Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[NH2:10][NH2:11]>>[NH:10]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1)[NH2:11]
Reactant: NN
Reactant: COc1cccc(Cl)n1
Product: COc1cccc(NN)n1
Temperature: 23 °C
Yield: 57 %

Procedure:
A mixture of 2-chloro-6-methoxypyridine (compound 12; 2.87 g, 20 mmol) and anhydrous hydrazine (11 mL, excess) was heated under argon on a steam bath overnight. The mixture was allowed to cool to 23° C. and then was extracted with Et2O (10×10 mL). The combined ether extracts were rotary evaporated to afford 1.58 g (57%) of 2-hydrazino-6-methoxypyridine 13 as a yellow liquid that was -95% pure by NMR: 1H NMR (CDCl3) δ 7.38 (pseudo-t, 1), 6.20 (d, J=8.0 Hz, 1), 6.09 (d, J=8.0 Hz, 1), 5.71 (bs, 1, exchanges upon addition of D2O, NH), 3.84 (s, 3, OCH3), 3.1 (bs, 2, exchanges upon addition of D2O, NH2). A solution of this hydrazine (1.58 g, 11 mmol) in 10 mL of absolute ethanol was combined with a solution of 1 (1.8 g, 10 mmol) in 20 mL of absolute ethanol, and the reaction mixture produced a precipitate within several minutes. The mixture was allowed to stand at 23° C. overnight. The solid was collected by suction filtration, washed with a small amount of ethanol, and was dried in vacuo, giving 1.65 g of the methoxy precursor 14. An additional 510 mg of this precipitated from the filtrate after it had been concentrated on a rotary evaporator to a small volume. Combined yield: 2.15 g (76%): mp 161-162° C. (ethanol). 1H NMR ((CD3)2SO) δ 10.45 (s, 1, exchanges upon addition of D10, OH), 8.25 (s, 1, H4), 8.04 (d, J=8.2 Hz, 1), 7.88 (pseudo-t, 1), 7.54 (d, J=8.2 Hz, 1), 7.36 (s, 1), 7.26 (d, J=8.25 Hz, 1), 6.68 (d, J=7.9 Hz, 1), 6.64 (pseudo-t, 1), 3.92 (s, 3, OCH3), 3.90 (s, 3, OCH3). Low-resolution DCI mass spectrum, m/z 284 (100%, MH+). Exposure of this compound to molten C5H5N○HCl for 10 min effected removal of the hydroxy pyridine protecting group only, by 1H NMR. Exposure to BBr3 in CH2Cl2 solution at 23° C. overnight effected the removal of the phenolic protecting group only, giving 15: mp 198-199° C. (ethanol). 1H NMR ((CD3)2SO) δ 8.17 (s, 1, H4), 7.98 (d, 1), 7.88 (pseudo-t, 1), 7.54 (d, 1), 7.12 (m, 3), 6.67 (d, 1), 3.92 (s, 3, OCH3). Low-resolution DCI mass spectrum, m/z 270 (100%, MH+). X-ray quality crystals of 15 were grown from absolute ethanol and a crystal structure determination was made; the crystal structure of the compound is shown in FIG. 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=2)[O:9][N:8]=1.B1([C:25]2[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=2)OCCCO1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:17]=2)[O:9][N:8]=1
Reactant: Brc1cncc(-c2nc(-c3ccccn3)no2)c1
Reactant: c1cncc(B2OCCCO2)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: COCCOC
Product: c1ccc(-c2noc(-c3cncc(-c4cccnc4)c3)n2)nc1
Yield: 34.8 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole (60.6 mg, 0.2 mmole), pyridine-3-boronic acid 1,3-propanediol cyclic ester (48.9 mg, 0.3 mmol) and Pd(PPh3)4 (34.65 mg, 0.03 mmole) in a solution of 2M sodium carbonate (2 mL) and ethylene glycol dimethyl ether (2 mL) was heated overnight at 105° C. Standard work up afforded 21 mg (35%) 3-(2-pyridyl)-5-[5-(3-pyridyl)-pyrid-3-yl]-1,2,4-oxadiazole.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][Cl:17])[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CO>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][Cl:17])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOCCCl)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOCCCl)C(=O)O)cs1
Yield: 85.3 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-(2-chloroethoxyimino)acetate (syn isomer, 30.5 g.), 1N aqueous solution of sodium hydroxide (220 ml.), methanol (110 ml.) and tetrahydrofuran (140 ml.) were treated in a similar manner to that of Example F-(4) to give 2-(2-aminothiazol-4-yl)-2-(2-chloroethoxyimino)-acetic acid (syn isomer, 23.4 g.), mp 201° C. (dec.).
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].N1C=CC=CC=1.[O:11]=[C:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=2)[NH:13]1>>[CH:2]([O:4][S:21]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:11])[CH2:20]2)(=[O:22])=[O:23])([CH3:3])[CH3:1]
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: CC(C)O
Solvent: c1ccncc1
Product: CC(C)OS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-propanol (1.8 mL, 23.8 mmol) and pyridine (7.0 mL, 86.4 mmol) at 0° C. was added 2-oxo-2,3-dihydro-1H-indole-5-sulfonyl chloride (5.0 g, 21.6 mmol) in one portion. The resulting suspension was stirred at 0° C. for 45 mins and then warmed RT for 1 h. The reaction mixture was partitioned between DCM and 1M HCl. The organic layer was washed successively with 50 mL of 1M HCl, water, and brine. The organic layers were dried over MgSO4 and concentrated to produce an orange solid. Yield: 4.06 g (74%). 1H-NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1H), 7.74 (dd, J=8.2, 1.9 Hz, 1H), 7.70 (s, 1H), 7.01 (d, J=8.2 Hz, 1H), 4.68-4.58 (m, 1H), 3.75-3.69 (m, 2H), 1.19 (d, J=6.2 Hz, 6H). LC/MS (10-99%): M/Z: M+(obs) 256.1; tR=2.10 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][S-:10].[Na+].O>C(OCC)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:10][CH3:9])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1ccc(Br)cn1
Temperature: 160 °C
Yield: 89 %

Procedure:
2,5-Dibromo-pyridine (3.0 g, 12.7 mmol) and sodium thiomethoxide (0.84 g, 12 mmol) were dissolved in 18 ml anhydrous N N-dimethylformamide. The mixture was heated at 160° C. under nitrogen for 6 hrs. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The aqueous layer was extracted with ethyl acetate several times. The combined extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0→6% EtOAC/Hexane) to give 5-Bromo-2-methylsulfanyl-pyridine as a white solid (2.18 g, 84% yield). 1H-NMR (400 MHz, CDCl3): δ 2.55 (s, 3H), 7.09 (dd, 1H, J=0.7, J=8.6), 7.59 (dd, 1H, J=2.4, J=8.6), 8.50 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:11][CH:12]([C:19](=[O:39])[N:20]([CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=CC=C(C(OO)=[O:48])C=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:11][CH:12]([C:19](=[O:39])[N:20]([CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])(=[O:48])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CCC(CS(=O)c1ccc(Cl)c(Cl)c1)C(=O)N(CCCc1ccccc1)CCCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CCC(CS(=O)(=O)c1ccc(Cl)c(Cl)c1)C(=O)N(CCCc1ccccc1)CCCc1ccccc1
Temperature: 0 °C
Yield: 88.5 %

Procedure:
Into a solution of methyl 5-(3,4-dichlorophenylsulfinyl)-4-[N,N-bis(3-phenylpropyl)carbamoyl]pentanoate (220 mg) in dry dichloromethane (20 ml) were added portions of m-chloroperbenzoic acid (80%, 120 mg) with stirring at 0° C. After stirring at room temperature for 4 hours, sodium sulfite was added. The reaction mixture was washed with a saturated sodium bicarbonate solution and water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica by eluting with chloroform/ethanol (50:1) to give 200 mg of methyl 5-(3,4-dichlorophenylsulfonyl)-4-[N,N-bis(3-phenylpropyl)carbamoyl]pentanoate as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:14])=[N:12][C:11]([C:15]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[O:17][N:16]=3)=[N:10]2)[CH:5]=[CH:4][N:3]=1.[CH3:31][S:32]([CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])=[O:33]>CC(O)(C)C>[CH3:14][C:13]1[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:38]3[CH2:39][CH2:40][CH:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:36][CH2:37]3)[CH:7]=2)[N:10]=[C:11]([C:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[O:17][N:16]=2)[N:12]=1
Reactant: CS(=O)(=O)C1CCNCC1
Reactant: Cc1nc(-c2cc(-c3ccc(OC(F)(F)F)cc3)on2)nn1Cc1ccnc(Cl)c1
Solvent: CC(C)(C)O
Product: Cc1nc(-c2cc(-c3ccc(OC(F)(F)F)cc3)on2)nn1Cc1ccnc(N2CCC(S(C)(=O)=O)CC2)c1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-5-(4-(trifluoromethoxy)phenyl)isoxazole (50 mg, 0.12 mmol) in t-BuOH (0.5 mL), was added 4-(methylsulfonyl)piperidine (75 mg, 0.46 mmol). The mixture was stirred at 140° C. for 16 h, then cooled to RT and purified by prep-HPLC (Mobile phase: A=10 mM ammonium bicarbonate/H2O, B=MeCN; Gradient: B=60%-95% in 18 min; Column: XBridge C18, 5 um, 30 mm×150 mm) to give the title compound as a white solid; MS (ES+) C25H25F3N6O4S requires: 562. found: 563 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J=5.0 Hz, 1H), 7.88 (d, J=8.7 Hz, 2H), 7.34 (d, J=8.3 Hz, 2H), 7.03 (s, 1H), 6.43 (m, 2H), 5.30 (s, 2H), 4.47 (bd, J=13.4 Hz, 2H), 3.07 (m, 1H), 2.97-2.81 (m, 5H), 2.50 (s, 3H), 2.20 (bd, J=12.4 Hz, 2H), 1.86-1.79 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].C([Li])CCC.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>O1CCCC1.CCCCCC>[OH:23][CH:22]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6])[C:21]1[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CNC(=O)c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(C(O)c2ccc(F)cc2)c1
Reaction time: 0.25 h
Yield: 38 %

Procedure:
A solution of 3-bromo-N-methylbenzamide (3.48 g, 16.25 mmol) in dry tetrahydrofuran (100 ml) was cooled to −78° C. and treated dropwise over 10 min. with 13 ml (32.5 mmol) of a 2.5 M solution of n-butyllithium in hexane. After 15 min. at −78° C., a solution of 4-fluorobenzaldehyde (2.5 g, 20.1 mmol) in tetrahydrofuran (10 ml) was added dropwise over 10 min. and the resulting mixture was stirred for another 45 min at the same temperature. The temperature was then allowed to reach −20° C. and the mixture was quenched by the addition of saturated ammonium chloride. The reaction mixture was then extracted with ethyl acetate and the organic layer was washed with 0.1N hydrochloric acid, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and crystallization of the residue from ethyl acetate gave 1.60 g (38%) of the title compound as a white solid: mp: 138-139° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.0 and 3.01 (3H, 2 s, NCH3), 5.88 (1H, s, CH), 6.19 (1H, broad, NH), 7.03 (2H, m, aromatics), 7.36 (2H, m, aromatics), 7.41 (1H, t, J=7.6 Hz, aromatic), 7.49 (1H, d, J=7.6 Hz, aromatic), 7.66 (1H, d, J=7.6 Hz, aromatic), 7.79 (1H, s, aromatic). Anal. Calcd for C15H14FNO2: C, 69.49; H, 5.44; N, 5.40. Found: C, 69.41; H, 5.41; N, 5.63.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:7]=1[CH2:8][NH:9][C:10]([C@:12]1([CH:18]([CH3:20])[CH3:19])[CH2:16][C:15](=[O:17])[CH:14]=[CH:13]1)=[O:11])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][C:7]=1[CH2:8][NH:9][C:10]([C@@:12]1([CH:18]([CH3:20])[CH3:19])[CH2:13][CH2:14][C:15](=[O:17])[CH2:16]1)=[O:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)[C@]1(C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)C=CC(=O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@]1(C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)CCC(=O)C1

Procedure:
(1S)—N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]-1-isopropyl-4-oxocyclopent-2-ene-1-carboxamide (32 g, 80.6 mmol) was dissolved in MeOH and was hydrogenated for 18 hr with a hydrogen balloon in the presence of a catalytic amount of 10% palladium on carbon. The palladium was filtered through a celite plug. The filtrate was evaporated to dryness to give (1S)—N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]-1-isopropyl-3-oxocyclopentanecarboxamide as a yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH:35]1(O)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O.O1CCOCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[N:32]=[CH:31][C:30]([O:33][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:29][N:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OC1CCCCC1
Reactant: CCCCc1nc(C)n(-c2ncc(O)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCCCc1nc(C)n(-c2ncc(OC3CCCCC3)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
Process 1: 4′-{[4-butyl-1-(5-hydroxypyrimidin-2-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (27 mg, 0.060 mmol), cyclohexanol (12 mg, 0.120 mmol) and triphenylphosphine (32 mg, 0.122 mmol) were dried for 3 hrs in vacuo, purged with argon, added 1,4-dioxane (1 mL) and diethyl azodicarboxylic acid (2.2 mol/L toluene solution, 70 μL, 0.154 mmol), and then stirred at 80° C. for 3 hrs. The reaction mixture was added water and extracted with ethyl acetate. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residues were subjected to silica gel column chromatography (chloroform:methanol=10:1) to obtain 4′-{{4-butyl-1-[5-(cyclohexyloxy)pyrimidin-2-yl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl}biphenyl-2-carbonitrile (18 mg, 56%).
Reaction SMILES: [N+:1]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:10][C:9]1[N:8]=[C:6]([C:5]2[CH:30]=[CH:31][CH:32]=[CH:33][C:4]=2[N+:1]([O-:3])=[O:2])[N:16]2[C:11]=1[CH:12]=[N:13][C:14]([NH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[N:15]2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3[N+](=O)[O-])nn2)cc(OC)c1OC
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccccc4[N+](=O)[O-])n3n2)cc(OC)c1OC
Yield: 0.7 %

Procedure:
In a similar manner as described for Example 1, 2-nitro-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 10) (0.50 g, 1.5 mmol) in 1,2-dichloroethane (20 mL) and phosphorus oxychloride (1.1 mL, 12 mmol) gave 5-methyl-7-(2-nitrophenyl)-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.0046 g) as a yellow solid. 1H NMR (CDCl3): δ8.82 (s, 1H), 8.09 (dd, J=8.0, 1.1 Hz, 1H), 7.90 (dd, J=7.7, 1.3 Hz, 1H), 7.76 (ddd, J=7.7, 7.5, 1.3 Hz, 1H), 7.64 (ddd, J=8.2, 7.5, 1.5 Hz, 1H), 6.89 (s, 1H), 6.67 (s, 2H), 3.79 (s, 3H), 3.66 (s, 6H), 2.63 (s, 3H). MS m/z 437 (M+1).
Reaction SMILES: [NH:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]=O)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19])[CH3:16].O1CCCC1>O>[NH:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]=[CH:20][C:18]([O:17][CH2:15][CH3:16])=[O:19])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1csc(Nc2ccccc2)n1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=Cc1csc(Nc2ccccc2)n1
Temperature: 60 °C

Procedure:
A mixture comprising 3.5 g of 2-anilinothiazole-4-carbaldehyde, 6.5 g of (ethoxycarbonylmethylene)triphenylphosphorane and 35 ml of tetrahydrofuran was heated at 60 ° C. for 2 hours. The reaction mixture was poured into water and extracted with benzene. The benzene extract was dried over anhydrous sodium sulfate, and the solvent was evaporated off under reduced pressure, giving an oil. This oil was purified by silica gel column chromatography. using as eluent a 9:1 mixture of benzene and ethyl acetate, giving the desired compound as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][C:10]2[CH:23]=[CH:22][C:13]([CH2:14][NH:15]C(=O)C(F)(F)F)=[CH:12][CH:11]=2)[N:3]=1.CN>CO>[NH2:15][CH2:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][O:8][C:4]2[N:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]=2)=[CH:23][CH:22]=1
Reactant: Nc1ccnc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Agent: CN
Solvent: CO
Product: NCc1ccc(COc2nccc(N)n2)cc1
Temperature: 25 °C

Procedure:
150 mg (0.46 mmol) of N-(4-((4-Aminopyrimidin-2-yloxy)methyl)benzyl)-2,2,2-trifluoro-acetamide (1) is dissolved in 2 mL methanol and treated with 5 mL methylamine (33% in ethanol). The reaction mixture is stirred at room temperature over night and all volatiles are removed in vacuo. The product is used without further purification in the next step. ESI-MS m/z 231 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][OH:11].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>O1CCCC1>[CH2:15]([O:11][CH2:10][C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH2:5][CH2:4][F:3])[CH:8]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1cccc(OCCF)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FCCOc1cccc(COCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
Sodium hydride (0.24 g; 60% in oil) was suspended in 30 ml of dry tetrahydrofuran, and then 1.0 g of 3-(2-fluoroethoxy)benzyl alcohol was added. The mixture was stirred at 50° to 60° C. for 30 minutes, and 1.7 g of benzyl bromide was added. The mixture was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with toluene. The toluene layer was washed with water and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure. The resulting crude ether was purified by silica gel (50 g) column chromatography (developing solvent: toluene) to give 1.2 g of 3-(2-fluoroethoxy)benzyl benzyl ether.
Reaction SMILES: C([NH:8][C:9]([CH3:22])([CH3:21])[CH2:10][O:11][CH:12]1[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][C:13]1([CH3:20])[CH3:19])(OC(C)(C)C)=O.O.[OH-].[K+]>FC(F)(F)C(O)=O>[NH2:8][C:9]([CH3:22])([CH3:21])[CH2:10][O:11][CH:12]1[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][C:13]1([CH3:20])[CH3:19]
Reactant: CC(C)(COC1C(C)(C)CCC1(C)C)NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(N)COC1C(C)(C)CCC1(C)C
Reaction time: 8 h

Procedure:
N-Boc-1-(2-amino-2-methylpropoxy)-2,2,5,5-tetramethyl cyclopentane is dissolved in trifluoroacetic acid and stirred overnight. The solution is poured into 0 water and neutralized with 20% aqueous KOH. The mixture is extracted with ethyl acetate, dried over MgSO4, filtered and evaporated to give 1-(2-amino-2-methylpropoxy)-2,2,5,5-tetramethylcyclopentane.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([C:19]3[C:20]([Cl:25])=[N:21][CH:22]=[CH:23][CH:24]=3)=[O:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(OC(=O)C)C.Cl>C(#N)C>[O:2]=[C:3]1[C:8]([CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][C:17]([C:19]3[C:20]([Cl:25])=[N:21][CH:22]=[CH:23][CH:24]=3)=[O:18])[CH2:14][CH2:15]2)=[CH:7][CH:6]=[CH:5][NH:4]1
Reactant: COc1ncccc1CN1CCC(CC(=O)c2cccnc2Cl)CC1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(CC1CCN(Cc2ccc[nH]c2=O)CC1)c1cccnc1Cl
Yield: 47.9 %

Procedure:
In acetonitrile (4 ml) were dissolved 100 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-chloro-3-pyridyl)-2-oxoethyl)piperidine obtained in Example 62 and 0.35 ml of a 4 M hydrogen chloride ethyl acetate solution, followed by heating under reflux for 1 hour. The solvent was evaporated, and then the residue was dissolved in ethyl acetate and a 1N sodium hydroxide aqueous solution. The organic layer was separated, washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was recrystallized from ethanol, to give 46 mg of the title compound as colorless crystals.
Reaction SMILES: [CH2:1]([C:3]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH3:24])[CH:18]=1)([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:8]=2[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Br[CH2:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([C:3]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[C:19]([CH3:24])[CH:18]=1)([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:8]=2[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc2cc(OC)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(OC)ccc2s1
Yield: 91.6 %

Procedure:
4-[1-Ethyl-1-(5-methoxy-benzo[b]thiophen-2-yl)-propyl]-2-methyl-phenol (7.80 g, 22.9 mmol), 1-bromopinacolone (8.20 g, 45.8 mmol), and K2CO3 (6.32 g, 45.8 mmol) in acetone (100 mL) are reacted analogous to Example 1D to provide the title compound (9.20 g, 92%).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5].[CH3:13][Mg]Br>O1CCCC1>[O:9]1[CH2:8][CH2:7][CH:6]([C:4](=[O:5])[CH3:13])[CH2:11][CH2:10]1
Reactant: CON(C)C(=O)C1CCOCC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)C1CCOCC1
Temperature: -25 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
To a solution of N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide (3.5 g, 20.2 mmol) in tetrahydrofuran (30 mL) was added methylmagnesium bromide (12 mL, 36.4 mmol) at −65° C. under N2. The reaction was stirred at −65-15° C. for 3 hrs. Then the mixture was quenched by water, extracted with ethyl acetate. The organic layer was washed with 1 M HCl, saturated aqueous NaHCO3 and concentrated in vacuo to give 1-(tetrahydro-2H-pyran-4-yl)ethanone (1.9 g, 73.6%) as a yellow oil. 1H NMR (CDCl3, 400 M Hz) δ 4.01-3.97 (m, 2H), 3.45-3.39 (m, 3H), 2.57-2.49 (m, 1H), 1.80-1.71 (m, 2H), 1.70-1.62 (m, 2H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][C@H:19]([C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:24]=4)[C@@H:20]([NH2:22])[CH3:21])=[CH:15][CH:16]=3)[CH:11]=[N:10]2)=[CH:5][CH:4]=1.CN(C)C(N(C)C)=N.[F:41][C:42]([F:49])([F:48])[C:43](OCC)=[O:44]>CO>[F:41][C:42]([F:49])([F:48])[C:43]([NH:22][C@@H:20]([CH3:21])[C@H:19]([O:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:9]([C:6]1[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=1)[N:10]=[CH:11]2)[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)=[O:44]
Reactant: CCOC(=O)C(F)(F)F
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2ccccc2c1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CO
Product: C[C@H](NC(=O)C(F)(F)F)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2ccccc2c1

Procedure:
(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(naphthalen-2-yl)propan-2-amine hydrochloride (50 mg, 0.11 mmol), 1,1,3,3-tetramethylguanidine (100 μl, 0.79 mmol) and Ethyl trifluoroacetate (200 μl, 1.68 mmol) in MeOH (2.5 mL) was stirred at r.t. for 1 h. The reaction mixture was concentrated by evaporation. The residual material was purified by