Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:29][CH:28]=2)[C:12](N2[C@H](CC3C=CC=CC=3)COC2=O)=[O:13])=[CH:6][CH:5]=1.[OH:40]O.[Li+].[OH-]>C1COCC1.O>[CH3:1][O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C@@H:11]([C:12]([OH:13])=[O:40])[C:27]2[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:29][CH:28]=2)=[CH:6][CH:5]=1
Reactant: OO
Reactant: COC(=O)c1ccc(CC(C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccc(C=CC(C)(C)C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C[C@@H](C(=O)O)c2ccc(C=CC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 134.8 %

Procedure:
To a stirred solution of the (R)-diastereomer of 4-{3-(4-(R)-Benzyl-2-oxo-oxazolidin-3-yl)-2-[4-(3,3-dimethyl-but-1-enyl)-phenyl)-3-oxo-propyl}-benzoic acid methyl ester (0.43 g, 0.81 mmol) in THF/H2O (20 mL) (3:1) at room temperature were added H2O2 (2.2 mL, 8.1 mmol 35% in H2O) followed by LiOH (40 mg, 1.63 mmol). The reaction mixture was stirred for 3 h, at room temperature, quenched with (0.1 N HCl). The reaction mixture was extracted with ethyl acetate (100 mL) and dried over MgSO4, filtered and concentrated under reduced pressure to afford corresponding acid. The crude product was purified by column chromatography on silica gel, eluting with CH2Cl2/MeOH 2%-15% to afford the title compound (0.4 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=1[C:15]([F:18])([F:17])[F:16])[CH3:2].Cl[CH2:21][C:22]1[C:23]([CH3:38])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1.[Na+].[I-].C1CCN2C(=NCCC2)CC1>CS(C)=O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:14])[CH2:21][C:22]2[C:23]([CH3:38])=[N:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)=[CH:9][C:8]=1[C:15]([F:17])([F:18])[F:16])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Reactant: CCOC(=O)COc1ccc(NC)cc1C(F)(F)F
Agent: [I-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: CCOC(=O)COc1ccc(N(C)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C(F)(F)F
Reaction time: 4 h

Procedure:
To 0.080 g (0.29 mmol) of the above prepared (4-methylamino-2-trifluoromethyl-phenoxy)-acetic acid ethyl ester and 0.124 g (0.43 mmol) of 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (see example 1N], dissolved in 1.0 ml of abs. DMSO, were added successively 0.048 g (0.32 mmol) of NaI and 0.066 g (0.43 mmol) of DBU. The reaction was allowed to proceed for 4 h at ambient temperature, when TLC still indicated some starting amine. Therefore, another 33 mg (0.4 eq.) of 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine was added and stirring continued for 3 h. Pouring onto crashed ice, extraction with AcOEt, filtration over Celite, washing of the organic layer with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=8/2), afforded 0.046 g of the title compound as colorless oil.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1.[OH-].[K+].C1C2C(CCCC2)CCC1>[Cu].C(Cl)(Cl)Cl>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([N:8]2[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[CH:19]=[CH:18][CH:17]=[CH:16][C:7]2=3)=[CH:23][CH:22]=1
Reactant: c1ccc2c(c1)Nc1ccccc1-c1ccccc1-2
Reactant: Brc1ccc(Br)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCC2CCCCC2C1
Solvent: ClC(Cl)Cl
Product: Brc1ccc(N2c3ccccc3-c3ccccc3-c3ccccc32)cc1
Temperature: 200 °C
Yield: 25.1 %

Procedure:
A mixture of 9.2 g (38 mmol) of 9H-tribenz[b,d,f]azepine (synthesized in accordance with J. Org. Chem., vol. 56, p. 3906 (1991)), 44.8 g (190 mmol) of 1,4-dibromobenzene, 5.6 g (100 mmol) of potassium hydroxide, 1.6 g (25 mmol) of copper powder, and 50 ml of decalin was heated at an external temperature of 200° C. for 36 hours in a nitrogen stream while stirring. The reaction mixture was cooled nearly to room temperature, chloroform was added thereto, followed by filtration using Celite to remove the insoluble matter. The filtrate was concentrated. To remove decalin, n-hexane was added to the residue, followed by filtration. The filter cake was purified by silica gel column chromatography to give 3.8 g (25%) of 9-(4-bromophenyl)-9H-tribenz[b,d,f]azepine.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=O)[CH2:12][C:13](=O)[CH3:14])=[CH:7][CH:6]=1.O>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([CH3:14])[N:3]=[N:2][C:16]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[CH:7][CH:6]=1
Reactant: CSc1ccc(C(=O)C(CC(C)=O)c2ccc(Cl)cc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CSc1ccc(-c2nnc(C)cc2-c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 7 h
Yield: 64.4 %

Procedure:
Hydrazine hydrate (72 mg, 1.44 mmol) was added to a solution of 4-(4-chlorophenyl)-5-[4-(methylthio)phenyl]pentane-2,5-dione (317 mg, 0.953 mmol) in ethanol (6 ml), and the resulting mixture was stirred for 7 hours at a bath temperature of 80° C. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed successively with water and brine, and was then dried over anhydrous sodium sulfate. The solvent was distilled off and the residue (320 mg) was dissolved in chloroform. The thus-obtained solution was stirred at room temperature for 7 hours to conduct air oxidation. The solvent was distilled off and the residue (296 mg) was separated and purified by preparative thin-layer chromatography on silica gel (developing solvent: chloroform), whereby the title compound was obtained as a pale yellow oil (200.5 mg, 64.3%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12](=[O:17])[C:13](Br)([CH3:15])[CH3:14])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].C(N(CC)CC)C>N1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([C:12](=[O:17])[C:13](=[CH2:14])[CH3:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8]
Reactant: CC(C)(Br)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A solution of 3',4'-dihydroxy-5'-nitro-2-bromoisobutyrophenone (2.6 g) and triethylamine (20 ml) in pyridine (20 ml) was heated for 3 hours at 100° C. Triethylamine and pyridine were evaporated in vacuo. Ether and 2N H2SO4 were added. The organic phase was separated and dried over Na2SO4. The ether solution was treated with charcoal for 2 hours, filtered and evaporated to dryness. The residue was crystallized from dichloromethane-petroleum ether (40°-60° C). Yield 0.48 g, mp 98°-102° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C:8](=[O:14])[CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:15])[CH2:7][C:8](=[O:14])[CH2:9][C@H:10]([OH:13])[CH2:11][O:12][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CO
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(=O)C[C@H](O)COC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 16.8 g (77 mmol) of the (5S)-5,6-dihydroxy-3-oxohexanoic tert-butyl ester produced in Example 1 in 120 mL of methylene chloride were added 11.2 mL of pyridine and 10.2 mL of benzoyl chloride at 0° C., and the mixture was stirred at 0° C. for 2 hours. After completion of the reaction, the reaction mixture was diluted with 38 mL of water and adjusted to pH 7 with 20% aqueous NaOH solution. The aqueous layer was separated and further extracted with 2 portions of methylene chloride, 120 mL each. The organic layers were combined and dehydrated over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give an oil. This residue was purified by silica gel column chromatography (Kieselgel 60, product of Merck; hexane:acetone=5:1) to give 19.3 g of (5S)-6-benzoyloxy-5-hydroxy-3-oxohexanoic tert-butyl ester (white solid).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[Hg](C#N)C#N.[C:17]([O:20][C@@H:21]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@@H:22]1Br)(=[O:19])[CH3:18]>>[C:17]([O:20][C@@H:21]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@H:22]1[S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:1])([F:10])[F:11])(=[O:19])[CH3:18]
Reactant: FC(F)(F)c1ccccc1S
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Agent: N#C[Hg]C#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccccc2C(F)(F)F)SC[C@H]1OC(C)=O
Yield: 34 %

Procedure:
If the procedure described in Preparation I is followed starting from 1.8 g (10.10-3 mol) of 2trifluoromethylbenzenethiol, 2.55 g (10.10-3 mol) of mercuric cyanide (Hg(CN)2) and 3.95 g (11.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 1.53 g (yield: 34%) of the expected product are obtained.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:14]1(=[O:21])[CH:19]=[CH:18][C:17](=[O:20])[CH:16]=[CH:15]1.[Li+].[C-]#CC1C=CC=CC=1.CN1C(=O)N(C)CCC1.[CH2:40]=[C:41]1[O:45][C:43](=[O:44])[CH2:42]1>C1COCC1.CCCCCC>[C:41]([CH:42]1[CH:16]2[CH2:15][C:14](=[O:21])[CH:19]=[CH:18][C:17]2([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:20][C:43]1=[O:44])(=[O:45])[CH3:40]
Reactant: C#Cc1ccccc1
Reactant: O=C1C=CC(=O)C=C1
Reactant: C=C1CC(=O)O1
Agent: [C-]#Cc1ccccc1
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CC(=O)C1C(=O)OC2(C#Cc3ccccc3)C=CC(=O)CC12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
Phenylacetylene (1 mL, 9.3 mmole) was placed in dry THF (10 mL) in a dry, 50 mL, 3-necked, round bottomed flask fitted with a mechanical stirrer, thermometer and argon inlet. The solution was cooled to -78° C. and treated with 1.6M n-butyllithium (5.8 mL, 9.3 mmole) in hexane. The reaction was stirred at -78° C. for 30 min, warmed to 0° C., then recooled to -78° C. Benzoquinone (1 g, 9.3 mmole) and dry THF (10 mL) were added, under argon, to a separate 100 mL, 3-necked, round bottomed flask. The mixture was cooled to -78° C. and treated with the lithium phenylacetylide solution prepared above. The flask which contained the lithium phenyacetylide solution was washed with dry THF (10 mL) and the solvent was added to the larger flask. Upon addition of the lithium phenylacetylide, the reaction mixture turned dark blue. The reaction was stirred for 20 min at -78° C. then dry DMPU (18 mL, 0.15 mole) was added. The reaction was stirred for five min before diketene (0.8 mL, 10.2 mmole) in THF (10 mL) was added. The reaction was stirred for 1 hr at -78° C., then allowed to warm to room temperature, stirred overnight and concentrated in vacuo. The residue was treated with water (50 mL) and saturated ammonium chloride (50 mL), acidified with 3N hydrochloric acid, and extracted with CH2Cl2 (4×75 mL). The combined CH2Cl2 extracts were washed with water (50 mL) and brine (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in Et2O (150 mL), and the solution was washed with water (3×50 mL and 1×75 mL) and brine (75 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gal; eluting with hexane: EtOAc (4:1) to yield 2.4 g (88%) of the title compound. Crystallization from acetone/ethyl acetate gave a white solid, m.p. 168°-171° C. (dec).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.I[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]I.N#N.[C:22](=[O:25])([O-])[O-].[K+].[K+]>CS(C)=O>[OH:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:22][OH:25])=[CH:4][CH:3]=2)=[CH:7][CH:6]=1
Reactant: OCCCc1ccc(O)cc1
Reactant: ICCCCCCI
Reactant: O=C([O-])[O-]
Agent: N#N
Agent: [K+]
Solvent: CS(C)=O
Product: OCCCc1ccc(OCCCCCCOc2ccc(CCCO)cc2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
A solution of 3-(4-hydroxyphenyl)-1-propanol 35(3.3 g, 21.7 mmole) and 1,6-di-iodohexane (3.5 g 8.88 mmole) in dimethylsulfoxide (40 mL) was degassed and saturated with N2 gas and potassium carbonate 4.5 g, 32.56 mmole) was added. The reaction mixture was stirred at 80° C. for 18 h under nitrogen atmosphere and then quenched with brine (150 mL). The product was extracted with EtOAc (200 mL) and the organic extracts were washed with 0.1 M NaOH and brine, and dried with MgSO4. The organics were removed in vacuo to give a pale brown solid. The solid was purified by flash silica column chromatography: 4/1 hexane/EtOAc to 5% MeOH in 1/1 hexane/EtOAc to give 1,6-bis[4-(3-hydroxypropyl)phenoxy]hexane 36 (Rf=0.17 in 1/1 hexane/EtOAc) in 65% yield (2.23 g). 1H-NMR (CD3OD, 299.96 MHz): δ (ppm) 7.08-7.05 (d, 4H), 6.80-6.77 (d, 4H), 3.93-3.89 (t, 4H), 3.56-3.52 (t, 4H), 2.64-2.56 (t, 4H), 1.81-1.69 (m, 8H), 1.44-1.21 (m, 4H).
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.[CH3:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]([CH3:14])[C:8]=1[OH:15].ClCl.[N+]([O-])(O)=[O:19]>O>[CH3:6][C:7]1[C:8](=[O:15])[C:9]([CH3:14])=[CH:10][C:11](=[O:19])[C:12]=1[CH3:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C)c(O)c1C
Agent: ClCl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1=CC(=O)C(C)=C(C)C1=O
Reaction time: 2 h

Procedure:
1000 g of carbon tetrachloride was charged in a 5-liter four neck flask equipped with a stirrer, a condenser, a chlorine-bubbling pipe and a thermometer, and 408 g (3 moles) of 2,3,6-trimethylphenol was dissolved therein. Thereafter, 210 g (3 moles) of chlorine gas was bubbled thereinto at 40°C in 2 hours. After the completion of the bubbling, a mixture of 210 g of a commercially available nitric acid (63 percent by weight) and 600 g of water was immediately added dropwise thereto at 40°C for 2 hours. After the completion of the dropwise addition, the stirring was continued for further 1 hour. Then, the reaction solution was allowed to stand, and the separated lower layer of carbon tetrachloride was taken out, and washed with water, followed by distilling off carbon tetrachloride. Thus, 460 g of the residue was obtained as a red oil, in which 405 g of 2,3,6-trimethyl-p-benzoquinone was included. (90 percent in yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])(=[O:15])=[O:14])=[O:11])[N:3]=1.C(N(CC)CC)C.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[CH2:32]([O:19][C:18]([C:17]1[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=1[S:13]([NH:12][C:10]([NH:9][C:4]1[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=1)=[O:11])(=[O:15])=[O:14])=[O:20])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OCc2ccccc2)n1

Procedure:
To 1.75 g of 2-(4,6-dimethylpyrimidin-2-ylaminocarbonylsulfamoyl)benzoic acid was added 0.51 g of triethylamine in 10 ml tetrahydrofuran and 0.88 g of benzyl bromide in 10 ml of tetrahydrofuran. The mixture was heated to reflux for 1.5 hours, filtered and the tetrahydrofuran evaporated in-vacuo. The residue was extracted with hot 1-chlorobutane, diluted with ethyl acetate, washed with water and saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered and the solvents evaporated in-vacuo. The resultant residue was crystallized from 1-chlorobutane to a melting point of 157°. This product showed absorption peaks in the infrared region at 1720, 1600, 1560 cm-1 consistent for the desired ester and absorption by nuclear magnetic resonance at 2.45', singlet, for CH3 ; 5.3 singlet, CH2 on benzyl; 6.65' singlet CH of pyrimidine and aryl peaks at 7-8%.
Reaction SMILES: [F:1][C:2]1[C:7](CO)=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].[C-:11]#N.[Na+].C[N:15]([CH3:18])C=O>O>[F:1][C:2]1[C:3]([OH:10])=[C:4]([CH2:11][C:18]#[N:15])[CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cccc(O)c1F
Reactant: [C-]#N
Reactant: CN(C)C=O
Agent: [Na+]
Solvent: O
Product: N#CCc1cccc(F)c1O

Procedure:
A solution of 4.89 g of 2-fluoro-hydroxymethylphenol and 2.08 g of sodium cyanide in 120 ml of N,N-dimethylformamide is stirred at 120° C. over 24 hours. The reaction mixture is cooled, diluted with water and concentrated by evaporation. The residue is diluted with water and neutralized with conc. acetic acid (cautionl hydrocyanic acid). The mixture is extracted with dichloromethane (3×). The combined organic phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a violet solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.32 (1:2 EtOAc-heptane); Rt=3.12.
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([C:13]([OH:15])=O)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][NH2:31])=[C:25]([CH3:32])[N:24]=1)([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][NH:31][C:13]([C:11]2[O:10][N:9]=[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:12]=2)=[O:15])=[C:25]([CH3:32])[N:24]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(O)c1nc(Cc2ccccc2)no1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1nc(Cc2ccccc2)no1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-Benzyl-[1,2,4]oxadiazole-5-carboxylic acid (330 mg, 1.5 mmol), (5-Aminomethyl-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (389 mg, 1.5 mmol), HATU (1.1 g, 3.1 mmol) and DIPEA (0.8 mL, 4.7 mmol) in 10 mL DMF was stirred at room temperature for 16 h. The mixture was evaporated and the residue was partitioned between ethyl acetate and 1 N aq. HCl. The organic layer was dried over MgSO4 and evaporated in vacuo. The crude product was purified by preparative HPLC (Waters Sunfire Prep C18 PBD 5 um, 30×100 mm, 5 to 100% ACN and 0.1% TFA, flow 40 ml/min). LCMS (method A) RtA=1.834 min; [M+H]+=438.1.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[N:4]=1.[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:19]=1[C:20]([Cl:22])=[O:21]>O1CCOCC1>[ClH:22].[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:1])[CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[N:4]=1)=[O:21]
Reactant: CN1CCC(N(C)c2cccc(N)n2)CC1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Solvent: C1COCCO1
Product: CN1CCC(N(C)c2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Product: Cl
Yield: 80.3 %

Procedure:
Prepare according to procedure in Example 66 starting with N-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34) (200 mg, 0.907 mmol), 2,4,6-trifluorobenzoyl chloride (130 μL, 0.998 mmol), and 1,4-dioxane (10 mL) to yield 302 mg (80%) of the title compound: mass spectrum (ion spray): m/z=379.2 (M+1); Analysis calc'd for C19H22N4OF3Cl.0.5H2O: C, 53.84; H, 5.47; N, 13.22. Found: C, 54.02; H, 5.32; N, 13.56. mp 302° C. (dec.).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.C(#N)C.[C:32]([O:36][C:37]([NH:39][C:40]1[C:49]([N+:50]([O-:52])=[O:51])=[CH:48][CH:47]=[CH:46][C:41]=1[C:42]([O:44][CH3:45])=[O:43])=[O:38])([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:32]([O:36][C:37]([N:39]([C:40]1[C:49]([N+:50]([O-:52])=[O:51])=[CH:48][CH:47]=[CH:46][C:41]=1[C:42]([O:44][CH3:45])=[O:43])[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(=O)OC(C)(C)C
Reactant: COc1ccc(Cn2nnnc2-c2ccccc2-c2ccc(CBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1N(Cc1ccc(-c2ccccc2-c2nnnn2Cc2ccc(OC)cc2)cc1)C(=O)OC(C)(C)C

Procedure:
A mixture of 5-[4′-(bromomethyl)biphenyl-2-yl]-1-(p-methoxybenzyl)-1H-tetrazole (compound 5a, 9.25 g, 21.2 mmol), acetonitrile (107 ml), methyl 2-(tert-butoxycarbonylamino)-3-nitrobenzoate (compound 19a, 6.43 g, 21.7 mmol) and potassium carbonate (3.00 g, 21.7 mmol) was heated under reflux for 6 hr under a nitrogen atmosphere. The reaction was monitored by TLC (eluent: toluene/ethyl acetate (4:1)). The reaction mixture was cooled, and filtered, and the cake was washed with acetonitrile (35 mL). The filtrate was concentrated under reduced pressure at 35° C. or lower to give a crude product. The crude product was purified by silica gel column chromatography (eluent: toluene/ethyl acetate (100:0-4:1)), and the fraction was concentrated. To the residue was added chloroform (about 30 ml), and the mixture was concentrated. The operations were repeated four times. The residue was dried under reduced pressure in a bath at 40° C. to give methyl 2-(N-tert-butoxycarbonyl-N-{(2′-[1-(p-methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl)methyl}amino)-3-nitrobenzoate (compound 20a) as a yellowish brown amorphous solid (9.83 g (71.1%)).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([NH:10][CH3:11])[CH:3]=1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][CH3:11])[C:5]([CH:8]=[O:9])=[CH:6][N:7]=1
Reactant: CNc1cc(Cl)ncc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CNc1cc(Cl)ncc1C=O
Temperature: 30 °C
Reaction time: 6 h
Yield: 87.8 %

Procedure:
A mixture of (6-chloro-4-(methylamino)pyridin-3-yl)methanol (2.9 g, 16.7 mmol) and MnO2 (11.7 g, 133.6 mmol) in anhydrous DCM (25 mL) was stirred at 30° C. for 6 h. The reaction mixture was cooled to RT, filtered and concentrated in vacuo to give 6-chloro-4-(methylamino)nicotinaldehyde (2.5 g, 87% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.83 (s, 1H), 8.52 (br s, 1 H), 8.40 (s, 1 H), 6.75 (s, 1 H), 2.87 (d, J=5.8 Hz, 3 H); MS (ESI) m/z: 171.0 [M+H]+.