chloro-2-ethylimidazo[1,2-b]pyridazin-3-ylsulfonamide (0.30 g, 1.15 mmol) was added thereto and stirred at 50° C. for 3 hours. After the reaction was completed, the reaction solution was poured into water (50.0 ml) and adjusted to pH 2 with dilute hydrochloric acid, and the precipitated crystals were filtered, washed with water and washed with ether, to give the title compound as pale yellow crystals. The yield was 0.19 g (57.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[CH:13][N:14]=C3C[N+:8]([O-])=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[C:25]([O:28][C:29](=[O:31])[CH3:30])(=[O:27])[CH3:26]>C(O)(=O)C>[C:25]([OH:28])(=[O:27])[CH3:26].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[CH:13][N:14]=[C:30]3[CH:29]([OH:31])[N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=[N+]([O-])C2
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2O

Procedure:
A stirred mixture of 1.0 g. of 8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,2-a][1,4]benzodiazepine-5-oxide (III), 5 ml. of acetic anhydride and 3 ml. of acetic acid is warmed on the steam bath, under nitrogen, for 30 minutes and concentrated in vacuo. The residue is suspended in water, neutralized with sodium carbonate and extracted with methylene chloride. The extract is dried, concentrated and chromatographed on silica gel eluting with ethyl acetate to yield 8-chloro-6-(2-chlorophenyl)-4-hydroxy-1-methyl-4H-imidazo[1,2-a][1,4]benzodiazepine acetate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][C:10]=2[F:26])=[CH:4][CH:3]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.O>N1C=CC=CC=1>[F:26][C:10]1[CH:11]=[C:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:6]=[N:7][C:2]([NH:1][S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=2)(=[O:35])=[O:34])=[CH:3][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Oc2ccc(NC(=O)OCc3ccccc3)cc2F)cn1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(NC(=O)OCc4ccccc4)cc3F)cn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.1 %

Procedure:
To a solution of benzyl {4-[(6-aminopyridin-3-yl)oxy]-3-fluorophenyl}carbamate (28.2 g, 79.8 mmol) in pyridine (141 mL) was added p-toluenesulfonyl chloride (18.3 g, 98.5 mmol), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5N hydrochloric acid, water and saturated brine in this order, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/ethyl acetate and collected by filtration to give the title compound (29.2 g, 72%).
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[Br:11][C:12]1[N:13]=[CH:14][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:16]=1Br>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Br:11][C:12]1[N:13]=[CH:14][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:16]=1[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)CCOCn1cnc(Br)c1Br
Reactant: C[Sn](C)(C)c1cccnc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1cnc(Br)c1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.2 %

Procedure:
To a solution of 71 (0.82 g, 3.4 mmol) in anhydrous toluene (50 ml) were added 0.9 eq (1.10 g) of 4,5-dibromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (compound 72, LCMS (method A): Rt: 3.60 min, ([M+H]+=357)) and the resulting mixture was stirred for 2 hours under N2 (room temperature). To this reaction mixture were added 10 mol % of PdCl2(PPH3)2 (240 mg). After the addition, the temperature was raised to 100° C. and the resulting solution was stirred for 18 hours under N2. The reaction mixture was cooled, diluted with ethyl acetate, washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether followed by ethyl acetate) to afford 3-[5-bromo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-pyridine (73) as an oil (385 mg, 36%). LCMS (method A): Rt: 3.40 min, ([M+H]+=355). 1H-NMR (400 MHz, CDCl3 and HMBC): δ 8.79 (d, J=2 Hz, 1H), 8.66 (dd, J=5 Hz, 2 Hz, 1H), 7.91 (dt, J=8 Hz, 2 Hz, 1H), 7.66 (s, 1H), 7.44-7.40 (m, 1H), 5.17 (s, 2H), 3.56-3.50 (m, 2H), 0.94-0.87 (m, 2H), 0.0 (s, 9H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O>[Ni].[Fe].[Ni].[Fe]>[CH3:1][CH2:2][CH3:3].[CH:8]1([OH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1.[CH:8]1([OH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCCCCCCC(=O)O
Agent: [Fe]
Agent: [Ni]
Product: CCC
Product: OC1CCCCC1

Procedure:
Example 3 is repeated, except that octoic acid is added to the nickel and iron solution in a molar ratio of the acid to the metal (nickel+iron) of 0.20. The absorption of hydrogen ceases after 4 hours of reaction and dicyclohexanol propane is obtained quantitatively.
Reaction SMILES: Cl.O.[OH:3][B:4]1[C:8]2[CH:9]=[C:10]([O:14][C:15]3[S:16][C:17]([N+:20]([O-])=O)=[N:18][N:19]=3)[CH:11]=[C:12]([CH3:13])[C:7]=2[CH:6]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[O:5]1>C(O)C.[Fe]>[NH2:20][C:17]1[S:16][C:15]([O:14][C:10]2[CH:11]=[C:12]([CH3:13])[C:7]3[CH:6]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[O:5][B:4]([OH:3])[C:8]=3[CH:9]=2)=[N:19][N:18]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc([N+](=O)[O-])s3)cc(C)c21
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(N)s3)cc(C)c21
Temperature: 85 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
Concentrated aq. HCl (50 mL) and water (1000 mL) were added to a mixture of ethyl 2-(1-hydroxy-4-methyl-6-(5-nitro-1,3,4-thiadiazol-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (70 g, 0.18 mol) and iron powder (51 g, 0.9 mol) in ethanol (3000 mL) at room temperature. The resulting mixture was stirred at 85° C. for 2 hrs, cooled to room temperature and filtered through a pad of celite. The filtrate was evaporated and the residue dissolved in EtOAc, washed with brine, dried over Na2SO4 and concentrated to give compound ethyl 2-(6-(5-amino-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (40 g, 63% yield) which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (1H, s), 7.32 (1H, m), 7.16 (1H, m), 7.15 (2H, s), 5.50 (1H, m), 4.03 (2H, m), 3.08 (1H, m), 2.32 (4H, m), 1.10 (3H, m).