Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([CH2:7][NH:8][C:9](=[O:22])[CH:10]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[C:15]([OH:20])[C:14]=2[F:21])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].[F:25][C:26]1[CH:34]=[CH:33][C:29](C(O)=O)=[CH:28][CH:27]=1.CCN(CC)CC.CCOC(C)=O>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:22])[CH:10]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[C:15]([O:20][C:29]3[CH:33]=[CH:34][C:26]([F:25])=[CH:27][CH:28]=3)[C:14]=2[F:21])[O:11][CH3:12])=[CH:23][CH:24]=1)#[N:2]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(O)c1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(Oc2ccc(F)cc2)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.8 %

Procedure:
To a solution of (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-3-hydroxy-phenyl)-2-methoxy-acetamide (370 mg) in 1,2-dichloroethane (10 ml) was added copper(II)acetate (222 mg), 4-fluorobenzoic acid (467 mg) and powdered MS4 Å (2 g). Et3N (563 mg) was added and the mixture was stirred 2 days at rt. The mixture was passed over silica gel eluting with AcOEt. CC (AcOEt/Hept 1:3 to 3:1) yielded 203 mg (61%) of (RS)-N-(4-cyano-benzyl)-2-[2,6-difluoro-3-(4-fluoro-phenoxy)-phenyl]-2-methoxy-acetamide. Yellow oil. MS 427.0 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([N:19](C3C=CN=CC=3)C(=O)C)[CH2:11][C@@H:10]2[CH3:29])=[O:8])=[CH:5][CH:4]=1.FC1C=CC(C(Cl)=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH2:19])[CH2:11][C@@H:10]2[CH3:29])=[O:8])=[CH:30][CH:31]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccncc3)C[C@@H]2C)cc1
Agent: O=C(Cl)c1ccc(F)cc1
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N)C[C@@H]2C)cc1

Procedure:
N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-pyridin-4-ylacetamide was made following general procedure G, substituting 4-methoxybenzoyl chloride for 4-fluorobenzoyl chloride. The amine-aryl coupling was performed differently to what is described in procedure G. Therefore (2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-amine (obtained from the hydrogenation step, 356 mg, 1.2 mmol, 1 equ.) was dissolved in ethylene glycol dimethyl ether (4 mL) in a Schlenk tube. To this solution was added sequentially 4-bromopyridine hydrochloride (280 mg, 1.44 mmol, 1.2 equ.), cesium carbonate (940 mg, 2.88 mmol, 2.4 equ.), palladium acetate (32 mg, 0.048 mmol, 0.04 equ.) and 2-(Dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (48 mg, 0.096 mmol, 0.08 equ.). The reaction mixture was flushed with nitrogen and heated to 100° C. in the Schlenk tube for 48 h. Reaction mixture was concentrated to leave a residue which was partitioned between water and ethyl acetate and extracted. The aqueous layer was separated and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give a brown oil. The crude product was purified by silica gel chromatography (methylene chloride/methanol: 99/1 to 90/10 gradient) to provide (2S,4R)-1-(4-methoxybenzoyl)-2-methyl-N-pyridin-4-yl-1,2,3,4-tetrahydroquinolin-4-amine (125 mg, 28%).
Reaction SMILES: [O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[CH:11]\[C:12]1[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[C:15]3[NH:21]C(=O)OC(C)(C)C)=[CH:8][CH:7]=[CH:6][CH:5]=2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:21][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([CH:11]=[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[NH:3][C:2]3=[O:1])[CH:13]=2)[NH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)Nc1n[nH]c2ccc(/C=C3/C(=O)Nc4ccccc43)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1n[nH]c2ccc(C=C3C(=O)Nc4ccccc43)cc12
Reaction time: 3 h

Procedure:
To a solution of (E)-tert-butyl 5-((2-oxoindolin-3-ylidene)methyl)-1H-indazol-3-ylcarbamate (14 mg, 0.04 mmol) in CH2Cl2 (1 mL) was added TFA (0.25 mL) and the reaction was stirred for 3 h. The solution was concentrated to dryness and purified by preparatory HPLC to give the title compound as a 3:2 mixture of E/Z isomers. ESI 277.0 [M+H]+, calcd for [C16H12N4O+H]+ 277.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]([Cl:13])([Cl:12])[Cl:11])[OH:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]([Cl:11])([Cl:12])[Cl:13])[OH:9])=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: Oc1ccc(C(O)C(Cl)(Cl)Cl)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(O)C(Cl)(Cl)Cl)cc1
Yield: 98.5 %

Procedure:
A 0.1 mole quantity of p-hydroxyphenyl trichloromethyl carbinol was dissolved in 0.3 mole of pyridine. To the solution was dropwise added 0.22 mole of acetic acid anhydride with stirring. The resulting mixture was agitated for 2 hours. After completion of the reaction, the pyridine was distilled off at reduced pressure and the residue was washed with 50 ml of water. The crystals were filtered off to obtain ester of p-acetoxyphenyl trichloromethyl carbinol and acetic acid. Yield 98.5%, m.p. 152.5°-153° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([F:31])=[CH:5][C:6]([F:30])=[C:7]([C:9]23[CH2:18][O:17][C@@H:16]([CH2:19][OH:20])[CH2:15][CH:14]2[CH2:13][S:12][C:11]([NH:21]C(=O)C2C=CC=CC=2)=[N:10]3)[CH:8]=1)#[N:2].NC1SC[C@@H]2C[C@H](COCC3C=CC=CC=3)OC[C@]2(C2C(F)=CC(F)=C(C=2)C#N)N=1>>[NH2:21][C:11]1[S:12][CH2:13][C@@H:14]2[CH2:15][C@H:16]([CH2:19][OH:20])[O:17][CH2:18][C@:9]2([C:7]2[C:6]([F:30])=[CH:5][C:4]([F:31])=[C:3]([CH:8]=2)[C:1]#[N:2])[N:10]=1
Reactant: N#Cc1cc(C23CO[C@@H](CO)CC2CSC(NC(=O)c2ccccc2)=N3)c(F)cc1F
Agent: N#Cc1cc([C@]23CO[C@@H](COCc4ccccc4)C[C@H]2CSC(N)=N3)c(F)cc1F
Product: N#Cc1cc([C@]23CO[C@@H](CO)C[C@H]2CSC(N)=N3)c(F)cc1F

Procedure:
N-[(6R)-8a-(5-Cyano-2,4-difluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C11) was converted to the product using the method described for the synthesis of 5-[(4aR,6R,8aS)-2-amino-6-[(benzyloxy)methyl]-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzonitrile (2) in Example 2. Yield: 14.2 mg, 0.042 mmol, 62%. LCMS m/z 340.1 [M+H+]. 1H NMR (400 MHz, CD3OD), δ 7.64 (t, J=7.9 Hz, 1H), 7.30 (dd, J=12.1, 9.2 Hz, 1H), 4.02 (dd, J=11.1, 2.5 Hz, 1H), 3.64-3.70 (m, 2H), 3.50-3.58 (m, 2H), 2.85-2.93 (m, 2H), 2.68-2.72 (m, 1H), 1.68-1.78 (m, 1H), 1.50-1.55 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][NH:10][CH:11]=[C:5]2[N:4]2[C@H:12]3[CH2:17][CH2:16][CH2:15][C@H:13]3[N:14]=[C:3]12.Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][N:10]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:24][CH:25]=3)[CH:11]=[C:5]2[N:4]2[C@H:12]3[CH2:17][CH2:16][CH2:15][C@H:13]3[N:14]=[C:3]12
Reactant: ClCc1ccc(-c2ccccn2)cc1
Reactant: CN1C(=O)c2c[nH]cc2N2C1=N[C@@H]1CCC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2cn(Cc3ccc(-c4ccccn4)cc3)cc2N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
A suspension of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one (140 mg, 0.61 mmol), 2-(4-(chloromethyl)phenyl)pyridine (0.12 g, 0.61 mmol) and cesium carbonate (400 mg, 1.22 mmol) in anhydrous DMF is stirred at room temperature overnight. The mixture is filtered through a 0.2 μL microfilter. The filtrate is purified by a semi-preparative HPLC to give 41 mg of pure product as off white solids. MS (ESI) m/z 398.2 [M+H]+.
Reaction SMILES: [O:1]([C:3]#[N:4])[Na].[CH2:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[CH3:6]>>[CH2:5]([N:7]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:3]([NH2:4])=[O:1])[CH3:6]
Reactant: N#CO[Na]
Reactant: CCNc1ccc2c(c1)OCO2
Product: CCN(C(N)=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.3 %

Procedure:
To a solution of N-ethyl-3,4-(methylenedioxy)aniline (8.1 g) AcOH (100 mL) was added NaOCN (3.0 g) at 10° C. he cold bath was removed and the mixture was stirred at rt for 24 h. The solvent was removed in vacuo and the resulting residue was neutralized with 2 N NaOH. The mixture was extracted with chloroform (3×50 mL). The combined organic phase was washed with water and brine, dried over Na2SO4. The solvent was removed in vacuo and the resulting residue was recrystallized from chloroform/hexane to yield the title compound (5.7 g, 56%). 1H NMR ((CDCl3): 6.78-6.72 (m, 3H), 6.02 (s, 2H), 4.38 (br s, 2H), 3.66 (q, J=7.0, 2H), 1.11 (t, J=7.0 3H).
Reaction SMILES: Cl.[CH2:2]([CH:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2)[NH:12][CH2:11]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].Cl.[CH3:23]O>>[CH2:2]([CH:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([O:21][CH3:23])=[O:20])=[CH:16][CH:17]=2)[NH:12][CH2:11]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC1CNc2cc(C(=O)O)ccc21
Reactant: CO
Agent: Cl
Product: CCCCCCCCC1CNc2cc(C(=O)OC)ccc21

Procedure:
(RS)-3-(n-Octyl)indoline-6-carboxylic acid hydrochloride (7.5 g) in methanol (500 ml), containing hydrochloric acid (50 ml, of strength 36% w/v), was refluxed for 18 hours. The solvent was removed in vacuo and water (100 ml) was added to the residue to give a solid, which was collected, washed with water (2×200 ml) and dried. The solid was dissolved in dichloromethane and was washed with an aqueous solution of sodium bicarbonate (100 ml of strength 2% w/v) and then water (100 ml) and was dried over sodium sulphate. The solvent was removed in vacuo to give a pale yellow oil, which solidified. The solid was recrystallised from a mixture (4:1) of methanol and water to give (RS)-methyl 3-(n-octyl)indoline-6-carboxylate (4.8 g), in the form of a white solid, m.p. 57°-60° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH:6]=[C:7]([CH3:12])[C:8]=1[C:9]([OH:11])=[O:10].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)[CH:6]=[C:7]([CH3:12])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COc1cc(-c2cccc(C(F)(F)F)c2)cc(C)c1C(=O)O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)cc(O)c1C(=O)O
Temperature: 2 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
A suspension of 4.05 g (13.1 mmol) of 3-methoxy-5-methyl-3′-trifluoromethyl-biphenyl-4-carboxylic acid (intermediate 10 C) in 130 ml of CH2Cl2 was cooled down to 2° C. and then 26.1 ml (26.1 mmol) of a solution of boron tribromide (1 molar in CH2Cl2) was added below 5° C. The color of the reaction mixture changed from light to dark yellow. After stirring at RT for 2 hours, the reaction mixture was poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by re-crystallization from EtOAc/heptane to give 3.70 g (96%) of the title compound as off-white solid. MS: 295.1 (M−H−).
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:27])=O>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C>[Cl:27][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C)nc(SC)nc1O
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1c(C)nc(SC)nc1Cl
Temperature: 100 °C
Yield: 82.8 %

Procedure:
Ethyl 4-hydroxy-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (0.2 g, 0.876 mmol), tetraethylammonium chloride (0.145 g, 0.876 mmol), and N,N-dimethylaniline (0.112 mL, 0.876 mmol) were dispersed in acetonitrile (10 mL). The reaction mixture was stirred briefly followed by the addition of phosphorous oxychloride (0.204 mL, 2.190 mmol). The reaction was heated at 100° C. for 4 h. The solvent was subsequently removed in vacuo. The residue was poured onto ice to give an off-white oil, which was extracted with DCM (2×15 mL), and dried over anhydrous Na2SO4. The solvent was removed in vacuo to give the title compound as a yellowish-green oil (0.179 g, 83%). [M+H] calc'd for C9H11ClN2O2S, 247. found, 247.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[C:7]2[N:12]=[CH:13][C:14](I)=[CH:15][C:6]1=2.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[C:7]2[N:12]=[CH:13][C:14]([C:32]3[CH:31]=[N:30][C:29]([N:26]4[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]4)=[CH:34][CH:33]=3)=[CH:15][C:6]1=2
Reactant: CN1CCN(Cc2cc(Cl)ccc2Cl)c2cc(I)cnc21
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CN1CCN(c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3Cl)CCN4C)cn2)CC1
Yield: 43 %

Procedure:
1-(2,5-Dichlorobenzyl)-7-iodo-4-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (83 mg) was coupled to 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4B to give the title compound as a brown solid (43% yield). LCMS: m/z=483.33 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.33 (3H, s), 2.52 (4H, t, J=5.1 Hz), 3.16 (3H, s), 3.53 (8H, m), 4.45 (2H, s), 6.45 (1H, d, J=1.8 Hz), 6.65 (1H, d, J=8.8 Hz), 7.18 (1H, dd, J=8.5, 4.8 Hz), 7.25 (1H, d, J=2.3 Hz), 7.32 (1H, d, J=8.3 Hz), 7.52 (1H, dd, J=8.6, 2.5 Hz), 7.75 (1H, d, J=1.8 Hz), 8.22 (1H, d, J=2.5 Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)C(=O)OCC1C=CC=CC=1>[Pd].C(O)C>[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: COCCN(Cc1cccnc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COCCNCc1cccnc1
Reaction time: 9 h
Yield: 43.5 %

Procedure:
A mixture of benzyl N-(2-methoxyethyl)-N-(3-pyridylmethyl)carbamate (5.4 g) and 10% palladium on carbon (1.0 g) in ethanol (50 ml) was stirred under hydrogen atmosphere for 9 hours. The catalyst was removed by filtration, and the filtrate was concentrated under azeotropic condition with toluene and ethanol. The residue was dissolved in ethanol and diethyl ether was added thereto to give precipitates, which were collected by filtration to give N-(2-methoxyethyl)-N-(3-pyridylmethyl)amine (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])/[C:13]([NH:28][C:25]2[CH:26]=[CH:27][N:23]([CH3:22])[N:24]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cn1ccc(N)n1
Reactant: CC(C)CO/N=C(/C(=O)O)c1ccc(S(C)(=O)=O)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CO/N=C(/C(=O)Nc1ccn(C)n1)c1ccc(S(C)(=O)=O)c(Cl)c1
Reaction time: 2 h
Yield: 95.3 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-isobutoxyimino-acetic acid (104 mg, 0.31 mmol), 1-methyl-1H-pyrazol-3-ylamine (30 mg, 0.31 mmol) and N,N-diisopropylethylamine (163 μL, 0.94 mmol) were combined in methylene chloride (1.5 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (119 mg, 0.31 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-isobutoxyimino-N-(1-methyl-1H-pyrazol-3-yl)-acetamide (122 mg, 95%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C17H21ClN4O4S [M+] 412.10, found 413 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 0.94 (d, J=6.7 Hz, 6 H, 2×CH3), 2.05 (m, 1 H, CH), 3.29 (s, 3 H, SO2CH3), 3.84 (s, 3 H, NCH3), 4.06 (d, J=6.8 Hz, 2 H, OCH2), 6.68 (d, J=2.3 Hz, 1 H, Ar), 7.28 (d, J=2.3 Hz, 1 H, Ar), 7.58 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.69 (d, Jm=1.5 Hz, 1 H, Ar), 8.19 (d, Jo=8.2 Hz, 1 H, Ar), 9.13 (brs, 1 H, NH).
Reaction SMILES: C([O:5][C:6](=[O:59])[CH2:7][N:8]([CH2:51][C:52](=[O:58])[O:53]C(C)(C)C)[CH:9]([CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=1)[CH2:10][N:11]([CH2:20][CH2:21][N:22]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[CH2:23][C:24](=[O:30])[O:25]C(C)(C)C)[CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])(C)(C)C.Cl.CCOCC>O1CCOCC1>[C:6]([CH2:7][N:8]([CH2:51][C:52]([OH:58])=[O:53])[CH:9]([CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=1)[CH2:10][N:11]([CH2:20][CH2:21][N:22]([CH2:31][C:32]([OH:34])=[O:33])[CH2:23][C:24]([OH:30])=[O:25])[CH2:12][C:13]([OH:15])=[O:14])([OH:59])=[O:5]
Reactant: CC(C)(C)OC(=O)CN(CCN(CC(=O)OC(C)(C)C)CC(CCCc1ccc([N+](=O)[O-])cc1)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(O)CN(CCN(CC(=O)O)CC(CCCc1ccc([N+](=O)[O-])cc1)N(CC(=O)O)CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 40 h
Yield: 120.5 %

Procedure:
To a flask containing compound 4b (30 mg, 0.0358 mmol) at 0-5° C. was added dropwise 4M HCl (g) in 1,4-dioxane (2 mL) over 10 min. The resulting mixture was gradually warmed to room temperature and continuously stirred for 40 h. Ether (20 mL) was added to the reaction mixture which was then stirred for 10 min. The resulting precipitate was filtered and washed with ether. The solid product was quickly dissolved deionized water. The aqueous solution was concentrated in vacuo to provide 5b (24 mg, 100%) as an off-white solid. 1H NMR (D2O, 300 MHz) δ1.03-1.89 (m, 4H), 2.21-4.32 (m, 20H), 7.27 (s, 2H), 7.97 (s, 2H); 13C NMR (D2O, 300 MHz) δ25.0 (t), 26.3 (t), 34.6 (t), 46.9 (t), 48.7 (t), 52.3 (t), 52.7 (t), 53.6 (t), 54.6 (t), 55.3 (t), 62.4 (d), 123.7 (d), 129.4 (d), 145.9 (s), 150.0 (s), 168.5 (s), 170.5 (s), 172.7 (s).
Reaction SMILES: [CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][CH2:17][C:18]3[CH:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O-:28].[Na+]>CO>[CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([O:28][CH3:27])=[CH:22][CH:23]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Clc1ccc(CNc2ncnc3c2CN(Cc2ccccc2)CC3)cn1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2ncnc3c2CN(Cc2ccccc2)CC3)cn1
Yield: 81.4 %

Procedure:
A mixture of 6-benzyl-N-((6-chloropyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (2.5 g, 6.8 mmol), MeOH (5 mL), and 15% wt. sodium methoxide solution (10 g, 48 mmol) in MeOH was subjected to microwave irradiation at 150° C. for 60 min. The mixture was concentrated in vacuo and the residue was treated with water (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel column (MeOH/CH2Cl2: 0-15%) to yield a yellow solid (2.0 g, 79%).
Reaction SMILES: [C:1]([O:5][C:6](/[C:8](=[CH:13]\[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([F:22])[CH:15]=1)/[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([CH:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([F:22])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)/C(=C/c1ccc(OC)c(F)c1)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C(Cc1ccc(OC)c(F)c1)C(=O)OC(C)(C)C
Reaction time: 48 h

Procedure:
In a 500 mL round bottom flask, (Z)-methyl 2-(tert-butoxycarbonyl)-3-(3-fluoro-4-methoxyphenyl)acrylate (16 g, 49 mmol) was dissolved in MeOH (500 mL), and palladium hydroxide on carbon (0.069 g, 0.49 mmol) was added. The reaction mixture was stirred for 2 days under a hydrogen balloon and then filtered through Celite, and concentrated in vacuum to give the title compound as crude product. MS m/z: 326 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.F[O:10][C:11](=O)[CH3:12]>>[C:11]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)(=[O:10])[CH3:12]
Reactant: CC(=O)OF
Reactant: Cc1ccnc(O)c1
Product: CC(=O)Oc1cc(C)ccn1

Procedure:
As a process for the preparation of 2-hydroxy-4-methylpyridine, a process whereby [iv]-4-methylpyridine is reacted with acetyl hypofluorite at −10° C. to obtain a 2-acetoxy-4-methylpyridine, and thereafter the 2-acetoxy-4-methylpyridine is hydrolyzed to obtain 4-methyl-2-pyridone is reported [Journal of the American Chemical Society, 109, 3789-3790, (1987): Non-Patent Reference 2].
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5]Br.[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[OH-].[K+].[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC>ClCCl>[CH2:16]([O:15][C:7]([C:8]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH:4]1[CH:3]=[CH2:2])=[O:14])[CH3:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrC/C=C/CBr
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: C=CC1CC1(C(=O)OCC)C(=O)OCC
Yield: 89 %

Procedure:
Patent Document 1 and Example 21 of Patent Document 2 describe that trans-1,4-dibromo-2-butene is allowed to react with diethyl malonate in dichloromethane in the presence of potassium hydroxide (90% flake form) and tricaprylylmethylammonium chloride, so as to obtain 1,1-di-ethoxycarbonyl-2-vinylcyclopropane at a yield of 89%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][N:3]=1.[Br:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21](I)=[CH:20][C:19]=1[CH3:26]>>[Br:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[CH:20][C:19]=1[CH3:26]
Reactant: Cc1cc(I)cc(C)c1Br
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Product: Cc1cc(-c2cc(C)c(Br)c(C)c2)ccn1

Procedure:
The title compound is prepared from 2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine and 2-bromo-5-iodo-1,3-dimethyl-benzene following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=0.87 min; Mass spectrum (ESI+): m/z=276/278 (Br) [M+H]+.