Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.Cl.[CH3:7][O:8][C:9](=[O:31])[C@H:10]([CH2:12][C:13]1[CH:20]=[C:18]([I:19])[C:17]([O:21][C:22]2[CH:29]=[C:27]([I:28])[C:26]([OH:30])=[C:24]([I:25])[CH:23]=2)=[C:15]([I:16])[CH:14]=1)[NH2:11].C(N(CC)CC)C.[CH3:39][N:40]([CH2:45][C:46](O)=[O:47])[CH2:41][C:42]([OH:44])=[O:43]>C1COCC1>[CH3:7][O:8][C:9](=[O:31])[C@H:10]([CH2:12][C:13]1[CH:14]=[C:15]([I:16])[C:17]([O:21][C:22]2[CH:23]=[C:24]([I:25])[C:26]([OH:30])=[C:27]([I:28])[CH:29]=2)=[C:18]([I:19])[CH:20]=1)[NH:11][C:46](=[O:47])[CH2:45][N:40]([CH3:39])[CH2:41][C:42]([OH:44])=[O:43]
Reactant: COC(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reactant: CN(CC(=O)O)CC(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)CN(C)CC(=O)O
Reaction time: 0.17 h
Yield: 69 %

Procedure:
In 15 ml. of dimethylformamide (DMF) was dissolved 2 g. of thyroxine methyl ester hydrochloride, and to this was added 500 μl. of triethylamine. After 10 min., 0.55 g. of N-methyliminodiacetic acid in 5 ml. of THF was added to the resulting solution. This reaction mixture was concentrated in a rotary evaporator, and a residue was dissolved in 50 ml. of THF. After addition of 150 ml. of ethyl acetate, the mixture was shaken. The ethyl acetate phase was taken up and washed successively with three portions of distilled water and one portion of a saturated aqueous saline solution. The ethyl acetate phase was dried over anhydrous sodium sulfate, and the supernatant was concentrated in a rotary evaporator. To the residue were successively added 20 ml. of THF and a small amount of n-hexane. The produced precipitate was collected by filtration with suction to obtain a white crystalline product. The product was dried in a vacuum desiccator to give white crystals; yield 69%.
Reaction SMILES: C([Sn]([CH2:14][O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])(CCCC)CCCC)CCC.C([Li])CCC.[CH3:27][Si:28]([CH3:37])([CH3:36])[C:29]1[O:33][CH:32]=[C:31]([CH:34]=[O:35])[CH:30]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>O1CCCC1.CCCCCC>[C:38]([O:35][CH:34]([C:31]1[CH:30]=[C:29]([Si:28]([CH3:37])([CH3:36])[CH3:27])[O:33][CH:32]=1)[CH2:14][O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])(=[O:40])[CH3:39]
Reactant: CCCC[Sn](CCCC)(CCCC)COCOCCOC
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: CC(=O)OC(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCCOCOCC(OC(C)=O)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-methoxyethoxymethyl tributylstannylmethyl ether (620 mg, 1.5 mmole) in tetrahydrofuran (THF) (5 ml) at -78° C. was treated with n-butyl lithium (a 2.5M solution in hexane: 0.67 ml, 1.67 mmole). After 10 min., a solution of 5-trimethylsilyl-3-furaldehyde (254 mg, 1.5 mmole) in THF (2 ml) was added. The solution was stirred for 3 hours while the cooling bath warmed to room temperature. Acetic anhydride (309 mg, 3.03 mmole) was added and the solution stirred at room temperature overnight. The mixture was quenched with water and the aqueous phase extracted with ethyl ether. The combined organic portions were dried over MgSO4, filtered and concentrated. Purification by flash chromatography (silica, 50% ethyl ether/hexane) gave the title compound as a light yellow oil.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH:11][C:12]3[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14](O)=O)=[CH:9][CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+].[OH-].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:14]1[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=[C:10]2[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=[CH:8][C:9]=12
Reactant: O=C(O)c1ccccc1Nc1ccnn1C1CCCC1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Clc1c2ccccc2nc2c1cnn2C1CCCC1
Temperature: 0 °C

Procedure:
A mixture of N-(1-cyclopentylpyrazol-5-yl) anthranilic acid (21 g, 0.0775 mol) and POCl3 (100 ml) was refluxed for 8 hours. The reaction mixture was poured into ice-water and neutralized with NH4OH. A gum formed which was extracted with CH2Cl2. The CH2Cl2 layer was then washed with water, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with 40% to 70% CH2Cl2 /hexane to afford 7.5 g of 4-chloro-1-cyclopentyl-1H-pyrazolo[3,4-b]quinoline, m.p. 97°-98 ° C.
Reaction SMILES: [Br-].[CH2:2]1[CH2:29][O:28][C:4]([CH3:27])([CH2:5][CH2:6][CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:3]1.C([O:32][CH:33](OCC)[C:34](=O)[CH2:35][CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])C.CCCCCC>O1CCCC1.C(O)(=O)C>[CH2:29]1[CH2:2][O:3][C:4]([CH2:5][CH2:6][CH:7]=[C:34]([CH:33]=[O:32])[CH2:35][CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])([CH3:27])[O:28]1
Reactant: CC1(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)OCCO1
Reactant: CCOC(OCC)C(=O)CCC=C(C)C
Agent: [Br-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)=CCCC(C=O)=CCCC1(C)OCCO1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
In 160 ml of anhydrous tetrahydrofuran was suspended 38.5 g of 4,4-ethylenedioxypentan-1-yltriphenylphosphonium bromide, and to this was added the equimolar amount of a n-butyllithium-hexane solution at -20° C. in a stream of nitrogen. The reaction mixture was stirred for one hour and cooled to -60° C. To this was added 14.5 g of 1,1-diethoxy-6-methyl-5-hepten-2-one, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was, after addition of icewater, extracted with n-hexane and from the extract was obtained an oil. The oil was suspended in 250 ml of 50% acetic acid and stirred at room temperature for one hour. 2,2-Ethylenedioxy-6-formyl-10-methyl-5,9-undecadiene obtained by the n-hexane extraction, not purified, was reduced in 100 ml of ethanol by using 500 mg of sodium borohydride. The product thus obtained was chromatographed on the silica gel (100 g) column to yield 7.3 g of 2,2-ethylenedioxy-6-hydroxymethyl-10-methyl-5,9-undecadien.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]2[S:10][CH:11]=[C:12](Br)[CH:13]=2)[S:5][CH:6]=1.[CH2:15]([Mg]Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:15]([C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]2[S:10][CH:11]=[C:12]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])[CH:13]=2)[S:5][CH:6]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Brc1csc(/C=C/c2cc(Br)cs2)c1
Reactant: CCCCCCCCCCCC[Mg]Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Product: CCCCCCCCCCCCc1csc(/C=C/c2cc(CCCCCCCCCCCC)cs2)c1
Temperature: 60 °C
Yield: 38 %

Procedure:
A mixture of 16 (1.1 g, 3.14 mmol) and NiCl2(dppp) (0.17 g, 0.31 mmol) was degassed in a 2 necked RBF. Anhydrous THF (25 mL) was then added to the mixture. C12H25MgBr (1M in THF, 8 mL, 8 mmol) was added dropwise to the reaction mixture and heated at 60° C. overnight. The reaction was quenched with 2N aqueous HCl, extracted with CH2Cl2 and filtered through celite. The residue was purified by column chromatography (silica gel, hexane/CH2Cl2, 4:1) and recrystallized from hexane to give a yellow solid compound 17 in 38% yield. 1H-NMR (DCM-d2, 400 MHz) ppm 0.88 (t, 6H, J=6.8 Hz) ppm 1.29 (m, 36H) ppm 1.60 (td, 4H, J=7.2 Hz, J=14.6 Hz) ppm 2.55 (m, 4H) ppm 6.78 (s, 2H) ppm 6.88 (s, 2H) ppm 6.96 (s, 2H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:12][CH:13]([Cl:17])[C:14](Cl)=[O:15]>C1C=CC=CC=1>[CH:1]1([NH:4][C:14](=[O:15])[CH:13]([Cl:17])[Cl:12])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)C(Cl)Cl
Yield: 81.3 %

Procedure:
To a solution of cyclopropylamine (28.6 g, 0.5 mol) and 50 ml of triethylamine in 200 ml of anhydrous benzene was added dropwise with stirring and ice-bath cooling dichloroacetyl chloride (73.7 g, 0.5 mol). The solution was stirred 2 hr at room temperature. The benzene solution was washed successively with 10% HCl, H2O and saturated NaCl solution and dried over anhydrous MgSO4. The solvent was distilled affording 68.3 g (82%) of white crystalline product, m.p. 125-71/4. Recrystallization from ethanol-benzene yielded purified product; m.p. 130°-2°.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cc(Br)oc1C
Reactant: OB(O)c1cccc(F)c1
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+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2cccc(F)c2)oc1C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.2 g), 3-fluorophenylboronic acid (1.7 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 15% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.1 g, 92%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:28])=[C:4]([NH:10][C@H:11]([C:24]([OH:27])([CH3:26])[CH3:25])[C:12]([NH:14][NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:28])=[C:4]([NH:10][C@@H:11]([C:12]2[O:13][C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:15][N:14]=2)[C:24]([OH:27])([CH3:26])[CH3:25])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)C(C)(C)O)ccc(C#N)c1Cl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccccc3)o2)C(C)(C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Yield: 36.3 %

Procedure:
The crude material of (R)—N′-(2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoyl)benzohydrazide (intermediate 14b) (218 mg, 0.54 mmol) was added to THF (50 mL) stirred at room temperature. PS-BEMP (742 mg, 1.63 mmol base) was added to the solution, followed by slow addition of p-TSCl (114 mg, 0.60 mmol). The reaction mixture was stirred for 1.5 h and the progress of the reaction was monitored by TLC. After the completion of the reaction, the BEMP reagent was filtered off and the solution concentrated to give the crude material. The crude material was chromatographed with hexanes:EtOAc (6:4) to give the title compound (75 mg, 28%): 1H NMR(500 MHz, CDCl3, δ in ppm) 7.94 (d, J=9 Hz, 2H), 7.54 (m, 1H), 7.46 (m, 2H), 7.34 (d, J=9 Hz, 1H), 6.56 (d, J=9 Hz, 1H), 5.45 (d, J=9 Hz, 1H), 4.71 (d, J=9 Hz, 1H), 3.12 (s, 1H), 2.37 (s, 3H), 1.50 (s, 3H), 1.37 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-:9])=[CH:5][CH:4]=1)#[N:2].C[O-].[Na+].CS(O)(=O)=O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:30]2[CH:31]=[N:32][C:33]([F:36])=[CH:34][CH:35]=2)(N)[C@@H:26]([NH2:28])[CH3:27])=[CH:21][CH:20]=1>CO>[O-:9][N+:6]1[CH:7]=[CH:8][C:3]([C:1]2[NH:28][CH:26]([CH3:27])[C:25]([C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)([C:30]3[CH:31]=[N:32][C:33]([F:36])=[CH:34][CH:35]=3)[N:2]=2)=[CH:4][CH:5]=1
Reactant: N#Cc1cc[n+]([O-])cc1
Reactant: C[C@H](N)C(N)(c1ccc(F)cc1)c1ccc(F)nc1
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1NC(c2cc[n+]([O-])cc2)=NC1(c1ccc(F)cc1)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-cyanopyridine N-oxide (100 mg) in methanol (4 mL) were added sodium methoxide (13.5 mg), and the mixture was stirred at room temperature for 24 hrs. To the reaction mixture was added methanesulfonic acid (104 mg), and the reaction mixture was stirred at room temperature for an additional 10 minutes. To the 3.5 ml of this solution was added to the solution (2 mL) of (2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine described in Reference Example 5-1, and the mixture was stirred at room temperature for 15 hrs. After concentrating the reaction mixture in vacuo, the obtained residue was dissolved in ethyl acetate, washed with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution in this order, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was evaporated in vacuo. The obtained residue was purified by silica gel column chromatography (C-300; chloroform:methanol=9:1) to give 2-(1-oxido-pyridin-4-yl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline (172 mg) as colorless oil. To the solution (5 ml) of the obtained N-oxide compound in acetonitrile was added trimethylsilylcyanide (140 mg) and triethylamine (142 mg), and the mixture was stirred at 90° C. for 17 hrs. To the mixture was added trimethylsilylcyanide (140 mg) and triethylamine (142 mg), and the mixture was stirred at 90° C. for 2 hrs, and concentrated in vacuo. The obtained residue was dissolved in chloroform, washed with saturated sodium hydrogen carbonate aqueous solution, water and saturated sodium chloride aqueous solution in this order, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was evaporated in vacuo. The obtained residue was purified by silica gel column chromatography (C-300; hexane:ethyl acetate=1:1) and treated with 4N hydrogen chloride-ethyl acetate solution to give the title compound (108 mg).
Reaction SMILES: C(Cl)Cl.[CH2:4]([C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[CH:17]=[CH2:18])C=C>C=CC1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru]Cl.CCCCC>[F:16][C:13]([F:14])([F:15])[C:11]1[CH:12]=[C:7]2[C:8]([CH:17]=[CH:18][CH2:4]2)=[CH:9][CH:10]=1
Reactant: C=CCc1cc(C(F)(F)F)ccc1C=C
Agent: Cl[Ru]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Solvent: CCCCC
Product: FC(F)(F)c1ccc2c(c1)CC=C2

Procedure:
Methylene chloride (0.6 L) was added to a 1 L flask containing 2-allyl-4-(trifluoromethyl)-1-vinylbenzene (80.0 g, 0.377 mol). Bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (Grubbs catalyst, 1st generation) (3.1 g, 0.0038 mol) was added to the solution and the resulting solution was refluxed overnight (18 h). The solvent was evaporated to give a dark oil, which was passed through a silica gel plug using pentane. After pentane was carefully removed, 57 g (82.8%) of pure product was collected as slight brown oil. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.72 (s, 1H), 7.55 (d, 1H), 7.48 (d, 1H), 6.93 (m, 1H), 6.74 (m, 1H), 3.46 (brs, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:19])=[C:12]([CH2:17][NH2:18])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br-].[CH2:21]([Zn+])[CH2:22][CH2:23][CH3:24]>C1COCC1.CCOC(C)=O.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>[CH2:21]([C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:19])=[C:12]([CH2:17][NH2:18])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1)[CH2:22][CH2:23][CH3:24]
Reactant: NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Reactant: CCCC[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 60 °C
Yield: 74.7 %

Procedure:
To a solution of ({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (300 mg, 0.822 mmol) and tetrakis(triphenylphosphine)palladium(0) (950 mg, 0.822 mmol) in THF (4 ml) was added n-butyl zinc bromide (0.5 M solution in THF) (1.644 ml, 0.822 mmol) and the reaction mixture was heated at 60° C. for one hour. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give ({3-[(3-butyl-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (210 mg, 0.614 mmol, 75% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.43 (s, 2H), 6.97 (s, 1H), 6.68 (s, 1H), 6.64 (s, 1H), 3.71 (s, 2H), 2.50 (t, 2H), 1.88 (br. s., 2H), 1.45 (quin, 2H), 1.14-1.29 (m, 2H), 0.82 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:28][CH2:29][CH2:30][C:31](Cl)=[O:32]>N1C=CC=CC=1.C(Cl)Cl>[C:31]([O:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[O:17][C:16]([C@H:12]([NH:11][C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=3[CH3:10])[C@@H:13]([O:15][C:16](=[O:17])[CH2:12][CH2:13][CH3:14])[CH3:14])=[N:20][N:19]=2)=[CH:26][CH:25]=1)(=[O:32])[CH2:30][CH2:29][CH3:28]
Reactant: CCCC(=O)Cl
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(O)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)Oc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@H](C)OC(=O)CCC)o2)cc1
Reaction time: 23 h
Yield: 142.1 %

Procedure:
To a solution of 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile (example 8) (200 mg, 0.52 mmol) in pyridine (1.0 mL) and CH2Cl2 (7.0 mL) was added n-butyryl chloride (0.16 mL, 1.56 mmol). Upon complete addition the reaction mixture was stirred for 23 h, then quenched with 10% aqueous HCl (10 mL). The mixture was partitioned between H2O (25 mL) and CH2Cl2 (30 mL). The aqueous layer was extracted with CH2Cl2 (20 mL). The combined organic extracts were washed with NaHCO3 (30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide an orange viscous oil, which was purified by flash chromatography over silica gel (15-25% EtOAc in hexanes) to provide the title compound as a colourless solid (194 mg, 71%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.00 (dm, J=8.8 Hz, 2H), 7.36 (d, J=8.6 Hz, 1H), 7.23 (dm, J=8.8 Hz, 2H), 6.72 (d, J=8.8 Hz, 1H), 5.57 (pentet, J=5.9 Hz, 1H), 5.18 (d, J=8.0 Hz, 1H), 5.02 (dd, J=5.7, 8.0 Hz, 1H), 2.55 (t, J=7.4 Hz, 2H), 2.32 (dt, J=2.6, 7.4 Hz, 2H), 2.30 (s, 3H), 1.77 (sextet, J=7.4 Hz, 2H), 1.63 (sextet, J=7.4 Hz, 2H), 1.36 (d, J=6.5 Hz, 3H), 1.03 (t, J=7.4 Hz, 3H), 0.91 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13]C(C)(C)C)(=[O:12])=[O:11])=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[N:29]=[N:28][CH:27]=[N:26]3)=[CH:20][CH:19]=2)[CH:6]=1)[CH:2]([CH3:4])[CH3:3].B(Cl)(Cl)Cl.O>C(Cl)Cl>[CH2:1]([C:5]1[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[N:29]=[N:28][CH:27]=[N:26]3)=[CH:20][CH:19]=2)[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ncnn3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1cc(-c2ccc(Cn3ncnn3)cc2)c(S(N)(=O)=O)s1
Reaction time: 0.5 h

Procedure:
To a solution of 5-iso-butyl-N-tert-butyl-3-(4-tetrazol-2-ylmethylphenyl)-thiophene-2-sulfonamide (42.1 mg, 0.111 mmol, see step (c) above) in CH2Cl2 (10 mL) was added BCl3 (0.5 mL, 1M, 0.5 mmol) under N2 (g). The reaction mixture was stirred for 0.5 h. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine and dried over MgSO4 and the solvent was removed in vacuo. The crude product was used directly in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9](Cl)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N:13]1[CH:18]=[C:17](B(O)O)[CH:16]=[CH:15][CH:14]=1.[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24]1>>[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([NH:28][C:9]2[N:10]=[CH:11][C:2]([C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)=[C:3]3[C:8]=2[N:7]=[CH:6][CH:5]=[CH:4]3)=[N:24]1
Reactant: Clc1ncc(Br)c2cccnc12
Reactant: OB(O)c1cccnc1
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(Nc2ncc(-c3cccnc3)c3cccnc23)n1

Procedure:
The title compound, MS: m/e=303.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 5-bromo-8-chloro-[1,7]naphthyridine (Example H), 5-pyridineboronic acid and 1-methyl-1H-pyrazol-3-ylamine.
Reaction SMILES: B(Cl)(Cl)Cl.[CH:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12].CS[C:15]#[N:16].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[OH:11][C:10]1[CH:5]=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=1[C:15]#[N:16]
Reactant: Cc1cccc(O)c1
Reactant: CSC#N
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(C#N)c(O)c1
Temperature: 80 °C
Yield: 91.1 %

Procedure:
2-Hydroxy-4-methylbenzonitrile was prepared following a modification of the procedure reported by Makoto Adachi and Tsutomu Sugasawa (Synthetic Communications 1990, 20, 71-84.). To a cold (0° C.) solution of BCl3 (1.0 M in heptane, 12.0 mL, 12.0 mmol) in 1,2-dichloroethane was added neat m-cresol (1.00 mL, 9.56 mmol) followed by CH3SCN (0.83 mL, 12.1 mmol) and AlCl3 (1.38 g, 10.4 mmol). The cooling bath was removed and the resultant mixture was heated to 80° C. for 3 hours then cooled to room temperature. The mixture was poured into 4 N NaOH (35 mL) and the mixture was heated at 80° C. for 45 minutes then cooled to room temperature. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×50 mL). The aqueous phase was acidified with 6 N HCl (30 mL) and extracted with diethyl ether (3×50 mL). The combined ether extracts were dried (MgSO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1 CH2Cl2-EtOAc) provided 1.16 g (91%) of 2-Hydroxy-4-methylbenzonitrile as a white solid. 1H NMR (CDCl3) δ 2.36 (s, 3H), 6.20 (br s, 1H), 6.79-6.81 (m, 2H), 7.38 (d, 1H, J=9 Hz).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:8]=1[S:17][CH3:18].[C:19](=[O:21])=[O:20].O>O1CCCC1.C(OCC)C>[F:6][C:7]1[C:8]([S:17][CH3:18])=[C:9]([C:13]([F:15])([F:16])[F:14])[CH:10]=[CH:11][C:12]=1[C:19]([OH:21])=[O:20]
Reactant: CSc1c(F)cccc1C(F)(F)F
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSc1c(C(F)(F)F)ccc(C(=O)O)c1F
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Under an atmosphere of inert gas, 27.5 ml (1.6 M in hexane, 44 mmol) of n-butyllithium were added dropwise to a solution, cooled to −78° C., of 7.98 g (38 mmol) of 1-fluoro-2-methylthio-3-(trifluoromethyl)benzene in 60 ml of anhydrous tetrahydrofuran, where the temperature of the reaction mixture should not exceed −65° C. The mixture was stirred at −78° C. for 3 h, and at this temperature a carbon dioxide stream was then introduced such that the temperature of the reaction mixture did not exceed −45° C. The mixture was then warmed to RT and then once more cooled to 0° C. For work-up, water was added dropwise at this temperature until the precipitate formed had dissolved. Diethyl ether was added, and the organic phase was extracted three times with water. The combined aqueous phases were acidified with 10 percent strength hydrochloric acid. The aqueous phase was extracted repeatedly with dichloromethane, the combined organic phases were washed with saturated aqueous NaCl solution and dried over sodium sulfate and the filtrate was finally freed from the solvent. The crude product obtained in this manner was recrystallized from gasoline/ethyl acetate. This gave 6.8 g of 2-fluoro-3-methylthio-4-(trifluoromethyl)benzoic acid.