Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]1[CH:15]=[C:14]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:28]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)([C:30]3[S:31][CH:32]=[CH:33][N:34]=3)O)[CH:12]=2)[N:7]=1)(C)(C)C.O.O.[Sn](Cl)Cl.Cl>CC(O)=O>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([CH:28]([C:30]2[S:31][CH:32]=[CH:33][N:34]=2)[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:5])[CH:15]=[C:14]3[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:27])[F:25])=[CH:19][CH:18]=2)=[CH:36][CH:37]=1
Reactant: CC(C)(C)Oc1cc(Cc2ccc(OC(F)(F)F)cc2)c2cc(C(O)(c3ccc(Cl)cc3)c3nccs3)ccc2n1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc(Cc2ccc(OC(F)(F)F)cc2)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc2[nH]1
Temperature: 110 °C

Procedure:
(2-(tert-Butoxy)-4-(4-(trifluoromethoxy)benzyl)quinolin-6-yl)(4-chlorophenyl)(thiazol-2-yl)methanol (55 mg, 0.0918 mmol) and tin(II) chloride dihydrate (83 mg, 0.367 mmol) were combined in AcOH (2 mL). HCl (conc. 36%, 0.115 mL) was then added. The solution was heated to 110° C. After 45 min the reaction was cooled to room temperature and concentrated. The residue was taken up in CH2Cl2 and washed with NaHCO3 (satd), dried (Na2SO4) and concentrated. The resulting residue was purified by silica column (70-80% EtOAc/hexanes) chromatography to yield 6-((4-chlorophenyl)(thiazol-2-yl)methyl)-4-(4-(trifluoromethoxy)benzyl)quinolin-2(1H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([CH3:12])[N:6]=[C:5]2[Sn](CCCC)(CCCC)CCCC.[C:26]([CH:28]1[CH2:33][CH2:32][N:31]([C:34](=[O:60])[C@H:35]([NH:39][C:40]([C:42]2[C:50]3[C:45](=[N:46][CH:47]=[C:48](Br)[N:49]=3)[N:44]([CH2:52][O:53][CH2:54][CH2:55][Si:56]([CH3:59])([CH3:58])[CH3:57])[CH:43]=2)=[O:41])[CH:36]2[CH2:38][CH2:37]2)[CH2:30][CH2:29]1)#[N:27]>CN(C=O)C.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.[Cu]I>[C:26]([CH:28]1[CH2:33][CH2:32][N:31]([C:34](=[O:60])[C@H:35]([NH:39][C:40]([C:42]2[C:50]3[C:45](=[N:46][CH:47]=[C:48]([C:5]4[C:4]5[C:8](=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=5)[N:7]([CH3:12])[N:6]=4)[N:49]=3)[N:44]([CH2:52][O:53][CH2:54][CH2:55][Si:56]([CH3:58])([CH3:57])[CH3:59])[CH:43]=2)=[O:41])[CH:36]2[CH2:37][CH2:38]2)[CH2:30][CH2:29]1)#[N:27]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(Cl)c(Cl)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)cn3COCC[Si](C)(C)C)c2cc(Cl)c(Cl)cc21
Temperature: 90 °C
Yield: 86.7 %

Procedure:
To a solution of 5,6-dichloro-1-methyl-3-tributylstannyl-1H-indazole (crude from Step 5, 218 mg, 0.44 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (125 mg, 0.22 mmol) in DMF (2 mL) were added Pd(PPh3)4 (12.9 mg, 0.011 mmol) and copper(I) iodide (8 mg, 0.044 mmol). The yellow reaction mixture was heated at 90° C. for 1.5 h then cooled to room temperature, quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 50% to 100% EtOAc/hexanes to isolate 130 mg (86%) of 2-(5,6-dichloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a pale yellow foamy solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39]Br>C(#N)C>[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][N:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][C:13]([S:10](=[O:12])(=[O:11])[NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=3)=[CH:14][CH:15]=2)[CH2:20]1
Reactant: O=S(=O)(Nc1cccc(Cl)c1)c1ccc2c(c1)CNCC2
Reactant: COC(=O)c1ccccc1CBr
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1CN1CCc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 28 %

Procedure:
To a mixture of 7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.8 g, 5 mmol) and triethylamine (0.51 g, 5 mmol) in dry acetonitrile (25 ml), heated to 70° C., was added half of a solution of methyl-2-(bromomethyl)benzoate (1.15 g, 5 mmol) and triethylamine (0.51 g, 5 mmol) in acetonitrile (25 ml) over 0.5 hr. After 1.5 hr, the remainder of the solution was added slowly over 2 hr and stirred for a further 1 hr. After cooling and filtration the concentrated filtrate was chromatographed (silica gel, ether) to give a methyl-2-[[7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]methyl]benzoate (0.66 g, 28%) as an oil. To this, in methanol (30 ml), was added 15% sodium hydroxide solution (8 ml) and the mixture was stirred for 3 hr. The solvent was removed in vacuo, water was added and the pH was adjusted to 6 with 2N HCl to give, after recrystallisation from IPA, 2-[[7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]methyl]benzoic acid, H2O, 0.6HCl, 0.48(CH3)2CHOH.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[C:17]([O-])([O-])([O:19][CH2:20][CH3:21])[CH3:18].C(O)(=O)C>C1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:2]([N:1]=[C:17]([O:19][CH2:20][CH3:21])[CH3:18])=[C:3]([CH:12]=1)[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: CCOC(C)([O-])[O-]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(C)=Nc1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
A solution of 11.5 parts of 2-amino-5-chlorobenzophenone, 11.5 parts of ethyl orthoacetate and 6 volume parts of acetic acid in 100 volume parts of benzene is refluxed for 20 minutes, whereby 5-chloro-2-(1-ethoxyethylideneamino)-benzophenone are obtained as crystals. Recrystallization from methanol-water gives colorless needles melting at 62° to 63° C. Yield: 93%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[C:6](Cl)=[N:5]2.[NH2:16][CH2:17][CH2:18][CH2:19][OH:20]>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[C:6]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])=[N:5]2
Reactant: NCCCO
Reactant: Clc1nc2cc(Br)ccc2n2ccnc12
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: OCCCNc1nc2cc(Br)ccc2n2ccnc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 87.5 %

Procedure:
To a solution of 7-bromo-4-chloro-imidazo[1,2-a]quinoxaline (2.75 g; 9.6 mmol; 1 eq) in anhydrous dioxane (421 mL), 3-aminopropanol (1.83 mL; 24.1 mmol; 2.5 eq) is added under argon atmosphere. After 17 hours of stirring under reflux, the reaction mixture is cooled to room temperature and diluted in ethyl acetate (250 mL). The organic phase is washed three times with a molar solution of sodium hydroxide (3×150 mL). The recombined water phases are extracted one more time with ethyl acetate (300 mL) and the combined organic phases dried over sodium sulfate and concentrated under vacuum. The resulting beige powder is further washed with ether (200 mL) to provide the title compound (2.70 g; 8.4 mmol; 89%) as a grey powder.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[O:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].[Br:12][C:13]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2[C:33]#[N:34])=[CH:21][C:14]=1[O:15][CH:16]([CH3:20])[C:17](Cl)=[O:18]>C(Cl)Cl>[CH2:1]([N:5]([CH2:6][C:7]1[O:11][CH:10]=[CH:9][CH:8]=1)[C:17](=[O:18])[CH:16]([O:15][C:14]1[CH:21]=[C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2[C:33]#[N:34])[CH:23]=[CH:24][C:13]=1[Br:12])[CH3:20])[CH2:2][CH2:3][CH3:4]
Reactant: CC(Oc1cc(Oc2ccc(Br)cc2C#N)ccc1Br)C(=O)Cl
Reactant: CCCCNCc1ccco1
Solvent: ClCCl
Product: CCCCN(Cc1ccco1)C(=O)C(C)Oc1cc(Oc2ccc(Br)cc2C#N)ccc1Br
Temperature: -15 °C

Procedure:
N-Butyl-N-furfurylamine (0.015 mole) triethylamine (5 ml) and methylene chloride (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to about -15° C. and a solution of 2-[2-bromo-5-(2-cyano-4-bromophenoxy)phenoxy]propionyl chloride (0.01 mole) in methylene chloride (50 ml) is added dropwise with stirring. After this time the mixture is transferred to a separatory funnel and is washed with water and dilute aqueous sodium bicarbonate. The washed solution is then dried, filtered and stripped of solvent leaving a residue. This residue is then purified by subjecting it to elution chromatography using mixtures of ethyl acetate and hexane with increasing concentrations of ethyl acetate as the eluant. The desired fractions determined by IR spectroscopy are then stripped of solvent to yield the desired product N-butyl-N-furfuryl-2-[2-bromo-5-(2-cyano-4-bromophenoxy)phenoxy]propionamide.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([N:26]=[C:27]=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].N1C=CC=CC=1>O1CCCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:27](=[O:28])[NH:26][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCN=C=O
Reactant: Oc1ccc2c(c1)CCCN2Cc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Temperature: 65 °C
Reaction time: 48 h

Procedure:
Mixture of 1-benzyl-1, 2, 3, 4-tetrahydro-quinolin-6-ol (0.239 g., 1 mmol), heptyl isocyanate (0.169 g., 1.2 mmol) and pyridine (1 ml) in dry tetrahydrofuran (10 ml), was heated with stirring at 65° C. for 48 hours. Reaction mixture was quenched with water (1 ml) and concentrated under vaccum. The separated solid was washed with water (2×5 ml) and crystallised with ether to give (2 g) as oil; yield: 0.200 g. (52.6%), C24H32N2O2; 1H NMR δ ppm (CDCl3): 0.86 (bs, 3H), 1.20-1.29 (m, 6H), 1.55-1.58 (m, 4H), 1.96-2.06 (m, 2H), 2.79 (t, 2H), 3.17-3.36 (m, 4H), 4.44 (st, 2H), 4.87 (bs, 1H), 6.39-6.44 (m, 1H4), 6.71-6.75 (m, 2M), 7.25-7.34 (m, 5H); IR vmax (Neat) (cm−1): 757, 902, 1.70, 1160, 1199, 1228, 1348, 1458, 1502, 1618, 1718, 2362, 2857, 2928, 3028, 3342, 3854; MS: m/z=380 (M+).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13]O)=[O:6])#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>O1CCCC1>[Br:34][CH2:13][C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:6]
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
trans-N-Cyanomethyl-2-hydroxymethyl-cyclohexanecarboxamide (12.4 g, 63.2 mmol) and triphenylphosphine (19.9 g, 75.8 mmol) were weighed into a 1000 mL round bottom flask fitted with a stir bar, addition port and nitrogen inlet. A nitrogen atmosphere was established and maintained and then anhydrous tetrahydrofuran (300 mL) was added. The reaction mixture was stirred for 30 minutes at room temperature and N-bromosuccinimide (13.5 g, 75.8 mmol) was added to the flask. The reaction slowly cleared to an orange-red solution. The reaction mixture was stirred at room temperature for 18 h and then concentrated on a rotary evaporator. Product was purified from the residue by chromatography on 2360 cm3 of silica gel in a 10×30 cm column with ethyl acetate eluent. The product fractions were concentrated on a rotary evaporator and the residue dried under high vacuum to give trans-2-bromomethyl-N-cyanomethylcyclo-hexanecarboxamide as a white solid with a slight yellow tint.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:20])[C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH3:21][C:22]1[CH:23]=[C:24]([SH:29])[CH:25]=[CH:26][C:27]=1[CH3:28]>>[CH3:21][C:22]1[CH:23]=[C:24]([S:29][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]([CH3:20])[C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)[CH:25]=[CH:26][C:27]=1[CH3:28]
Reactant: Cc1cc(OCCCCCl)cc2c1NC(=O)OC2(C)C
Reactant: Cc1ccc(S)cc1C
Product: Cc1ccc(SCCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1C

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and 3,4-dimethyl-thiophenol.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O[N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16]>C1COCC1>[C:1]([O:8][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCC(=O)O
Solvent: C1CCOC1
Product: CCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 5 h
Yield: 87.1 %

Procedure:
To a solution of 55.2 g (0.475 mol) of hexanoic acid and 60.161 g (0.523 mol) of N-hydroxy succinimide in 600 mL THF, 107.855 g (0.523 mol) of DCCl was added. The mixture was cooled with an ice-water bath and stirred for 5 h. The dicyclohexyl urea (DCU) precipitate was removed by filtration, and the THF solvent was removed by vacuum rotary evaporation. The yellow oil residue was dissolved again in 600 mL hexane followed by another vacuum filtration to remove the excess dicyclohexyl urea (DCU). The filtrate was then concentrated under vacuum evaporation yield a white solid, which was vacuum dried at ambient temperature to give 88.187 g (87.07%) of N-hexanoyloxy succinimide. IR (KBr): 1816 cm−1 (ν(C═O) of ester), 1745-1786 cm−1 (ν(C═O) of imide). 1H-NMR (DMSO-d6, ppm): 0.86 (3H, —CH3), 1.31 (4H, —(CH2)2CH3), 1.62 (2H, CH2CH2COO—), 2.64 (2H, —CH2COO—), 2.80 (4H, —COCH2CH2CO—).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH2:12]=[CH2:13]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:12][CH2:13][C:9](=[O:11])[CH2:8]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: C=C
Product: O=C1CCc2ccc(Br)cc2C1

Procedure:
Scheme 3 illustrates a route to 7-substituted tetralin derivative 8. 3-Bromophenylacetic acid is converted to the corresponding acid chloride and this is subjected to Friedel-Crafts reaction with ethene, affording the 7-bromo-2-tetralone 7. This intermediate may be elaborated using the procedures described in Scheme 1 to provide the acid (8).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[O:13][C:11](=O)[C:10]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C(OCC)(=O)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:1]([N:8]1[C:9]2[C:10](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11]([OH:13])=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:14]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1oc(=O)n(Cc2ccccc2)c2ccccc12
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(O)c2ccccc2n(Cc2ccccc2)c1=O

Procedure:
Reagents: Comp 21 (3.4 mmols, 0.85 g); Sodium hydride (7.37 mmols, 0.18 g); Diethyl malonate (16.8 mmols, 2.7 g). Yield: 0.1 g (9%), white solid, m.p.=117° C.-118° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([F:19])([F:18])[CH2:11][N:12]1[CH:16]=[C:15](I)[CH:14]=[N:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.CO[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:8][CH2:9][C:10]([F:19])([F:18])[CH2:11][N:12]1[CH:16]=[C:15]([B:27]2[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]2)[CH:14]=[N:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: FC(F)(COCc1ccccc1)Cn1cc(I)cn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(CC(F)(F)COCc3ccccc3)c2)OC1(C)C
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 736.5 %

Procedure:
A solution of 1-(3-benzyloxy-2,2-difluoropropyl)-4-iodo-1H-pyrazole (Compound 59F, 1.8 g, 4.7 mmol) in THF (40 mL) was cooled to −78° C., treated with iPrMgCl (4.75 mL, 9.5 mmol, 2M) and the temperature was raised to −40° C. After 20 min stirring at −40° C., reaction mixture was cooled to −78° C. and treated with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.091 mL, 0.56 mmol). The reaction mixture was allowed to warm to RT, treated with sat. aq. ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give 1.56 g (89%) of desired product as an oil. 1H NMR (500 MHz, CDCl3) δ 7.81 (s, 1H), 7.78 (s, 1H), 7.36-7.33 (m, 5H), 4.64-4.59 (m, 4H), 3.56 (t, J=12 Hz, 2H), 1.26 (s, 12H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH:4]=O.[C:15]([NH:19][OH:20])([CH3:18])([CH3:17])[CH3:16]>>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH:4]=[N+:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[O-:20]
Reactant: CC(C)(C)NO
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Product: CC(C)(C)[N+]([O-])=Cc1cc(OC(F)(F)F)ccc1O

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 2-hydroxy-5-trifluoromethoxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 81.8% yield as a yellow crystalline solid, m.p. 82.6° C. (Rf=0.40 on a silica gel plate using 7:3 hexanes/EtOAc as an eluant).
Reaction SMILES: C1[O:19][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][N:13]=3)=[CH:7][CH:6]=2)OC1.C(N(CC)CC)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[Cl:37])[C:31](Cl)=[O:32]>C1COCC1>[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:36]([Cl:37])=[C:28]([Cl:27])[CH:29]=3)=[CH:14][N:13]=2)=[CH:9][CH:10]=1)=[O:19]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(Oc2ccc(C3OCCO3)cc2)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[(5-amino-2-pyridyl)oxy]benzaldehyde ethylene acetal (5.27 g, 20.4 mmol) and triethylamine (3.41 mL, 24.5 mmol) in THF (80 mL) was added dropwise a solution of 3,4-dichlorobenzoyl chloride (4.49 g, 21.4 mmol) in THF (30 mL) under ice cooling. The resulting solution was stirred for 2 hours at the same temperature. The reaction solution was concentrated under reduced pressure, to the residue, 80% acetic acid (55 mL) was added, and the mixture was heated at 80° C. with stirring for 1 hour. The reaction solution was concentrated under reduced pressure and to the residue was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The obtained solid was recrystallized from isopropanol, to thereby yield 5.63 g of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Cl[C:9]1[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=1>CN(C=O)C.O>[CH:1]1([CH2:4][O:5][C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: N#Cc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCC2CC2)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a disposable tube were added cyclopropylmethanol (0.44 ml, 5.41 mmol) in DMF (2 ml) and followed by addition of sodium hydride (60% dispersion in mineral oil) (260 mg, 6.50 mmol) slowly. It was stirred at RT for 15 min. Then 5-chloro-2-cyanopyridine (500 mg, 3.61 mmol) was added. It was stirred at RT for 1 h. Then the reaction mixture was diluted with water and extracted with EtOAc and tBuOMe. The organic extract was washed with brine and dried over MgSO4. The solution was filtered and concentrated to give the crude material as a dark brown oil. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 15% to 30% to 45% EtOAc in heptane, to provide 5-(cyclopropylmethoxy)picolinonitrile as white solid mixed with cyclopropylmethanol. It was washed by heptane/tBuOMe (˜5:1), and the white precipitate was collected by filtration to yield 5-(cyclopropylmethoxy)picolinonitrile (380 mg, 2.181 mmol, 60.4% yield) as white crystals. MS m/z=175.2 (M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=O.C1(C)C=CC=CC=1>O>[O:5]1[C:4]2[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=2[CH:1]=[C:6]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)COc1ccccc1C=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2ccccc2o1
Temperature: 111 °C

Procedure:
The crude product 2 was placed into a 5-liter 3-necked round-bottomed flask equipped with a mechanical stirrer and a water trap. Toluene (1,900 ml) was added and the solution heated at reflux temperature (111° C.) until all water had been removed. Diazabicyclounde-7-ene (DBU) (65 g) was then added and the mixture was stirred at 111° C., without the water trap, until the starting material was no longer present, i.e., was not detectable by TLC monitoring. Most of the solvent (90%) was then distilled off. The residue was cooled to 25° C., and ethyl acetate (1,000 ml) was added. The mixture was transferred to a separatory funnel and the organic solution washed with 2N HCl (2×1,000 ml), then with water (1,000 ml). Drying was done over magnesium sulfate. The crude product (326.56 g) was a dark oil and was used directly in the next step. A small sample was purified for the purpose of structure elucidation: the crude material (2 g) was dissolved in ethyl ether and washed with 1N KOH. Drying was done over magnesium sulfate, the material was filtered, and the solvent evaporated. The oily residue was crystallized from isopropanol. The melting range is 53.8°-54° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:5]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:6][C@H:7]([CH2:11][NH:12][C:13](=[O:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH:8]([CH3:10])[CH3:9])[OH:4].C(=O)([O-])[O-].[Na+].[Na+].[C:41](Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43].O>C(OCC)(=O)C>[CH3:43][C:42]([CH3:45])([CH3:44])[C:41]([NH:1][CH2:2][C@@H:3]([C@@H:5]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:6][C@H:7]([CH2:11][NH:12][C:13](=[O:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH:8]([CH3:9])[CH3:10])[OH:4])=[O:46]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN)C(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNC(=O)C(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The stirred solution of 0.030 g of tert-butyl (1(S)-(2-amino-1(S)-hydroxyethyl)-3(S)-{[2-(3-methoxypropoxy)benzoylamino]methyl}4-methylpentyl)carbamate in 0.60 ml of ethyl acetate is admixed successively with 0.60 ml of 2M sodium carbonate solution and 0.012 ml of pivaloyl chloride and stirred at room temperature over 1 hour. The reaction solution is admixed with water and extracted with ethyl acetate (2×). The combined organic phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a colourless oil. Rf=0.45 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=4.71 (gradient I)