Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:6]=1[C:15]([F:18])([F:17])[F:16])(=[O:3])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)C>[C:12]([NH:11][C:8]1[CH:7]=[C:6]([C:15]([F:16])([F:17])[F:18])[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc(NC(C)=O)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(C(F)(F)F)c(NC(C)=O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 12 h

Procedure:
91.5 g (0.3 mol) of 1,4-bisacetylamino-2-trifluoromethylbenzene (prepared according to B.) are initially introduced into 300 ml of glacial acetic acid, and a mixture of 25 g of glacial acetic acid and 20 g of nitric acid (density 1.5) is added dropwise at 50° C. in the course of 60 minutes. The mixture is subsequently stirred at the same temperature for 12 hours and then poured onto 2.5 kg of ice. The product which has precipitated is filtered off with suction, washed with water and dried.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.[CH3:34][N:35]1[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:37]=[N:36]1.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:39]2[N:35]([CH3:34])[N:36]=[CH:37][CH:38]=2)[CH:3]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
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: [Na+]
Product: Cn1nccc1-c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Yield: 66.7 %

Procedure:
N-(4-Fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.250 g, 0.44 mmol) was reacted with 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.183 g, 0.88 mmol), sodium carbonate (0.150 g, 1.41 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.10 g) to give 0.152 g (65% yield) of the title material as a white solid after chromatography on silica gel. 1H NMR 400 MHz (CDCl3) δ (ppm): 1.63 (6H, s, 2×CH3), 3.69 (3H, s, NCH3), 4.0–4.1 (4H, m, 2×CH2), 4.34 (2H, d, J=6.6 Hz, NCH2), 5.29 (2H, s, OCH2), 6.26 (1H, d, J=2.0 Hz, CH), 6.98 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic), 7.13 (1H, m, aromatic), 7.3–7.35 (3H, m, aromatics), 7.47–7.55 (4H, m, aromatics and NH), 7.57 (1H, d, J=2.0 Hz, CH). MS (ESI+) m/z 518 [M+H+].
Reaction SMILES: [NH:1]([CH2:4][CH3:5])[CH2:2][CH3:3].[Br:6][C:7]([F:14])([F:13])[C:8]([O:10]CC)=O>>[Br:6][C:7]([F:13])([F:14])[C:8]([N:1]([CH2:4][CH3:5])[CH2:2][CH3:3])=[O:10]
Reactant: CCNCC
Reactant: CCOC(=O)C(F)(F)Br
Product: CCN(CC)C(=O)C(F)(F)Br
Reaction time: 1 h

Procedure:
Et2NH (7.9 g, 108 mmol) was added to ethyl bromodifluoroacetate (20.1 g, 99 mmol) at 30° C. The mixture was stirred for 60 min; then all volatiles were removed under reduced pressure. To the residue was added another 7.9 g of Et2NH and the mixture was stirred another 60 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[CH:9]=[CH:10]\[CH2:11]O)=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O-:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.[CH2:24]([N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C(#N)C>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([O-:23])(=[O:22])=[O:21])=[CH:18][CH:19]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][N+:33]2[CH:34]=[CH:35][N:31]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:32]=2)=[CH:4][CH:3]=1
Reactant: OC/C=C\Cc1ccc(Cl)cc1
Reactant: CCCCCCCn1ccnc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC#N
Product: CCCCCCCn1cc[n+](C/C=C\Cc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Add 3.37 g (0.01 mole) of (Z)-4-(4-chlorophenyl)-2-buten-1-ol 4-methylbenzenesulfonate (ester) and 1.50 g (0.009 mole) of 1-heptyl-1H-imidazole in 40 ml of acetonitrile and stir at room temperature for two days. Evaporate the acetonitrile and triturate the residue with hexanes and ethyl acetate to yield a solid. Recrystallize from ethyl acetate to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([O:8]C(OC(C)(C)C)=O)=O)([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][NH2:18].[OH-].[Na+]>O1CCCC1.O>[C:1]([O:5][C:6]([N:17]([CH3:16])[NH2:18])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNN
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(N)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Di-t-butyl-dicarbonate (10.91 g, 50 mmole) was added to a solution of methyl hydrazine (2.3 g, 50 mmole) in 100 ml of tetrahydrofuran and 100 ml of water. The pH of the mixture was maintained at 8-9 with 2N sodium hydroxide, and the solution stirred overnight at this pH. The organic solvent was removed in vacuo and the aqueous residue was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and distilled in vacuo to give the title compound as an oil, 3.68g.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([CH3:15])[CH:8]=1.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>O1CCCC1>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([B:16]([OH:21])[OH:17])=[CH:8][C:9]=1[CH3:15])#[N:12]
Reactant: Cc1cc(Br)ccc1C#N
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(B(O)O)ccc1C#N
Reaction time: 0.5 h

Procedure:
10.21 ml of n-butyllithium solution (1.6M in hexane) are added dropwise to a solution of 3.00 g of 4-bromo-2-methylbenzonitrile in 50 ml of dry tetrahydrofuran at −78° C. after stirring at this temperature for 30 minutes, 4.22 ml of triisopropyl borate are added, and then the mixture is stirred at −78° C. for a further 45 minutes. 30 ml of 1N are added to the reaction mixture. The phases are separated and the aqueeous phase is extracted three more times with 100 ml of diethyl ether/tetrahydrofuran (1,1) each time. The combined organic phases are dried with sodium sulphate, filtered and concentrated to 4 ml in vacuo. The remaining oil is mixed with 100 ml of pentane, and the precipitate which has separated out is filtered off with suction and washed twice with penteane. Drying under high vacuum results in 1.82 g of the title compound as a white solid. Rt. 2.93.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Sc2ccccc2Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(Sc2ccccc2Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 133.4 %

Procedure:
To a solution of 4-[(2-bromophenyl)thio]benzaldehyde (Step 1, 5 g, 12.7 mmol) in ethanol under nitrogen (63 mL) was added sodium borohydride (5.7 g, 127.2 mmol). The reaction was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4 and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica, eluting with 40% ethyl acetate/isohexane, to yield {4-[(2-bromophenyl)thio]phenyl}methanol as a colourless oil (5.0 g, 99%). δH (400 MHz, d6 DMSO): 7.65-7.60 (1H, m), 7.41 (4H, s), 7.27-7.21 (1H, m), 7.14-7.08 (1H, m), 6.83 (1H, dd, J=1.4, 7.9 Hz), 5.32-5.28 (1H, m), 4.56-4.53 (2H, m).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.C(N(CC)[C:16](=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[S:25][CH3:26])C>C1COCC1>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]2[C:16](=[O:27])[CH2:26][S:25][C:18]=2[CH:19]=1
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1SC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc2c(c1)SCC2=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-BuLi (1.6 M in hexanes, 13 mL, 20.8 mmol) was added slowly to a solution of diisopropylamine (2.91 mL, 20.8 mmol) in THF at −78° C. The mixture was stirred under nitrogen for 30 min and N,N-diethyl-4-methoxy-2-(methylthio)benzamide (2.4 g, 9.47 mmol), dissolved in 10 mL of anhydrous THF was added to the reaction dropwise. Stirring was continued at −78° C. for 1 h and the cooling bath was removed. After 12 h, the reaction was cooled back down to −78° C. and a 1:1 mixture of methanol and acetic acid (10 mL) was added to the mixture. The reaction was stirred for 15 min and the cooling bath was removed and allowed to warm up to room temperature. The reaction was diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, concentrated and purified by flash chromatography using a gradient of 15 to 40% ethyl acetate in hexanes to obtain an off white solid. Yield=1.4 g. MS (M−H)-179.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[CH3:12][C:13]([S@@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14].O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])/[CH:5]=[N:18]/[S@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17]
Reactant: COc1ccc(C=O)cc1F
Reactant: CC(C)(C)[S@@](N)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(/C=N/[S@@](=O)C(C)(C)C)cc1F
Temperature: 65 °C
Yield: 89.7 %

Procedure:
To a solution of 3-fluoro-4-methoxybenzaldehyde (2.0 g, 13 mmol) in THF (40 mL) was added (S)-2-methylpropane-2-sulfinamide (2.84 g, 23.4 mmol) and Ti(OEt)4 (5.92 g, 26.0 mmol). The reaction mixture was heated at 65° C. for 12 h. After cooling to RT, the mixture was poured into water. The solid was filtered, and the filtrate was extracted with EtOAc (3×100 mL). The filtrate was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with EtOAc/petroleum ether (1:4) to afford 3.0 g (90%) of (S,E)-N-(3-fluoro-4-methoxybenzylidene)-2-methylpropane-2-sulfinamide (66). LCMS (ESI) m/z: 258.1 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([Si](C=[N+]=[N-])(CC)CC)C>C(Cl)Cl>[CH2:1]([NH:8][C:9]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH:15]=[CH:14][C:10]=1[C:11]([O:13][CH3:32])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1NCc1ccccc1
Reactant: CC[Si](C=[N+]=[N-])(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1NCc1ccccc1
Yield: 29.1 %

Procedure:
A solution of 2-(benzylamino)-4-(4-benzoylpiperazin-1-yl)benzoic acid (100 mg, 0.24 mmol) in 15 ml DCM was cooled to 0° C. under argon atmosphere, followed by the addition of triethylsilyldiazomethane (0.12 ml, 0.24 mmol). The run was quenched with 1 ml water and all the solvents were evaporated under vacuum. Methyl 2-(benzylamino)-4-(4-benzoylpiperazin-1-yl)benzoate (30 mg, 30%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes), and its hydrochloride was made by bubbling HCL gas in ether solution. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 3.31-3.68 (m, br, 11H), 4.42 (s, 2H), 6.06 (d, J=1.8 Hz, 1H), 6.25 (dd, J=1.8, 9.1 Hz, 1H), 7.26-7.48 (m, 10H), 7.64 (d, J=9.1 Hz, 1H), 8.06 (s, 3H). 13C NMR (125 MHz, DMSO-d6): δ (ppm) 46.1, 51.0, 95.3, 100.4, 102.8, 127.0, 127.4, 128.4, 128.5, 129.6, 132.4, 135.7, 139.3, 151.7, 154.6, 167.8, 169.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>CN(C=O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CN1CCc2cc([N+](=O)[O-])ccc21)OCc1ccccc1
Temperature: 65 °C
Yield: 41.1 %

Procedure:
To a solution of 5-nitroindoline (1 g, 6.09 mmol) in dry DMF (20 ml), K2CO3 (1.094 g, 7.92 mmol) and benzyl 2-bromoacetate (1.242 ml, 7.92 mmol) were added, and the resulting suspension was heated at 65° C. for 2 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and the solvent was removed. The residue was purified by flash chromatography on silica gel column (DCM:petroleum ether=60:40) affording benzyl 2-(5-nitroindolin-1-yl)acetate (0.782 g, 2.504 mmol, 41% yield). MS/ESI+ 312.9 [MH]+.
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:15])[C:6]=2[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].CCN(CC)CC.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[CH3:16][C:4]1[C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:2]([O:1][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:15])[C:6]=2[N:5]=1
Reactant: CCOC(=O)c1c(C)nc2c(c1O)c1ccccc1n2C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc2c(c1OS(=O)(=O)C(F)(F)F)c1ccccc1n2C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
An ice cold mixture of ethyl 4-hydroxy-2,9-dimethyl-9H-pyrido[2,3-b]indole-3-carboxylate (210 mg, 0.739 mmol) in dichloromethane (DCM) (3.5 mL) was treated with Et3N (0.154 mL, 1.108 mmol) and Tf2O (0.137 mL, 0.812 mmol), and then stirred at 0° C. for 90 min. The mixture was concentrated and purified with column chromatography (0-100% DCM/Hexane) to afford ethyl 2,9-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-9H-pyrido[2,3-b]indole-3-carboxylate (286.8 mg, 0.689 mmol, 93% yield) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.23 (d, J=7.9 Hz, 1 H), 7.65-7.57 (m, 1 H), 7.49 (d, J=8.2 Hz, 1 H), 7.42-7.34 (m, 1 H), 4.46 (q, J=7.1 Hz, 2 H), 3.98 (s, 3 H), 2.88 (s, 3 H), 1.45 (t, 3 H); LCMS (m/z) ES+=417 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=1)[CH:2]=[CH2:3].[Cl:12][CH2:13][NH:14][CH2:15][CH2:16][CH:17]=[O:18]>C1C=CC=CC=1>[Cl:12][CH2:13][N:14]([CH2:15][CH2:16][CH:17]=[O:18])[C:10]([NH:9][C:7]1[S:8][C:4]([CH2:1][CH:2]=[CH2:3])=[N:5][N:6]=1)=[O:11]
Reactant: C=CCc1nnc(N=C=O)s1
Reactant: O=CCCNCCl
Solvent: c1ccccc1
Product: C=CCc1nnc(NC(=O)N(CCl)CCC=O)s1

Procedure:
A mixture of 5-allyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-chloromethylamino-propionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-chloromethyl-3-(5-allyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(C)=O.O>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)Cc1cc(O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
A solution of methyl [3,5-dihydroxyphenyl]acetate (2.1 g, 11.5 mmol) in acetone (100 mL) was treated with potassium carbonate (2.4 g, 17.4 mmol), potassium iodide (0.38 g, 2.31 mmol) and benzyl bromide (1.5 mL, 12.7 mmol), and the mixture was stirred at room temperature overnight. The reaction was diluted with water, and was extracted with dichloromethane (×3). Combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The crude material was purified on a Biotage™ 40 M column (silica), eluting with 40% ethyl acetate/hexane, to give methyl [3-benzyloxy-5-hydroxyphenyl]acetate (1.0 g, 33%). 1H NMR (400 MHz, CDCl3): δ 7.32-7.42 (m, 5H), 6.48 (d, J=1.4 Hz, 1H), 6.38-6.39 (m, 2H), 4.99 (s, 2H), 3.69 (s, 3H), 3.53 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:22][CH2:23][CH2:24][OH:25])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C)C=O>[C:1]([O:5][C:6]([C@@:8]1([CH2:22][CH2:23][CH2:24][O:25][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](c1ccccc1)N1C[C@@](CCCO)(C(=O)OC(C)(C)C)CC1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1C[C@@](CCCO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 59.5 h
Yield: 48.6 %

Procedure:
(3S)-3-(3-Hydroxy-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (46 g) and imidazole (11.9 g) were dissolved in dimethylformamide (600 mL). After addition of tert-butyldimethylsilyl chloride (23.2 g) under ice-cooling, the mixture was stirred at room temperature for 59.5 hours. The reaction solution was extracted with a 10% citric acid solution and ethyl acetate. Then, the organic layer was sequentially washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, and filtered. Thereafter, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=9:1→8:2→2:1) to give 29.7 g of the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C:12]2([CH3:15])[CH2:14][O:13]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[F:16][C:17]([F:27])([F:26])[O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C:12]([CH3:15])([OH:13])[CH2:14][O:25][C:22]2[CH:21]=[CH:20][C:19]([O:18][C:17]([F:26])([F:27])[F:16])=[CH:24][CH:23]=2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CC1(CCn2cc([N+](=O)[O-])nc2Cl)CO1
Product: CC(O)(CCn1cc([N+](=O)[O-])nc1Cl)COc1ccc(OC(F)(F)F)cc1
Yield: 77 %

Procedure:
Reaction of epoxide 140 with 4-trifluoromethoxyphenol as in Example 2AA at 82° C. for 10 h, followed by chromatography of the product on silica gel, eluting with CH2Cl2 (foreruns) and then with 0-2% EtOAc/CH2Cl2, gave 4-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-methyl-1-[4-(trifluoromethoxy)phenoxy]-2-butanol (141) (77%) as a pale yellow oil; 1H NMR (CDCl3) δ 7.81 (s, 1H), 7.17 (br dd, J=9.1, 0.7 Hz, 2H), 6.90 (dt, J=9.2, 3.1 Hz, 2H), 4.29 (ddd, J=14.1, 9.5, 6.3 Hz, 1H), 4.24 (ddd, J=14.1, 9.6, 6.5 Hz, 1H), 3.85 (d, J=9.0 Hz, 1H), 3.82 (d, J=9.0 Hz, 1H), 2.23 (ddd, J=13.8, 9.3, 6.5 Hz, 1H), 2.21 (s, 1H), 1.40 (s, 3H); HRESIMS calcd for C15H16ClF3N3O5 m/z [M+H]+ 412.0697, 410.0725. found 412.0700, 410.0722.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19](Cl)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:29][CH2:30][CH2:31][N:32]([CH3:38])[S:33]([CH2:36][CH3:37])(=[O:35])=[O:34].C(OCC)(=O)C>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:29][CH2:30][CH2:31][N:32]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH3:38])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCS(=O)(=O)N(C)CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N(C)CCOc1ncnc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc(C)cc1
Temperature: 25 °C
Yield: 34.2 %

Procedure:
100 mg 4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide was dissolved in 5 ml dry THF. 162 mg of potassium-tert.-butylate and 200 mg of N-(2-hydroxyethyl)-N-methyl-ethanesulfonamide was added and the mixture was heated to reflux for 8 h then cooled to room temperature. Ethyl acetate was added and the precipitated side product was filtered off. The filtrate was concentrated in vacuo. The crude product was purified by column chromatography (silica gel; ethyl acetate) to give 45 mg of 4-tert.-butyl-N-{6-[2-(ethanesulfonyl-methyl-amino)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-benzenesulfonamide. LC-MS: tR=5.58 min, [M−1]−=545.54.
Reaction SMILES: [CH:1]12[NH:17][CH:5]([CH:6]([C:8]3[CH:9]=[CH:10][C:11]([N:14]([CH3:16])[CH3:15])=[N:12][CH:13]=3)[CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[C:18](Cl)([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19]>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>[CH:33]1[C:34]2[CH:22]([CH2:21][O:20][C:18]([N:17]3[CH:5]4[CH:6]([C:8]5[CH:13]=[N:12][C:11]([N:14]([CH3:15])[CH3:16])=[CH:10][CH:9]=5)[CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4]4)=[O:19])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: CN(C)c1ccc(C2CC3CCCC2N3)cn1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)c1ccc(C2CC3CCCC2N3C(=O)OCC2c3ccccc3-c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
219 mg (0.95 mmol, 1 eq) of (−)-[5-(8-aza-bicyclo[3.2.1]oct-6-yl)-pyridine-2-yl]-dimethylamine (VII-1) are dissolved in 1.8 ml of dioxane and 2.75 ml of 10% sodium carbonate solution. 257 mg (1 mmol, 1.05 eq) of Fmoc-Cl in portions is added and it is stirred for 1 h at RT. After this time it is diluted with EE and washed with water. The aqueous phase is re-extracted for three times with EE. The combined organic phases are dried over sodium sulphate and the solvent is removed in vacuo. The crude product is purified by column chromatography (EE:hex=1:2). 422 mg (0.93 mmol, 98%) of a colorless foam/solid is obtained.