Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])C.[OH-].[K+]>C(O)C.O>[Br:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)[C:6]([C:4]([OH:5])=[O:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2cc(Br)ccc2n1Cc1ccc([N+](=O)[O-])cc1
Yield: 77.6 %

Procedure:
To a stirred solution of 5-bromo-1-(4-nitro-benzyl)-1H-indole-2-carboxylic acid ethyl ester (2.3 g, 5.7 mmol) in ethanol/water (2:1, 45 ml) at room temperature was added potassium hydroxide (0.96 g, 17.1 mmol). The solution was warmed to reflux for about 3 hours, cooled, and most of the ethanol was removed under reduced pressure. To the residue was added water, 0.5N sodium hydroxide and methylene chloride, and the two-phase mixture was suction filtered to remove some insoluble material. The aqueous layer was acidified to pH 2 with 6N hydrochloric acid, and the precipitate was filtered off, washed with water, and air dried to afford the title compound, (1.66 g).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][C:15](/[CH:17]=[C:18](\[CH2:23][C:24]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=3)/[C:19]([O:21][CH3:22])=[O:20])=[CH:16][C:11]=2[O:10][CH2:9]1>ClCCl.C(OCC)(=O)C>[CH3:35][O:34][C:26]1[C:25]2[C:14]3[C:15]([CH:17]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[CH2:23][C:24]=2[CH:29]=[C:28]([O:30][CH3:31])[C:27]=1[O:32][CH3:33])=[CH:16][C:11]1[O:10][CH2:9][O:8][C:12]=1[CH:13]=3
Reactant: COC(=O)/C(=C/c1ccc2c(c1)OCO2)Cc1cc(OC)c(OC)c(OC)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1=Cc2cc3c(cc2-c2c(cc(OC)c(OC)c2OC)C1)OCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
Ferric perchlorate hexahydrate (342 mg, 0.74 mmol) and 0.5 ml of trifluoroacetic acid were added to a solution of methyl (E)-α-(1,3-benzodioxol-5-yl-methylene)-3,4,5-trimethoxybenzene- propionate [114 mg, 0.295 mmol; P. Magnus et.al., J. Am. Chem. Soc., 107, 4984, (1985)] in 5 ml of dichloromethane, followed by stirring at room temperature for 1 hour. The reaction mixture was dissolved in 20 ml of ethyl acetate. The resulting solution was washed successively with 2N-HCl, water and saturated NaHCO3, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Brown oil thus obtained (122 mg) was purified by TLC (silica gel: "MERCK #5744", eluent: 1:1 mixed solvent of ethyl acetate and hexane), whereby 96 mg of the title compound were obtained as colorless oil (yield: 85%).
Reaction SMILES: O[CH:2]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:5]=2[N:4]2[N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=[C:3]12.COCCN(S(F)(F)[F:32])CCOC>ClCCl>[F:32][CH:2]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:5]=2[N:4]2[N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=[C:3]12
Reactant: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2O
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2F
Yield: 82.1 %

Procedure:
Ethyl 4-hydroxy-9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxylate (400 mg, 1.00 mmol, 1.00 equiv) in dichloromethane (25 mL) was added [bis(2-methoxyethyl)amino]sulfur trifluoride (442 mg, 2.00 mmol, 2.00 equiv) at 0° C. After 4 h at room temperature the resulting mixture was washed with brine, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:10). It resulted in 330 mg (82%) of the titled compound as a yellow solid. LC-MS (ES, m/z) 403 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[F:10][CH:11]([F:22])[S:12]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17])(=[O:14])=[O:13].[H-].[Na+].C(Cl)Cl.CO>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[S:12]([CH:11]([F:22])[F:10])(=[O:14])=[O:13])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Nc1ccccc1S(=O)(=O)C(F)F
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)C(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4,5-trichloropyrimidine (1 mmol) and 2-(difluoromethylsulfonyl)aniline (1 mmol) in 10 mL of DMF was added sodium hydride (2 mmol) at 0° C. After the reaction mixture was warmed to room temperature and stirred at 50° C. for 1 hour. After work-up and flash chromatography (CH2Cl2/MeOH 9:1), product was obtained. MS (ES+): 353.96 (M+1)+.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:27][C:26]4[C:25]5=[N:35][N:36]=[C:37]([C:38]6[N:43]=[CH:42][CH:41]=[CH:40][N:39]=6)[N:24]5[CH:23]=[CH:22][C:21]=4[N:20]=3)=[CH:15][CH:14]=2)[CH2:9][C:8]([OH:12])([CH2:10][OH:11])[CH2:7]1)=O.[OH-].[Na+]>CCO>[NH2:5][C:6]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:28]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:27][C:26]4[C:25]5=[N:35][N:36]=[C:37]([C:38]6[N:43]=[CH:42][CH:41]=[CH:40][N:39]=6)[N:24]5[CH:23]=[CH:22][C:21]=4[N:20]=3)=[CH:15][CH:14]=2)[CH2:9][C:8]([CH2:10][OH:11])([OH:12])[CH2:7]1
Reactant: O=C(NC1(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)CC(O)(CO)C1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC1(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)CC(O)(CO)C1

Procedure:
To a mixture of 2,2,2-trifluoro-N-(3-hydroxy-3-(hydroxymethyl)-1-{4-[9-phenyl-3-(2-primidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-14) (5 mg, 0.009 mmol) in EtOH (6 mL) was added NaOH (5M in water, 0.5 mL, 0.50 mmol), and the mixture was refluxed for 3 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC eluting with 5% MeOH in CHCl3 to give 3-amino1-(hydroxymethyl)-3-{4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanol (4-15) as a white solid. HRMS (M+H)+: observed=516.2148, calculated=516.2147.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1([CH2:16][O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH:12]1[CH:14]=C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl.C1CCCCC1.C(OCC)(=O)C>[C:18]([O:17][CH2:16][C:11]1([CH2:10][O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH:12]1[CH2:14][OH:26])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=CC1CC1(COC(=O)c1ccccc1)COC(=O)c1ccccc1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: ClCCl
Product: O=C(OCC1(COC(=O)c2ccccc2)CC1CO)c1ccccc1
Reaction time: 1.5 h
Yield: 36 %

Procedure:
A solution of 11 g (33 mmoles) of 1,1-bis(benzoyloxymethyl)-2-vinylcyclopropane in 200 ml of CH2Cl2 was cooled to -70° and stirred while a stream of O3 was introduced over a period of 30 minutes, at which time a permanent blue color was obtained. TLC in cyclohexane-ethyl acetate (4:1) indicated that the starting material was no longer present and several new more polar products (Rf 0.55, 0.5, 0.47, 0.4) had been formed. The reaction mixture was treated with 6.6 g (174 mmoles) of NaBH4 and the cooling bath was removed. Stirring was continued for 1.5 hours and TLC showed the formation of a more polar (Rf 0.2) product. The reaction mixture was acidified by the continuous dropwise addition of 200 ml of 2N HCl. The mixture was concentrated to remove the CH2Cl2 and the aqueous layer was extracted with three 100 ml portions of EtOAc which was washed with 50 ml of water, 100 ml of saturated NaHCO3 and 50 ml of saturated NaCl. The EtOAc layer was dried (MgSO4), filtered and concentrated to give 11.3 g of crude product which was chromatographed on 600 ml of silica gel; first eluting with 2400 ml of cyclohexane-ethyl acetate (5:2) and finally with 1600 ml of 2:1 cyclohexane ethyl acetate. Fractions containing only product were combined and concentrated to give 4 g (36%) of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:27]2[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[BH4-].C([N+](CCCC)(CCCC)CCCC)CCC.O.Cl>C(Cl)Cl.O1CCCC1>[NH2:34][CH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][OH:9])=[C:2]([Br:1])[CH:3]=1
Reactant: CC(C)(C)[Si](OCc1ccc(-c2ccccc2C#N)cc1Br)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [BH4-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccccc1-c1ccc(CO)c(Br)c1
Temperature: 25 °C
Yield: 57 %

Procedure:
To a solution of 136 mg (0.258 mmol) of 3'-bromo-4'-t-butyldiphenylsilyloxymethyl-1,1'-biphenyl-2-nitrile (Step G) in 3 mL of dry methylene chloride under a nitrogen atmosphere was added 199 mg (0.775 mmol) of tetra-n-butylammonium borohydride. The reaction mixture was heated at reflux for 8 hours, cooled to room temperature, poured into 25 mL of water and extracted with ethyl acetate (3×35 mL). The combined organic extracts were washed with water (25 mL), saturated aqueous sodium bicarbonate (25 mL) and brine (25 mL). The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum to give an oil which was dissolved in 3 mL of tetrahydrofuran and treated with 1 mL of 6 N aqueous hydrochloric acid. The resulting solution was heated at reflux for 4 hours, cooled in an ice bath and quenched with 10 mL of 1 N aqueous sodium hydroxide. The mixture was extracted with ethyl acetate (3×35 mL). The organic extracts were washed with water (25 mL), saturated aqueous sodium bicarbonate (25 mL) and brine (25 mL). The organic layer was dried over sodium sulfate, filtered and the solvent removed under vacuum to give an oil which was purified by flash column chromatography on silica gel, eluting with chloroformB 10% ammonium hydroxide (33%) in methanol (9:1), to afford 43 mg (57%) of the product as an off-white solid. 1H NMR (200 MHz, CD3OD): δ 3.69 (s, 2H), 4.68 (s, 2H), 7.16 (dd; 7, 6 Hz; 1H), 7.21-7.41 (m, 4H), 7.47 (dd; 9, 8 Hz; 1H), 7.58 (d, 8 Hz, 1H). FAB-MS: calculated for C14H14BrNO 292; found 292, 293 (50%).
Reaction SMILES: Cl.[F:2][C:3]1([F:7])[CH2:6][NH:5][CH2:4]1.Cl[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1.C(N(CC)CC)C.O>CN(C)C=O.C(OCC)(=O)C>[F:2][C:3]1([F:7])[CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=2)[CH2:4]1
Reactant: FC1(F)CNC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CC(F)(F)C2)nc1
Temperature: 100 °C

Procedure:
A mixture of 0.367 g (2.84 mmol) of 3,3-difluoroazetidine hydrochloride, 0.3 g (1.89 mmol) of 2-chloro-5-nitropyridine and 0.41 mL (2.84 mmol) of triethylamine in 10 mL of dimethylformamide is heated overnight at 100° C. After this time, the suspension is poured into a mixture of 30 mL of water and 30 mL of ethyl acetate. The aqueous phase is separated, and then extracted with 20 mL of ethyl acetate. The organic phases are combined, washed three times with 25 mL of water, then dried over sodium sulfate and concentrated at reduced pressure. The resultant product is purified by chromatography on a silica column, eluting with dichloromethane. We thus obtain 0.34 g of the expected product in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11]C)=[CH:9][C:8]2[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH2:17][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:19]([O:21][CH2:22][CH3:23])=[O:20].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]2[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH2:17][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1cc2c(Cl)c(OC)cc3c2n1CCCCC3=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(Cl)c(O)cc3c2n1CCCCC3=O
Temperature: -20 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A solution of ethyl 5,6,7,8-tetrahydro-11-chloro-10-methoxy-8-oxo-4H-azocino [3,2,1-hi]indole-2-carboxylate (4.00 g, 11.8 mmol) in dichloromethane (80 ml) was cooled to -78° C., and boron tribromide (3.26 g, 13.0 mmol) was added dropwise. The reaction temperature was raised to -20° C. and the reaction mixture was stirred at -20° C. for 8 hours. The reaction mixture was poured into ice water and extracted three times with ethylacetate, and the extract solution was washed with a saturated aqueous ammonium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent:ethyl acetate/n-hexane= 1/9) to obtain 0.99 g of ethyl 5,6,7,8-tetrahydro-11-chloro-10-hydroxy-8-oxo-4H-azocino [3,2,1-hi]indole-2-carboxylate.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH-:11].[Na+].O>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][SH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [SH-]
Reactant: BrCCCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: SCCCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-phenylpropylbromide (1.08 g) in ethanol (8 ml) was added sodium hydrosulfide (0.871 g), and the mixture was stirred at room temperature for 20 hr. Water was added to the reaction mixture, extracted with diethyl ether, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 3-phenylpropanethiol. To a solution of the obtained 3-phenylpropanethiol in dioxane (15 ml) were added compound 227-1 (500 mg), diisopropylamine (0.327 ml), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (27 mg) And tris(dibenzylideneacetone)palladium(0)-chloroform adduct (24 mg), and the mixture was stirred at 120° C. for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give a mixture of (2,2-dimethyl-5-{2-[4-(3-phenylpropylthio)-3-trifluoromethylphenyl]ethyl}-1,3-dioxan-5-yl)carbamic acid t-butyl ester and a starting material (Compound 227-1). Again, 3-phenylpropanethiol in the same amount as the above was prepared, and the above-mentioned operation was repeated using the mixture of (2,2-dimethyl-5-{2-[4-(3-phenylpropylthio)-3-trifluoromethylphenyl]ethyl}-1,3-dioxan-5-yl)carbamic acid t-butyl ester and the starting material obtained above instead of compound 227-1 to give (2,2-dimethyl-5-{2-[4-(3-phenylpropylthio)-3-trifluoromethylphenyl]ethyl}-1,3-dioxan-5-yl)carbamic acid t-butyl ester as a pale-yellow oil. The pale-yellow oil was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, the residue was washed with diethyl ether to give a pale-yellow solid. The pale-yellow solid was purified by HPLC, the obtained residue was converted to hydrochloride by adding hydrogen chloride containing ether (1 mol/l, 15 ml), and the precipitate was collected by filtration and dried to give the object product (90 mg) as a white powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15]COCC[Si](C)(C)C)[C:12]2[C:7](=[C:8]([Br:26])[CH:9]=[C:10]([O:24][CH3:25])[CH:11]=2)[N:6]=1)=[O:4].O1CCCC1.O.O.[OH-].[Li+]>CO>[Br:26][C:8]1[CH:9]=[C:10]([O:24][CH3:25])[CH:11]=[C:12]2[C:7]=1[NH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:14][C:13]2=[O:15]
Reactant: COC(=O)c1cc(OCOCC[Si](C)(C)C)c2cc(OC)cc(Br)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(Br)c2[nH]c(C(=O)O)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.4 %

Procedure:
To a light brown solution of 8-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid methyl ester (Reference Example 24c) (4.98 g, 11.3 mmol) in 75 mL 3:1:1 tetrahydrofuran:methanol:water was added lithium hydroxide monohydrate (1.367 g, 32.6 mmol). The reaction was stirred at room temperature for 5 hours. The reaction mixture was concentrated and then poured into water. The solution was acidified to pH 2 with 1 N HCl and the resulting solids were isolated by filtration. The solids were then suspended in methanol and filtered to afford the desired product (2.6732 g, 80%). An additional 0.5768 g (17%) of product was obtained from the methanol filtrates. 1H NMR (300 MHz, DMSO, d6, TFA Shake) δ 7.86 (d, 1H, Jm=2.7 Hz, ArH5), 7.55 (d, 1H, Jm=2.7 Hz, ArH7), 7.32 (s, 1H, C═CH), 3.94 (s, 3H, OCH3); Mass Spec.: calc. for [C11H8BrNO4+H]+ Theor. m/z=298, 300; Obs.=298, 300.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>[B].B#[Zr]>[C:9](=[O:10])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: B#[Zr]
Agent: [B]
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
Example 1 was repeated with 14.1 g of a powdered zirconium diboride from H. C. Starck at 140° C. After 2 hours' reaction time, phenol conversion was 35.7%, wherein 0.4 g of phenyl chloroformate and 54.9 g of diphenyl carbonate were formed. Selectivity for carbonates was greater than 96%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=O)(C)(C)C.Cl>ClCCl>[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: Cl
Solvent: ClCCl
Product: O=C(O)[C@@H]1CCCNC1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (7.0 mmol) was added dichloromethane (48 mL) followed by hydrochloric acid (4M, 16 mL). The reaction mixture was stirred at 30° C. for 2 h. The solvent was removed under reduced pressure to afford (R)-piperidine-3-carboxylic acid which was used without further purification.
Reaction SMILES: C(OCC)(=O)C.[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]([N:18]([CH:27]([CH3:29])[CH3:28])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:17])=[C:10]([N+:30]([O-])=O)[CH:9]=1.[H][H]>[Pd].C(O)C>[NH2:30][C:10]1[CH:9]=[C:8]([F:7])[CH:13]=[CH:12][C:11]=1[NH:14][CH2:15][C:16]([N:18]([CH:27]([CH3:29])[CH3:28])[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)=[O:17]
Reactant: [H][H]
Reactant: COc1ccc(N(C(=O)CNc2ccc(F)cc2[N+](=O)[O-])C(C)C)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(N(C(=O)CNc2ccc(F)cc2N)C(C)C)cc1
Yield: 83.3 %

Procedure:
A solution of 30 mL ethyl acetate, 175 mL ethanol, and 2.50 g of 2-(4-Fluoro-2-nitrophenylamino)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (6.92 mmol) was combined with 0.25 g of palladium on carbon (10 wt %) and hydrogenated under a hydrogen balloon over 16 hrs. The reaction mixture was filtered and evaporated in vacuo to provide 1.91 g of the title compound as a solid. 1H NMR (300 MHz, CDCl3) d 7.03 (m, 2H), 6.94 (m, 2H), 6.36 (m, 3H), 4.99 (m, 1H), 4.37 (b, 3H), 3.86 (s, 3H), 3.39 (s, 2H), 1.07 (d, 6H, J=6.8); low resolution MS (FAB)m/e 332 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:11][C:10]=1[O:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.S(=O)(=O)(O)O.[N+:35]([O-])([OH:37])=[O:36]>C(O)(=O)C.O>[CH2:1]([O:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])=[C:23]([N+:35]([O-:37])=[O:36])[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C(=O)OCc2ccccc2)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 10 °C
Reaction time: 23 h

Procedure:
Benzyl 4-(benzyloxy)-3-methoxybenzoate (78 g) was mixed with dichloromethane (580 ml), water (72 ml) and glacial acetic acid (288 ml). The mixture was cooled to 10° C. Concentrated sulfuric acid (108 ml) was added in a controlled manner maintaining the temperature of the reaction mixture below 25° C. Concentrated nitric acid (17.5 ml) was then added keeping the temperature of the reaction mixture below 20° C. The reaction mixture was then stirred at 20° C. for 23 hours. The lower aqueous layer was removed and the organic layer was washed with water (290 ml). The organic layer was separated and distilled to 270 ml at atmospheric pressure. Isopropanol (750 ml) was added to the reaction mixture at 45° C. The reaction mixture was then heated to 40° C. and stirred at this temperature for 15 minutes. The resulting suspension was then cooled to 20° C., then to 5° C. and held at this temperature for one hour. The product (benzyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate) was isolated by filtration, washed with isopropanol (200 ml) and dried at less than 25° C. Yield: 78.4 g, 89.6%;
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12)(=[O:4])=[O:3].[CH3:13][Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.CI.[Cl-].[Na+]>C1COCC1>[CH2:1]([S:2]([C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12)(=[O:3])=[O:4])[CH3:13]
Reactant: CS(=O)(=O)c1ncn2ccsc12
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCS(=O)(=O)c1ncn2ccsc12
Reaction time: 0.5 h

Procedure:
A solution of 725 mg of 7-methanesulfonylimidazo[5,1-b]thiazole in 35 ml of THF was cooled in an argon atmosphere to −70° C. A 1 N-lithiumbis(trimethylsilyl)amide/THF solution (3.9 ml) was added dropwise thereto at the same temperature. The mixture was stirred for 30 min. Thereafter, 0.25 ml of methyl iodide was added thereto. The mixture was stirred at the same temperature for 70 min. A saturated aqueous sodium chloride solution was added thereto, followed by extraction four times with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=9:1) to give 0.79 g of 7-ethanesulfonylimidazo[5,1-b]thiazole.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14].CN(C)CC(O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.[Cu]I>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([O:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:3][CH:4]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: Nc1ccc(Br)cn1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cccc(Oc2ccc(N)nc2)c1
Temperature: 120 °C
Yield: 51.2 %

Procedure:
A procedure described by D. Ma and Q. Cai (Org. Lett. 3799, 2003) was followed. To a solution of 5-bromopyridin-2-amine (346 mg, 2 mmol) in dioxane (10 mL) were added methyl 3-hydroxybenzoate (400 mg, 2.6 mmol), CuI (50 mg), N,N-dimethylglycine (60 mg) and Cs2CO3 (1.0 g). The resulting mixture was heated to 120° C. for 5 h, then cooled and partitioned between water and dichloromethane. The organic layer was separated, dried, and concentrated. The residue was purified by silica gel column eluting with ethyl acetate in dichloromethane (1:1) to obtain methyl 3-(6-aminopyridin-3-yloxy)benzoate (250 mg, 50%) as an oil. LC/MS; (M+H)+=245.