Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8]([OH:10])=[O:9].[CH2:22](O)[CH3:23]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8]([O:10][CH2:22][CH3:23])=[O:9]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1

Procedure:
A mixture of 3-(2,4-difluorophenoxy)-4-nitrobenzoic acid (1.0 g) and sulfuric acid (3 drops) in ethanol (5 ml) was refluxed for 8 hours. Ethanol was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and concentrated to give pale brown needles of ethyl 3-(2,4-difluorophenoxy)-4-nitrobenzoate (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[Cl:27][C:28]1[CH:37]=[CH:36][C:31]([C:32](=[N:34]O)[NH2:33])=[CH:30][CH:29]=1.[H-].[Na+]>C1COCC1>[Cl:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]2[N:34]=[C:19]([C:18]3[CH:23]=[CH:24][C:15]([N:11]4[C:12](=[O:14])[NH:13][C:9]([C:3]5[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=5[Cl:8])=[N:10]4)=[CH:16][C:17]=3[O:25][CH3:26])[O:21][N:33]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Reactant: NC(=NO)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1-c1nc(-c2ccc(Cl)cc2)no1
Yield: 11.7 %

Procedure:
The title compound was prepared by following the procedure as described for Example-40 by using methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.100 g, 0.25 mmol), 4-chloro-N′-hydroxybenzimidamide (Intermediate-19, 0.064 g, 0.38 mmol), sodium hydride (0.020 g, 0.50 mmol) and dry THF (5.0 mL) at RT to afford 0.015 g of desired product. 1H NMR (DMSO-d6): δ 4.00 (s, 3H), 7.66-7.72 (m, 5H), 7.81 (d, J=8.7 Hz, 1H), 7.89 (s, 1H), 8.10 (d, J=8.4 Hz, 2H), 8.22 (d, J=9.0 Hz, 1H), 12.82 (br s, 1H); MS (m/z): 515.84 [M+H]+.
Reaction SMILES: [Cl:1]([O-:4])(=[O:3])=[O:2].[Na+:5].[H][H]>>[Cl:1]([O-:4])(=[O:3])=[O:2].[Na+:5].[Cl:1]([OH:4])(=[O:3])=[O:2]
Reactant: [H][H]
Agent: [Na+]
Agent: [O-][Cl+2]([O-])[O-]
Product: [O-][Cl+2]([O-])O

Procedure:
Table 8 shows the average overall throughput rates and concentrations of products obtained in this experiment. Slightly diluted purified sulfuric acid from the GAP system of Example 1 (173 g/L H2SO4 and 22 g/L Na2SO4) was fed to the DCU (sodium form) at a net feed average rate of 2.7 L/h thereby converting the DCU to the hydrogen form and producing a sodium sulfate-rich regeneration product (101 g/L Na2 SO4 and 83 g/L H2SO4 with 8g/L residual NaClO3) at 3.0 L/h. In a subsequent step, a concentrated sodium chlorate solution (628 g/L NaClO3) was fed to the DCU (hydrogen form) at 1.5 L/h thereby producing a sodium chlorate/chloric acid mixture (241 g/L NaClO3 and 165 g/L HClO3 with 10.7 g/L Na2SO4) at a rate of 2.4 L/h. The amount of sulfuric acid fed to the DCU was 2.13 times the stoichiometric amount of acid required to remove the sodium.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1>CC(C)=O.O>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:1]=[N+:2]=[N-:3])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
Sodium azide (2.7 g, 42 mmol) was added to a cold (0-4° C.) stirred solution of (4-methyl-benzenesulfonyl chloride (8 g, 42 mmol) in acetone:water (1:1, 240 mL) and continued stirring at 0° C. for 2 hr. Concentrated the reaction mixture to get the residue. The residue was extracted with diethyl ether and the organic phase was dried Na2SO4 and concentrated under reduced pressure to afford 7.3 g (88.2% yield) of 4-methyl-benzenesulfonyl azide.
Reaction SMILES: [CH3:1][C:2]1([CH3:56])[CH2:7][O:6][C:5]([CH2:15][S:16][C@@H:17]([C:42](=[O:55])N2[C@@H](C3C=CC=CC=3)COC2=O)[C@H:18]([C:27]2[CH:41]=[CH:40][C:30]([O:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:29][CH:28]=2)[NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[O:4][CH2:3]1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:56][C:2]1([CH3:1])[CH2:7][O:6][C:5]([CH2:15][S:16][C@H:17]2[C:42](=[O:55])[N:19]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C@@H:18]2[C:27]2[CH:41]=[CH:40][C:30]([O:31][CH2:32][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])=[CH:29][CH:28]=2)([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[O:4][CH2:3]1
Reactant: Cc1ccc(C2(CS[C@@H](C(=O)N3C(=O)OC[C@@H]3c3ccccc3)[C@@H](Nc3ccc(F)cc3)c3ccc(OCC(=O)OC(C)(C)C)cc3)OCC(C)(C)CO2)cc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C2(CS[C@H]3C(=O)N(c4ccc(F)cc4)[C@@H]3c3ccc(OCC(=O)OC(C)(C)C)cc3)OCC(C)(C)CO2)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
tert-Butyl (4-{(1S,2R)-2-({[5,5-dimethyl-2-(4-methylphenyl)-1,3-dioxan-2-yl]methyl}thio)-1-[(4-fluorophenyl)amino]-3-oxo-3-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]propyl}phenoxy)acetate (2.55 g, 3.25 mmol) was dissolved in dry toluene (250 ml) and heated to 90° C. under inert atmosphere. N,O-Bis(trimethylsilyl)acetamide (BSA, 2.38 ml, 9.75 mmol) was added and the mixture was stirred at 90° C. for one hour. The mixture was cooled to 45° C. and tetrabutylammonium fluoride (TBAF, 0.25 g) was added and the mixture was stirred at 45° C. for one hour. The mixture was concentrated under reduced pressure and purified by flash-chromatography (hexane:EtOAc 6:1). This afforded 1.06 g (52%) of the title compound as a white solid. 1H-NMR (CDCl3, 200 MHz): δ 0.6 (s, 3H), 1.3 (s, 3H), 1.5 (s, 9H), 2.4 (s, 3H), 3.0-3.2 (m, 2H), 3.3-3.5 (m, 4H), 3.9 (d, 1H), 4.5 (s, 2H), 4.8 (d, 1H), 6.8-7.0 (m, 6H), 7.1-7.4 (m, 6H).
Reaction SMILES: C([O:3][C:4](=O)[C:5](=[N:14]O)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.B.[Na].S(=O)(=O)(O)O.CO>COCCOC>[NH2:14][CH:5]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][OH:3]
Reactant: CCOC(=O)C(CCc1ccccc1)=NO
Agent: B
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CO
Solvent: COCCOC
Product: NC(CO)CCc1ccccc1
Temperature: 62 °C
Reaction time: 5 h

Procedure:
33.2 g (0.15 mole) 2-hydroxyimino-4-phenyl butyric acid ethyl ester were steadily introduced under agitation into a suspension of 24.15 g (0.64 mole) sodium boron hydride in 200 ml 1,2-dimethoxyethane (DME). Within 1 h a solution of 17.2 ml (0.32 mole) conc. sulfuric acid in 60 ml DME was added dropwise thereto, during which the temperature was maintained at 20°-30° C. The mixture was subsequently heated slowly to 62° C., then agitated 5 h at this temperature and cooled overnight under agitation to room temperature. After a careful addition of 50 ml methanol the batch was evaporated to dryness, the residue taken up in 120 ml water and compounded with 25 ml conc. hydrochloric acid, during which a vigorous development of gas began. After the addition of 150 ml toluene the mixture was agitated until the end of the development of gas, then alkalinized with 35 ml 50% sodium hydroxide solution and heated to 60° C. The organic phase was separated and the aqueous phase extracted again with 80 ml toluene at this temperature. The combined organic phases were dried over sodium sulfate and evaporated. 25.0 g raw (RS)-2-amino-4-phenyl-1-butanol remained as residue in the form of a brownish, viscous oil. The structure was corroborated by a 1H-NMR spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[CH3:11].CCCCCCCCCCCCN>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][NH2:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:12])([F:13])[CH3:11]
Reactant: CC(F)(F)COc1ncc(CN2C(=O)c3ccccc3C2=O)cc1Cl
Agent: CCCCCCCCCCCCN
Product: CC(F)(F)COc1ncc(CN)cc1Cl
Yield: 96 %

Procedure:
The title compound is prepared in 96% yield (734 mg, colorless oil) from 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (1.18 g, 3.22 mmol, Step-2) in a similar manner to Step-5 of Amine-12.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH:4]=O.[CH3:8][C@@H:9]([NH2:14])[CH2:10][CH2:11][CH2:12][CH3:13]>CO.[Pd]>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:14][C@@H:9]([CH2:10][CH2:11][CH2:12][CH3:13])[CH3:8]
Reactant: CCCC[C@@H](C)N
Reactant: COC(C=O)OC
Agent: [Pd]
Solvent: CO
Product: CCCC[C@@H](C)NCC(OC)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2,2-Dimethoxyacetaldehyde (7.54 mL) was added to a solution of (R)-hexan-2-amine (5.06 g) in methanol (20 mL) and the mixture stirred at ambient temperature for 5 h. A slurry of 10% palladium on carbon (200 mg) in methanol (5 mL) was added and the mixture hydrogenated at 5 bar for 16 h, then filtered and concentrated in vacuo to afford the sub-titled compound as a colourless liquid (9.22 g). 1H NMR (400 MHz, CDCl3) δ 4.46 (t, J=5.5 Hz, 1H), 3.39 (s, 6H), 2.72 (ddd, J=31.1, 11.9, 5.6 Hz, 2H), 2.60 (sextet, J=6.0 Hz, 1H), 1.36-1.24 (m, 6H), 1.04 (d, J=6.2 Hz, 3H), 0.90 (t, J=6.9 Hz, 3H)
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.O1CCCC1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O>[N:17]1([C:1]([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)=[O:3])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(C(=O)N2CCCCC2)cc1
Reaction time: 1 h

Procedure:
A mixture of 12.0 g. of 4-carboxybenzaldehyde, 13.6 g. of N,N'-carbonyldiimidazole and 100 ml. of tetrahydrofuran is allowed to stand for one hour, then 9.4 ml. of piperidine is added. The reaction mixture is allowed to stand for 18 hours, then heated at reflux temperature for one hour. Water is added and the solvent is distilled off. Methylene chloride is added and the solution is washed with 25 ml. of concentrated hydrochloric acid, then with water then is dried over magnesium sulfate. The mother liquor is concentrated to yield p-piperidinocarbonylbenzaldehyde as an oil.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:12]([Si:19]1(C2C=CC=CC=2)[CH2:24][CH2:23][CH:22]([C:25](O)=[O:26])[CH2:21][CH2:20]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:12]([Si@H:19]1[CH2:20][CH2:21][C@H:22]([C:25]([O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:11])[F:1])=[CH:9][CH:8]=2)=[O:26])[CH2:23][CH2:24]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Oc1ccc(OC(F)F)cc1
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(C(=O)O)CC1
Product: CCCCCCC[Si@H]1CC[C@H](C(=O)Oc2ccc(OC(F)F)cc2)CC1

Procedure:
The general procedure of Example 3 was repeated using 4-difluoromethoxyphenol and 4-n-heptyl-4-phenyl-4-silacyclohexanecarboxylic acid, thereby obtaining the intended product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].Cl>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:17]([CH3:16])(=[O:19])=[O:18]
Reactant: Nc1ccc(I)cc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
2-fluoro-4-iodophenylamine (1.50 g) was dissolved in dichloromethane (40 ml) and to the solution were added pyridine (1.02 ml) and methanesulfonylchloride (700 μl). The mixture was stirred at room temperature for 1 hour and 1.5 N aqueous hydrochloric acid was added thereto to quench the reaction. The resulting mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was column-chromatographed (ethyl acetate/hexane=1/1) to yield the compound 3-2 (1.89 g, 95%).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[N+](=[CH2:19])=[N-]>CCOCC>[N+:14]([C:3]1[CH:4]=[C:5]([O:12][CH3:13])[C:6]([O:10][CH3:11])=[C:7]([O:8][CH3:9])[C:2]=1[O:1][CH3:19])([O-:16])=[O:15]
Reactant: C=[N+]=[N-]
Reactant: COc1cc([N+](=O)[O-])c(O)c(OC)c1OC
Solvent: CCOCC
Product: COc1cc([N+](=O)[O-])c(OC)c(OC)c1OC

Procedure:
1-Hydroxy-2-nitro-4,5,6-trimethoxybenzene (4.58 g, 0.02 mol) was treated with diazomethane (prepared from 1-methyl-3-nitro-1-nitrosoguanidine, 5.88 g, 0.04 mol) in ether (300 ml) for 4 hours at room temperature. The reaction mixture was evaporated in vacuo to dryness, and the residue was chromatographed on a silica gel column (3×40 cm) using hexane/ethyl acetate (9:1) as the eluent. 1-Nitro-2,3,4,5-tetramethoxybenzene was obtained as syrup, 3.45 g (71%). 1NMR (CDCl3): δ3.80, 3.94, 3.96, and 3.98 (each 3H, s, 4×OMe), 7.18 (1H, s, H-6). Analyses: Calculated for C10H13NO6 : C, 49.38; H, 5.39; N, 5.76. Found: C, 49.14; H, 5.53; N, 5.75.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][C:9]2[C:10]([Cl:23])=[N:11][CH:12]=[N:13][C:14]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=O)=[C:4]([F:26])[CH:3]=1>O=P(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:23][C:10]1[N:11]=[CH:12][N:13]=[C:14]2[C:9]=1[N:8]=[C:6]([C:5]1[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=1[F:26])[N:15]2[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1
Reactant: O=C(Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1)c1ccc(Cl)cc1F
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1cc(Cl)ccc1-c1nc2c(Cl)ncnc2n1-c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
A suspension of 4-chloro-N-[4-chloro-6-(4-chlorophenylamino)-pyrimidin-5-yl]-2-fluorobenzamide I-(7A-91)a (8.3 g, 20 mmol) in POCl3 (100 ml) was heated to reflux. The light brown reaction became homogeneous over 2 hours. After refluxing 3 hours, the reaction mixture was cooled and concentrated under reduced pressure to give a viscous oil. The residue was diluted with ethyl acetate and poured over ice/aqueous sodium bicarbonate. The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated. Crystallization from diethyl ether afforded product I-(7A-91)b (5.8 g, 73%) as an off-white solid: +ESI MS (M+1) 393.0; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 7.72 (t, J=8.1 Hz, 1H), 7.60–7.55 (m, 3H), 7.50–7.42 (m, 3H).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([OH:23])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[C:35]1([CH3:42])[C:36](Cl)=[CH:37][CH:38]=[CH:39][CH:40]=1>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([O:23][C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:42])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1Cl
Reactant: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2O)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2Oc2ccccc2C)cc1

Procedure:
Following a procedure similar to that described in Example 30A above, when 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with o-toluyl chloride there is obtained 3-(o-toluyloxy)-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3-(o-toluyloxy)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O)([OH:15])[CH2:6][CH2:5]2.[CH3:29][NH2:30]>CCO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][CH2:17][NH:30][CH3:29])([OH:15])[CH2:6][CH2:5]2
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@]2(O)CCc3cc(F)ccc3[C@@H]2C(C)C)cc1
Solvent: CCO
Solvent: ClCCl
Product: CNCC[C@@]1(O)CCc2cc(F)ccc2[C@@H]1C(C)C
Temperature: 40 °C
Reaction time: 8 h

Procedure:
8 g of toluene-4-sulfonic acid 2-((1S,2S)-6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-ethyl ester were dissolved in a 8 M solution of MeNH2 in EtOH (100 mL). The mixture was stirred overnight in at 40° C., diluted with DCM and washed with sat.-NaHCO3. The organic phase was dried over anh. Na2SO4 and concentrated to give 5.29 g of (1S,2S)-6-fluoro-1-isopropyl-2-(2-methylamino-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol as beige solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:23])[C:9]3[CH2:14][CH:13]([CH3:15])[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][NH:36][C:35](=[O:39])[CH:34]=2)=[N:29][CH:30]=1>>[CH3:15][CH:13]1[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]2[C:5]3[C:6]([N:8]([CH3:23])[C:9]=2[CH2:14]1)=[N:7][C:2]([N:36]1[CH:37]=[CH:38][C:33]([O:32][CH2:31][C:28]2[CH:27]=[CH:26][C:25]([F:24])=[CH:30][N:29]=2)=[CH:34][C:35]1=[O:39])=[CH:3][CH:4]=3
Reactant: O=c1cc(OCc2ccc(F)cn2)cc[nH]1
Reactant: CC1Cc2c(c3ccc(Br)nc3n2C)CN1C(=O)OC(C)(C)C
Product: CC1Cc2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)nc3n2C)CN1C(=O)OC(C)(C)C
Yield: 73.3 %

Procedure:
tert-Butyl 2-bromo-7,9-dimethyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (200 mg, 0.520 mmol) and 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (115 mg, 0.520 mmol) were reacted following the procedure for Example 2 (step e) to provide the title compound (198 mg, 73%) as a yellow oil: ESI MS m/z 520 [M+H]+.
Reaction SMILES: [O:1]([CH2:13][C@H:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[CH2:15]1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[F:26][C:27]1[CH:28]=[C:29]([N:42]2[CH2:46][C@H:45]([CH2:47][N:48]3[CH:52]=[CH:51][N:50]=[N:49]3)[O:44][C:43]2=[O:53])[CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.C1(P([Pd-4](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)C=CC=CC=1>[O:1]([CH2:13][C@H:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:32]3[CH:31]=[CH:30][C:29]([N:42]4[CH2:46][C@H:45]([CH2:47][N:48]5[CH:52]=[CH:51][N:50]=[N:49]5)[O:44][C:43]4=[O:53])=[CH:28][C:27]=3[F:26])=[CH:21][N:20]=2)[CH2:15]1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CC1(C)OB(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)OC1(C)C
Reactant: OC[C@H]1O[C@@H](OC[C@@H]2CC(c3ccc(Br)cn3)=NO2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)C3)nc2)c(F)c1
Temperature: 70 °C
Yield: 38.4 %

Procedure:
[(5S)-3-(5-Bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methyl β-D-glucopyranoside (Intermediate 20, 0.150 g, 0.36 mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Intermediate 7, 0.153 g, 0.39 mmol), sodium carbonate (0.152 g, 1.43 mmol), and tetrakis(triphenylphosphino)palladium(0) (0.041 g, 0.036 mmol) were mixed in DMF/water (10:1, 5 mL) under nitrogen and heated at 70° C. bath temperature for 4 hours. The solvent was evaporated under reduced pressure. Chromatography on silica gel with dichloromethane/methanol 5:1 followed by crystallization from ethanol gave the product as colourless solid (83 mg). MS (ESP): 601.06 (MH+) for C27H29FN6O9
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[Br:10]N1C(=O)CCC1=O>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([Br:10])[C:5]([F:8])=[CH:4][C:3]=1[F:9]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: Fc1cc(F)c(Br)cc1Br
Temperature: 25 °C
Reaction time: 17 h
Yield: 96.7 %

Procedure:
A total of 1.6 g of 1-bromo-2,4-difluorobenzene was suspended in 8.29 ml of sulfuric acid, and 1.62 g of N-bromosuccinimide was added under ice-cooling. After stirring at room temperature for 17 hours, the reaction mixture was poured onto ice-water and extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (hexane), to give 2.18 g of the title compound as a pale yellow oil.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][Zn+].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20]([C:24](=[O:40])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:27][CH:26]=1)=[C:19](OS(C(F)(F)F)(=O)=O)[CH:18]=[CH:17]2>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN1C(=O)CCC1.C1COCC1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20]([C:24]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:27][CH:26]=1)=[O:40])=[C:19]([CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[O:3][CH3:2])[CH:18]=[CH:17]2
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: COc1ccccc1C[Zn+]
Agent: [Fe+2]
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(Cc3ccccc3OC)ccc2c1
Yield: 87 %

Procedure:
Add a solution of 2-methoxybenzylzinc chloride (8 mL, 0.5 M/THF) to a mixture of trifluoro-methanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (1.0 g, 1.86 mmol), Bu4NI (2.1 g, 5.7 mmol), Pd(dba)2 (68 mg 0.12 mmol) and dppf (66 mg, 0.12 mmol) in NMP/THF (5 mL, 3:2). Heat the mixture to reflux for 2 h. Quench the reaction with water and dilute with CH2Cl2. Wash the organic phase with water and brine, dry over MgSO4, filter and concentrate. Load the crude product on an SCX cartridge, wash with MeOH and elute with 2M NH3/MeOH. Purify the resulting product by flash chromatography (0-5% (2M NH3/MeOH)/CH2Cl2) to afford [6-methoxy-2-(2-methoxy-benzyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (820 mg, 87%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C1[O:19][C:8]([CH3:18])([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)OC1>CCOCC>[C:1]([O:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:8](=[O:19])[CH3:18])=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC1(Cc2ccc(CO)cc2)OCCO1
Reactant: CC(=O)Cl
Solvent: CCOCC
Product: CC(=O)Cc1ccc(COC(C)=O)cc1

Procedure:
Acetyl chloride (5.0 ml) in dry ether (20 ml) was added dropwise to a stirred solution of 1-(4-hydroxymethylphenyl)propane-2-one ethylene ketal (3.0 g) (as prepared in description 1) in dry ether (50 ml). The mixture was refluxed for 1 h, evaporated and deketalised as described in description 1, to give the title compound as a colourless oil which was bulb distilled, bath temperature 120°-130°/o. 1 mm Hg.