Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[CH:18]3[CH2:19][CH:16]([CH2:17]3)[C:8]3[N:9]([CH3:15])[C:10]([C:12]([NH2:14])=[O:13])=[N:11][C:7]=3[C:6]=2[CH:20]=1.[CH3:21][C:22]([OH:26])([C:24]#[CH:25])[CH3:23]>N1CCCCC1.[Cu]I.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>[OH:26][C:22]([CH3:23])([CH3:21])[C:24]#[C:25][C:2]1[CH:3]=[CH:4][C:5]2[CH:18]3[CH2:19][CH:16]([CH2:17]3)[C:8]3[N:9]([CH3:15])[C:10]([C:12]([NH2:14])=[O:13])=[N:11][C:7]=3[C:6]=2[CH:20]=1
Reactant: Cn1c(C(N)=O)nc2c1C1CC(C1)c1ccc(I)cc1-2
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cn1c(C(N)=O)nc2c1C1CC(C1)c1ccc(C#CC(C)(C)O)cc1-2
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 4.2 %

Procedure:
To a solution 9-iodo-3-methyl-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide (100 mg, 0.26 mmol) in piperidine (2 mL) was introduced 2-methyl-3-butyn-2-ol (89 mg, 1.05 mmol) and copper(I) iodide (2.5 mg, 0.01 mmol). The solution was de-oxygenated by nitrogen bubbling for five minutes, then tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) added and bubbling continued for a further two minutes. The pressure tube was closed under an atmosphere of nitrogen and the reaction mixture warmed to 40° C. for 2.5 hr. After evaporation of the reaction mixture in vacuo, the residue was suspended in ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate (6 mL), water (2×10 mL) and brine (5 mL). The organic extract was dried over sodium sulfate, filtered, and the filtrate adsorbed onto silica gel in vacuo. Purification of the dry-loaded material by silica gel flash column chromatography (eluent: heptane/ethyl acetate gradient) was followed by suspension of the product in acetonitrile (0.6 mL). The solid was collected by filtration to furnish the title compound (4.5 mg, 0.011 mmol, 4%) as a colorless solid: 1H NMR (500 MHz, CDCl3) delta 1.65 (s, 6H), 1.71 (d, J=9.46 Hz, 2H), 2.15 (br. s., 1H), 2.91-3.00 (m, 2H), 3.48 (td, J=7.41, 3.78 Hz, 1H), 3.65 (td, J=8.04, 3.47 Hz, 1H), 4.01 (s, 3H), 5.37 (br. s., 1H), 7.03 (d, J=7.57 Hz, 1H), 7.14 (dd, J=7.72, 1.42 Hz, 1H), 7.49 (br. s., 1H), 8.47 (br. s., 1H); LC-MS: m/z=+336.10 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[CH:5][C:4]=1[NH:24][CH3:25])#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][NH:24][C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CNc1cc(CCN2CCN(C(=O)OC(C)(C)C)CC2)ccc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc(CCN2CCNCC2)ccc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 4-{2-[4-cyano-3-(methylamino)phenyl]ethyl}piperazine-1-carboxylate (18 mg, 0.05 mmol) in 5 mL of DCM was added TFA (3 mL), and then stirred at room temperature for 2 hours. The solvents were removed off under vacuum to afford crude 2-(methylamino)-4-(2-piperazin-1-ylethyl)benzonitrile.
Reaction SMILES: [CH2:1]=[C:2]([CH2:12][CH3:13])[CH2:3][CH2:4][C:5]1([OH:11])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(OO)(=[O:16])C>C(Cl)Cl>[CH2:12]([C:2]1([CH2:1][OH:16])[CH2:3][CH2:4][C:5]2([CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)[O:11]1)[CH3:13]
Reactant: C=C(CC)CCC1(O)CCOCC1
Reactant: CC(=O)OO
Solvent: ClCCl
Product: CCC1(CO)CCC2(CCOCC2)O1
Reaction time: 4 h
Yield: 69.2 %

Procedure:
To a stirred solution of 16.52 g of tetrahydro-4-(3-methylenepentyl)-2H-pyran-4-ol in 100 ml of methylene chloride under nitrogen was added portionwise 15.32 g of peracetic acid (with 0.40 g of anhydrous sodium acetate added). The reaction mixture was refluxed for 1 hour, allowed to set for 4 hours, diluted with 150 ml of methylene chloride, washed successively with water, twice with 25% potassium carbonate, and saturated sodium chloride, dried and filtered. The resulting solution was stripped to yield 12.42 g of the desired product as a pale yellow liquid.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]1)[OH:2].[CH2:11]([N:13]=[C:14]=[O:15])[CH3:12]>>[CH2:11]([NH:13][C:14]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]1)=[O:15])[CH3:12]
Reactant: CCN=C=O
Reactant: CC1=NC(=NO)SC1(C)C
Product: CCNC(=O)ON=C1N=C(C)C(C)(C)S1

Procedure:
2-oxo-4,5,5-trimethyl-3-thiazoline-oxime was reacted with ethyl isocyanate as described in Example 4 to yield 2-oxo-4,5,5-trimethyl-3-thiazoline-O-(ethylcarbamoyl)-oxime, m.p. 84°-86° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12](O)=[O:13])=[CH:4][CH:3]=1.[C:16]([O-])(=[O:18])[CH3:17].[Na+].C(OC(=O)C)(=O)C>O>[C:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:15])[CH:10]=[CH:11][C:12]2=[O:13])=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: O=C(O)/C=C\C(=O)Nc1ccc(O)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Oc1ccc(N2C(=O)C=CC2=O)cc1
Reaction time: 2 h
Yield: 53 %

Procedure:
To a three-neck 1 liter reaction vessel equipped with a condenser, a teflon stirring rod and a thermometer, 97 g (0.49 moles) of N-(4-hydroxyphenyl)maleamic acid, 27.7 g (0.38 moles) of sodium acetate and 400 g of acetic anhydride are added and then heated by using silicone oil. When the reaction solution reaches 70° C. for 2 hours with stirring, the solution is poured into a large amount of distilled water and a great amount of precipitates are formed. The precipitate is taken by filtration and washed several times with distilled water to remove acetic acid, followed by recrystallization from ethanol to give the titled compound. Yield 53%. B.P. 155°-158° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:23](=[O:25])[CH3:24])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C(C)(C)Oc1cccc(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1cccc(NC(C)=O)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
To a solution of 2-(3-Amino-phenoxy)-2-methyl-propionic acid ethyl ester (0.54 g, 2.42 mmol) in DCM (5 ml) at 0° C. was added pyridine (0.23 ml, 2.9 mmol). The reaction mixture was cooled to 0° C. and a solution of acetyl chloride (0.21 ml, 2.9 mmol) in DCM (4 ml) was added drop wise over 5 min. The reaction mixture was stirred at r.t. for 18 hrs, quenched with water (10 ml) and extracted in DCM (2×20 ml). The organic layer was dried over Na2SO4 and concentrated to afford the crude oil (0.64 g) which was used for the next step without purification.
Reaction SMILES: [CH3:1][C:2]#[N:3].[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])[CH3:5].[NH4+].[Cl-]>C1COCC1>[OH:6][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:5])[CH2:1][C:2]#[N:3]
Reactant: CC(=O)c1ccccc1
Reactant: CC#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)(CC#N)c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
Dry THF was cooled to −20° C. and 2.5 M n-Bull (100 mL, 0.25 mol) was added. A solution of CH3CN (11.25 g, 0.25 mol) in dry THF was added dropwise over 10 min. Then the mixture was stirred for 1 h at −20° C. and a solution of acetophenone (30 g, 0.25 mol) in THF was added dropwise over 10 min. The mixture was stirred at −20° C. for 15 min and warmed to rt over 15 min. Aq NH4Cl was added to quench the reaction. The solution was extract with EtOAc. The organic layer washed with brine, dried over anhydrous Na2SO4 and concentrated to give 3-hydroxy-3-phenylbutanenitrile (30 g, yield 75%). 1H NMR (CDCl3, 400 MHZ): δ=1.76 (s, 3H), 2.83 (s, 2H), 7.34 (m, 1H), 7.41 (m, 2H), 7.5 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([CH2:32][OH:33])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[CH2:36](I)[CH3:37].C(O)C>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([CH2:32][O:33][CH2:36][CH3:37])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1ccc(CC(=O)NC(CO)c2ccccc2N2CCCCC2)cc1OCC
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1
Reaction time: 1 h

Procedure:
Ethyl 2-ethoxy-4-[N-(α-hydroxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate (0.64 g, 1.4 mmol) is added with stirring at ambient temperature to sodium hydride (0.061 g, 1.4 mmol) (55% in oil) in absolute tetrahydrofuran (6.4 ml). The mixture is stirred for 1 hour, then ethyl iodide (0.113 ml, 1.4 mmol) is added and the mixture is stirred for a further 16 hours at ambient temperature. Then ethanol (2 ml) is added and the mixture is evaporated down in vacuo. The evaporation residue is partitioned between chloroform and water. The organic phase is washed twice with water, dried, filtered and concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/acetone=17/3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([OH:17])=O)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1NC=CN=1)(C1NC=CN=1)=O>C1COCC1>[O:17]=[C:15]1[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11][C:12](=[O:14])[NH:13]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(=O)NC1=O
Yield: 44.7 %

Procedure:
2,6-Dioxo-3-(t-butoxycarbonylamino)piperidine (3) was prepared and isolated as follows. A solution of N-(t-butoxycarbonyl)-L-glutamine (4.92 g) and carbonyl diimidazole (1.70 g) in THF (100 mL) was refluxed for 9 h. The solvent was removed and the crude product was recrystallized from hot EtOAc to give compound 3 (2.04 g, 45%) as white crystals: mp 214-215° C.; 1H NMR (DMSO-d6) δ 4.22 (dd, J=6.2 Hz, J=11.0 Hz, 1H), 2.77-2.65 (m, 1H), 2.45 (m, 1H), 1.96-1.87 (m, 2H), 1.40 (s, 9H); MS (CI/CH4) 227 [M-1]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1([CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].Cl>CN(C=O)C.C(N(CC)CC)C.ClCCl>[CH:7]1([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:19])=[CH:20][CH:21]=2)[CH2:8][CH2:9]1
Reactant: O=C(O)c1ccc(OCCC2CC2)cc1
Reactant: NCC(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 96.2 %

Procedure:
Oxalyl chloride (8.64 mL, 99.0 mmol) and one drop of DMF were added to a solution of dichloromethane (30 mL) containing 4-(2-cyclopropylethoxy)benzoic acid (9.28 g, 45.0 mmol) prepared in Example 9 (9a) under ice-cooling. The mixture was stirred at room temperature for 1.75 hours, and the solvent was evaporated. Then, the resulting residue was suspended in THF (3 mL). This suspension added dropwise to a 50% THF aqueous solution (120 mL) containing glycine (4.41 g, 58.7 mmol) and triethylamine (15.7 mL, 112 nmol) under ice-cooling. The mixture was stirred at room temperature for 1.5 hours, and then 10% hydrochloric acid (40 mL) was added thereto under ice-cooling. The produced precipitate was collected by filtration, washed with water, and dried by heating under reduced pressure to give 11.4 g of the title compound (powder, yield: 97%).
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]4[O:22][CH:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8]>C(O)(=O)C>[CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]4[O:22][C@H:6]5[C:7]([CH2:9][CH2:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8]
Reactant: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Solvent: CC(=O)O
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Reaction time: 0.08 h
Yield: 70 %

Procedure:
14-Hydroxycodeinone (4.98 g) and acetic acid (155 g) were added to a Parr shaker equipped with hydrogen inlet and outlet connectors. The mixture was shaken for about 5 minutes to completely dissolve the 14-hydroxycodeinone at ambient temperature. The system was then evacuated and the Parr shaker was filled with nitrogen. In one portion, under the nitrogen atmosphere, 10% Pd/C (50% water wet, 4.0 g) was added. The system was then evacuated, and was filled with hydrogen gas to a pressure of about 38 psi. The hydrogen inlet from the supply tank was then closed and the mixture was shaken at an initial pressure of 38 psi for about 3 hours (at ambient temperature). After 3 hours of shaking, the system was evacuated and filled with nitrogen. The contents were filtered over a hyflo-supercel filtering pad (3 g, wetted with water). The Parr bottle and wet cake were then rinsed with acetic acid (2×21 g). The filtrate was concentrated in vacuo to dryness at temperature NMT 50° C. The residue was then dissolved with de-ionized water (50 g), and the pH adjusted to about 11.0 to 12.0 using 20% aqueous KOH solution and concentrated ammonium hydroxide (4 g). The mixture was then extracted with ethyl acetate (4×135 g), and the combined organic layers concentrated in vacuo to dryness. A yield of 3.51 to 4.26 g of crude oxycodone with HPLC purity of over 85A % (70.0 to 85.0% yield) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:30][C@H:31]1[C@H:34]([O:35][C:36](=[O:38])[CH3:37])[NH:33][C:32]1=[O:39]>ClCCl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([NH:30][C@H:31]1[C@H:34]([O:35][C:36](=[O:38])[CH3:37])[NH:33][C:32]1=[O:39])=[O:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1N
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: -2.5 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-alanine (1.604 g, 7.188 mmole) and triethylamine (799 mg, 7.91 mmole) in dichloromethane (30 ml), ethyl chloroformate (738 mg, 6.83 mmole) was added at -15° C. The reaction mixture was stirred at -10 to 5° C. for 1.5 hrs. Then a precooled (ca. -15° C.) solution of (3S,4S)-3-amino-4-acetoxy-azetidin-2-one in ethyl acetate (see above) was added at -15° C. and the resulting mixture was stirred at 0° C. to room temperature for 2 hrs. After removal of solvent, the residue was dissolved in ethyl acetate, washed with cold saturated NaHCO3 solution, water, brine and dried over sodium sulfate. After removal of solvent, the residue was recrystallized from dichloromethane and (3S,4S)-3-(N-benzyloxycarbonyl-L-alanyl) amino-4-acetoxy-azetidin-2-one was obtained (1.36 g, 54% yield).
Reaction SMILES: [C:1]1([C:9]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[CH:14][CH:13]=2)=O)[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.O1CCOCC1.Cl>[Zn].C1(C)C=CC=CC=1>[CH3:17][O:16][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:9][C:1]2[CH:2]=[CH:3][C:4]([O:5][CH3:6])=[CH:7][CH:8]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Zn]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1ccc(CCc2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 60 g of desoxyanisoin, 120 g of amalgamated zinc, 200 ml of dioxane, 100 ml of toluene and 200 ml of concentrated hydrochloric acid was refluxed for 24 hours. Another 50 ml of concentrated hydrochloric acid was added after the first 6 hours. The reaction mixture was cooled to room temperature and the organic layer was separated and mixed with 300 ml of ethyl acetate. It was washed with water, dried over anhydrous magnesium sulfate and concentrated to give 26 g of white waxy solid.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([Cl:13])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)nc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(F)nc1
Temperature: 80 °C

Procedure:
In a 100-mL round-bottom flask was placed a solution of 6-fluoropyridine-3-carboxylic acid (5.0 g, 35.4 mmol) in thionyl chloride (20 mL). The resulting solution was heated at 80° C. for 2 hours and concentrated under vacuum to give the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1.Br[CH2:17][C@@H:18]([N:20]1[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]1[CH3:26])[CH3:19]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:17][C@@H:18]([N:20]2[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]2[CH3:26])[CH3:19])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1
Reactant: Cc1ccc(C)n1[C@@H](C)CBr
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Product: Cc1cc(CC[C@H](C)n2c(C)ccc2C)nc(-n2c(C)ccc2C)c1

Procedure:
By analogy to Example 71, Step A, the anion of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine was alkylated with (S)-1-(2-bromo-1-methylethyl)-2,5-dimethylpyrrole to give (S)-4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-(3-(2,5-dimethylpyrrol-1-yl)-3-methylpropyl)pyridine.
Reaction SMILES: FC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2)=C(N)C=1.Cl.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:26](O)=O.[F:41][C:42]1[CH:43]=[CH:44][C:45]([CH:66]2[CH2:75][CH2:74][C:73]3[C:68](=[CH:69][CH:70]=[C:71]([O:76][CH3:77])[CH:72]=3)[CH2:67]2)=[C:46]([NH:48][CH2:49][C:50]2C=CC(OCCN3CCCCC3)=C(F)C=2)[CH:47]=1>>[CH2:49]([N:48]([C:46]1[CH:47]=[C:42]([F:41])[CH:43]=[CH:44][C:45]=1[CH:66]1[CH2:75][CH2:74][C:73]2[C:68](=[CH:69][CH:70]=[C:71]([O:76][CH3:77])[CH:72]=2)[CH2:67]1)[CH2:26][C:25]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:23]([F:22])[CH:24]=1)[CH3:50]
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Reactant: COc1ccc2c(c1)CCC(c1ccc(F)cc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Agent: COc1ccc2c(c1)CCC(c1ccc(F)cc1N)C2
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(F)ccc1C1CCc2cc(OC)ccc2C1

Procedure:
Synthesized from 5-fluoro-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 282, [5-fluoro-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl][3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amine (376 mg) was used according to an analogous synthetic method to Example 36 to provide ethyl[5-fluoro-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl][3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amine (317 mg). This compound (315 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (265 mg).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][C:17]2[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[N:18]=2)=[CH:8][CH:7]=1>ClCCl.O>[CH3:24][O:23][C:21]1[CH:20]=[C:19]([O:25][CH3:26])[N:18]=[C:17]([O:16][C:9]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[N:11][C:6]([N:5]=[C:1]=[S:2])=[CH:7][CH:8]=2)[N:22]=1
Reactant: COC(=O)c1nc(N)ccc1Oc1nc(OC)cc(OC)n1
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1nc(N=C=S)ccc1Oc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
0.82 g (7.15 mmol) of thiophosgene was dropwise added at room temperature to a solution of 2 g (6.5 mmol) of methyl 6-amino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate in 70 ml of dichloromethane and 50 ml of water. The mixture was stirred at room temperature for two hours. After completion of the reaction, the dichloromethane layer was separated and washed with water. Then, the organic layer was dried and concentrated. The obtained residue was recrystallized from a mixture of dichloromethane and diisopropyl ether to obtain the desired product as slightly yellow transparent crystals.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[OH:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[N:26]1[CH:27]=[CH:28][C:23]([O:22][C:2]2[N:6]3[CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=4)[CH:9]=[CH:10][C:5]3=[N:4][N:3]=2)=[CH:24][CH:25]=1
Reactant: Oc1ccncc1
Reactant: FC(F)(F)Oc1ccc(-c2ccc3nnc(Cl)n3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: FC(F)(F)Oc1ccc(-c2ccc3nnc(Oc4ccncc4)n3c2)cc1
Temperature: 150 °C
Reaction time: 6 h
Yield: 23.6 %

Procedure:
In a 15 mL round-bottom flask 3-chloro-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridine (100 mg), 4-hydroxypyridine (60 mg), and potassium carbonate (88 mg) were suspended in DMA (3 mL). The reaction mixture stirred at 150° C. for 6 h, concentrated, the residue subjected to gradient chromatography (MeOH/dichloromethane) to produce 3-(pyridin-4-yloxy)-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridine as amber oil (28 mg, 24%).
Reaction SMILES: [C:1]([O:5][P:6]([CH:13]([OH:27])[C:14]1[CH:26]=[CH:25][C:17]([CH2:18][CH:19]([C:21]([O:23][CH3:24])=[O:22])[NH2:20])=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>C1COCC1.CCOCC>[C:9]([O:8][P:6]([CH:13]([OH:27])[C:14]1[CH:26]=[CH:25][C:17]([CH2:18][CH:19]([C:21]([O:23][CH3:24])=[O:22])[NH:20][C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])=[CH:16][CH:15]=1)([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:10])([CH3:12])[CH3:11]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C(N)Cc1ccc(C(O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)C(Cc1ccc(C(O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a solution of 8 (876 mg, 2.18 mmol) in THF (22 mL) at 0° C. was added NEt3 (1.22 mL, 8.74 mmol), followed by benzyl chloroformate (0.34 mL, 2.40 mmol) dropwise via syringe. The reaction was stirred at 0° C. for 0.5 hours, then diluted with Et2O (20 mL) and quenched by dropwise addition of brine (1 mL). Additional brine (20 mL) was added and the organic phase separated and combined with an Et2O extract (2×20 mL) of the residual brine. The combined Et2O was dried (MgSO4), filtered and solvent removed by rotary evaporation under reduced pressure to yield crude 9 (1.03 g, 88%). Silica gel chromatography [EtOAc/hexanes (4:3)] provided pure 9 (621 mg, 53%).