Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][P:4]([CH:9]1[N:14]2[C:15](=[O:27])[C:16](=[O:26])[NH:17][C:18]3[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=[C:12]([C:13]=32)[CH2:11][CH2:10]1)(=[O:8])[O:5]CC)C.S(=O)(=O)(O)O.II.[I:35](O)(=O)=O>C(O)(=O)C.O>[I:35][C:21]1[C:20]([C:22]([F:25])([F:24])[F:23])=[CH:19][C:18]2[NH:17][C:16](=[O:26])[C:15](=[O:27])[N:14]3[CH:9]([P:4]([OH:5])(=[O:8])[OH:3])[CH2:10][CH2:11][C:12]=1[C:13]=23
Reactant: [O-][I+2]([O-])O
Reactant: CCOP(=O)(OCC)C1CCc2cc(C(F)(F)F)cc3[nH]c(=O)c(=O)n1c23
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(C(F)(F)F)c(I)c3c2n(c1=O)C(P(=O)(O)O)CC3
Temperature: 80 °C
Reaction time: 15 h
Yield: 31.7 %

Procedure:
406 mg of 9-trifluoromethyl-2,3-dioxo-1,2,3,5,6,7-hexahydro-pyrido[1,2,3-de]quinoxaline-5-phosphonic acid diethyl ester in 2 ml of glacial acetic acid is mixed with 0.05 ml of water, 0.025 ml of concentrated sulfuric acid, 178 mg of iodine and 70 mg of iodic acid and stirred for 15 hours at 80° C. bath temperature. After concentration by evaporation, it is mixed with water and the product is suctioned off. 60 mg of 8-iodo-9-trifluoromethyl-2,3-dioxo-1,2,3,5,6,7-hexahydro-pyrido[1,2,3-de]quinoxaline-5-phosphonic acid of melting point 307° C. (with decomposition) is obtained.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.Cl.[F:14][C:15]1[CH:34]=[C:33]([CH3:35])[C:32]([O:36][C:37]([O:39][CH3:40])=[O:38])=[CH:31][C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([OH:30])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:60][C:61]1[CH:66]=[C:65]([CH2:67]O)[CH:64]=[C:63]([CH3:69])[N:62]=1>C(Cl)Cl>[Cl:60][C:61]1[CH:66]=[C:65]([CH2:67][O:30][C:24]2[CH:23]=[C:22]3[C:27]([C:18]([NH:17][C:16]4[CH:31]=[C:32]([O:36][C:37]([O:39][CH3:40])=[O:38])[C:33]([CH3:35])=[CH:34][C:15]=4[F:14])=[N:19][CH:20]=[N:21]3)=[CH:26][C:25]=2[O:28][CH3:29])[CH:64]=[C:63]([CH3:69])[N:62]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Reactant: Cc1cc(CO)cc(Cl)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4cc(C)nc(Cl)c4)c(OC)cc23)c(F)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
Diethyl azodicarboxylate (296 μl, 1.88 mmol) was added dropwise to a solution of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (350 mg, 0.94 mmol), (prepared as described for the starting material in Example 22), triphenylphosphine (492 mg, 1.88 mmol) and 2-chloro-4-hydroxymethyl-6-methylpyridine (178 mg, 1.12 mmol) in methylene chloride (30 ml) and the mixture stirred for 30 minutes at ambient temperature. The solvent was removed by evaporation and the residue was purified by column chromatography eluting with ethyl acetate/methylene chloride (75/25). The purified product was triturated with ether, the solid collected by filtration, washed with ether and dried under vacuum to give 7-((2-chloro-6-methyl-4-pyridyl)methoxy)-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline (373 mg, 78%). 1H NMR Spectrum: (DMSOd6) 2.15(s, 3H); 2.5(s, 3H); 3.85(s, 3H); 3.98(s, 3H); 5.35(s, 2H) 7.25(s, 1H); 7.3(d, 1H); 7.35(s, 1H); 7.4(m, 2H); 7.85(s, 1H); 8.35(s, 1H); 9.58(1H) MS-ESI: 513 [MH]+
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:14](O)=[CH:15][C:16](=[O:18])[CH3:17])=[CH:7]2.O.C([O-])(=O)C.[Na+].C([O-])(=O)C.[Na+].[H][H]>O.[Pd].CO>[CH3:13][O:12][C:11]1[CH:2]=[C:3]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH:5]=[CH:4]2
Reactant: COc1ccc2cc(C(O)=CC(C)=O)ccc2c1Br
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2cc(CCC(C)=O)ccc2c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 52.6 %

Procedure:
48 Grams (0.150 moles) of 4-(5-bromo-6-methoxy-2-naphthyl)-4-hydroxybut-3-en-2-one, 6.1 g of sodium acetate hydrate containing 32.4% of water, equivalent to 0.050 moles of sodium acetate, 4 g of a 50% suspension in water of 10% palladium on carbon, equivalent to 0.0019 moles of palladium, and 500 ml of methanol are put in a hydrogenator. The hydrogenator is washed with nitrogen in order to eliminate the oxygen and then hydrogen is introduced at the pressure of 2 atmospheres. The temperature of reaction is kept at 40° C. for a period of time of 6 hours, then the hydrogen is let off, the hydrogenator is washed with nitrogen and the reaction mixture is filtered to eliminate the catalyst. The solution is brought to pH 6 with a 5% aqueous solution of sodium hydroxide and concentrated under vacuum. The oily residue is dissolved into 130 ml of isopropanol and 30 ml of N,N-dimethylformamide and the solution is added with 45 ml of water and 17.6 g of sodium bisulfite obtaining a suspension that is stirred for one hour at 60° C., then is cooled to 5° C. and is filtered. The obtained solid is washed with 75 ml of methanol, suspended in 200 ml of a 5% aqueous solution of sodium hydroxide and kept under stirring at room temperature for three hours. The suspension is then filtered, the solid is washed with water until neutrality and dried in oven under vacuum obtaining 18 g of product with a yield equal to 52.8%.
Reaction SMILES: Cl.[CH2:2]([CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([C:19](=[NH:21])[NH2:20])=[CH:15][CH:16]=2)[C:11]1=[O:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C[O-].[Na+]>CO>[CH2:2]([CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([C:19]3[N:20]=[CH:13][C:12]([CH2:11][CH2:10][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:17][N:21]=3)=[CH:15][CH:16]=2)[C:11]1=[O:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC1Cc2ccc(C(=N)N)cc2C1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCc1cnc(-c2ccc3c(c2)C(=O)C(CCCCCCCC)C3)nc1
Yield: 82.3 %

Procedure:
1.0 g (3.1 mM) of 2-octyl-6-amidino-1-indanone hydrochloride, 0.38 g (7.0 mM) of sodium methylate, 0.78 g (3.26 mM) of α-decyl-β-dimethylaminoacrolein and 10 ml of methanol were placed in a 10 ml-round bottomed flask, followed by refluxing for 17 hours under stirring. After the reaction, the reaction mixture was cooled on an ice water bath to precipitate a crystal. The crystal was recovered by filtration and purified by silica gel column chromatography (eluent: toluene/ethyl acetate=100/1), followed by recrystallization from a mixture solvent (toluene/methanol) to obtain 0.59 g of 2-octyl-6-(5-decylpyrimidine-2-yl)-1-indanone (Yield: 41%, m.p.=83° C.).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:14]([O:16][C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=1)=[O:18])[CH3:15].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH2:14]([O:16][C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:8][CH:9]=2)=[O:29])=[CH:22][CH:21]=1)=[O:18])[CH3:15]
Reactant: CCCCCOc1ccc(O)cc1
Reactant: CCOC(=O)Oc1ccc(/C=C/C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCOc1ccc(OC(=O)/C=C/c2ccc(OC(=O)OCC)cc2)cc1
Reaction time: 22 h
Yield: 94.2 %

Procedure:
23.00 g (97 mmol) 4-pentoxyphenol, 17.6 g (97 mmol) (2E)-3-{4-[(ethoxycarbonyl)oxy]phenyl}acrylic acid and 1.18 g (9.7 mmol) 4-dimethylaminopyridine were dissolved in 300 ml of dichloromethane. A suspension of 18.6 g (97 mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbo-diimide hydrochloride and 200 ml dichloromethane were added dropwise in the course of 40 minutes. After 22 h at room temperature, the reaction mixture was partitioned between dichloromethane and water; the organic phase was washed repeatedly with water, dried over sodium sulphate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 200 g silica gel using cyclohexane:ethyl acetate (7:3) then (1:1) as eluent yielded 36.4 g (94%) 4-pentoxyphenyl (2E)-3-{4-[(ethoxycarbonyl)oxy]phenyl}acrylate as colourless crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH2:14][OH:15])=[CH:11][S:12][CH:13]=2)=[CH:5][CH:4]=1)[CH3:2].C(C1C=CC(C2C=C(C(F)(F)F)SC=2CO[C:35]2[C:40]([F:41])=[CH:39][C:38]([CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])=[CH:37][C:36]=2[F:49])=CC=1)C>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([CH2:14][O:15][C:35]3[C:36]([F:49])=[CH:37][C:38]([CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[CH:39][C:40]=3[F:41])=[CH:11][S:12][CH:13]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2cscc2CO)cc1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2sc(C(F)(F)F)cc2-c2ccc(CC)cc2)c(F)c1
Product: CCc1ccc(-c2cscc2COc2c(F)cc(CCC(=O)O)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 217 by coupling of (4-(4-ethylphenyl)thiophen-3-yl)methanol and ethyl 3-(4-hydroxy-3,5-difluoro phenyl) propanoate followed by hydrolysis of ethyl 3-(4-((3-(4-ethylphenyl)-5-(trifluoromethyl)thiophen-2-yl)methoxy)-3,5-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.48 (m, 3H), 7.25 (d, J=7.0 Hz, 2H), 6.72 (d, J=6.5 Hz, 2H), 5.08 (s, 2H), 2.88 (t, J=5.5 Hz, 2H), 2.70 (m, 4H), 1.30 (t, J=6.8 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][O:5][CH:6]=1.[CH2:13]([SH:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:13]([S:19][C:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][O:5][CH:6]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Brc1conc1-c1cccnc1
Reactant: CCCCCCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCCCSc1conc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
To a degassed solution of dioxane (30 ml) containing 64 (0.6 g, 2.66 mmol) (see Scheme 12), were added 1.2 eq (0.62 ml) of hexane-1-thiol and 2 eq of triethylamine (0.92 ml). The resulting mixture was stirred for another 2 hours under N2. Successively were added 2.5 mol % of Pd2(dba)3 (61 mg) and 5 mol % Xantphos (77 mg). After the addition, the resulting solution was stirred for 18 hours at 95° C. under N2. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether) to afford 3-(4-Hexylsulfanyl-isoxazol-3-yl)-pyridine (65B) as an oil (0.25 g, 37%). 1H-NMR (400 MHz, CDCl3): δ 9.24 (d, J=2 Hz, 1H), 8.73 (dd, J=5 Hz, 2 Hz, 1H), 8.49 (s, 1H), 8.31 (dt, J=8 Hz, 2 Hz, 1H), 7.45-7.41 (m, 1H), 2.61 (t, J=7 Hz, 2H), 1.52-1.43 (m, 2H), 1.35-1.13 (m, 6H), 0.85 (t, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4](C(OC(C)(C)C)=O)[N:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:57]1[C:58](=[O:65])[N:59]([CH3:64])[CH:60]=[C:61]([Br:63])[CH:62]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[NH:4]1[CH:5]=[CH:6][C:2]([NH:1][C:57]2[C:58](=[O:65])[N:59]([CH3:64])[CH:60]=[C:61]([Br:63])[CH:62]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2cc[nH]n2)c1=O
Temperature: 105 °C
Yield: 37.2 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 289a (2.2 g, 12 mmol), XantPhos (0.69 g, 1.2 mmol), Pd2(dba)3 (1.1 g, 1.2 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (6.4 g, 24 mmol), Cs2CO3 (15.6 g, 48 mmol), and 1,4-dioxane (50 mL). After bubbling nitrogen through the resulting mixture for 10 minutes, it was heated at 105° C. for 15 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue the mixture was washed with methanol (8 mL) to afford 289b as a pale yellow solid (1.2 g, 37%). MS-ESI: [M+H]+ 269.1.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1)C1C=CC=CC=1>CO.[Pd]>[CH3:26][N:25]1[C:21]([C:10]2[CH:11]=[C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:13]=[CH:14][C:9]=2[OH:8])=[CH:22][CH:23]=[N:24]1
Reactant: Cn1nccc1-c1cc(-c2ccccc2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cn1nccc1-c1cc(-c2ccccc2)ccc1O
Reaction time: 16 h
Yield: 77.2 %

Procedure:
To a stirred solution of 5-[4-(benzyloxy)biphenyl-3-yl]-1-methyl-1H-pyrazole (Preparation 27, 3.0 g, 8.8 mmol) in methanol (26 mL) was added palladium on carbon (300 mg). The mixture was stirred under hydrogen gas for 16 hours. The reaction mixture was filtered through Celite™, and washed with tetrahydrofuran. The resulting filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (26 mL) and degassed with argon prior to addition of palladium on carbon (300 mg). The reaction mixture was stirred under hydrogen gas for 6 hours. The reaction mixture was filtered through Celite™ and the filtrate concentrated in vacuo to give a solid. The solid was triturated with hexane to afford the title compound as a white solid (1.7 g, 77%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:19]([CH3:20])=[CH:18][N:17]([CH:21]([O:34][CH2:35][CH3:36])[C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)=[O:23])[N:16]=1)C1C=CC=CC=1>C(O)C.[Pd]>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][NH:24][C:22](=[O:23])[CH:21]([O:34][CH2:35][CH3:36])[N:17]2[CH:18]=[C:19]([CH3:20])[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[OH:8])=[N:16]2)=[CH:31][CH:30]=1)#[N:33]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)n1cc(C)c(-c2ccccc2OCc2ccccc2)n1
Agent: [Pd]
Solvent: CCO
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)n1cc(C)c(-c2ccccc2O)n1
Reaction time: 18 h
Yield: 43.9 %

Procedure:
To a stirred suspension of (RS)-2-[3-(2-benzyloxy-phenyl)-4-methyl-pyrazol-1-yl]-N-(4-cyano-benzyl)-2-ethoxy-acetamide (1.2 g, example 10.2) at r.t. in ethanol (20 ml) under an argon atmosphere was added 10% Pd/C (60 mg). The mixture was then stirred under a hydrogen atmosphere for 18 h. The catalyst was filtered off and washed with ethanol. The filtrate was concentrated. The crude product was isolated by chromatography (silica gel, gradient cyclohexane=>cyclohexane/EtOAc 2:3) to give (RS)-N-(4-cyano-benzyl)-2-ethoxy-2-[3-(2-hydroxy-phenyl)-4-methyl-pyrazol-1-yl]-acetamide (428 mg) as white solid. MS 389.5 ([M−H]−)
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=[N:8]O)[CH2:4][CH2:3]1.[OH:10]S(O)(=O)=O>>[CH3:1][CH:2]1[CH2:7][CH2:6][NH:8][C:5](=[O:10])[CH2:4][CH2:3]1
Reactant: O=S(=O)(O)O
Reactant: CC1CCC(=NO)CC1
Product: CC1CCNC(=O)CC1
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
4-methylcyclohexanone oxime in 5 mL 80% H2SO4 was added dropwise to H2SO4 (80%, 5 mL) while stirring and the reaction temperature was maintained at 120° C. with an external oil bath. An exotherm was observed. After 5 min, the reaction was removed from the oil bath and allowed to cool to room temperature. The reaction mixture was diluted with water (30 mL) and adjusted to pH 6 with concentrated NH4OH. This solution was further diluted with water (30 mL) and extracted with DCM (2×25 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate. After filtration and concentration, the crude product (1.6 g) was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Br)=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:22]2[CH2:23][CH2:24][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:20][CH:21]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncccc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ncccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 14 h
Yield: 64.2 %

Procedure:
3-Bromopyridine-2-carboxylic acid methyl ester (4.0 g, 18.6 mmol, 1.0 eq.) was combined with a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (5.8 g, 18.6 mmol, 1.0 eq.) in THF (100 mL), under nitrogen. A solution of Na2CO3 (7.9 g, 74.5 mmol, 4.0 eq.) in water (37 mL) was added, followed by the addition of PdCl2(PPh3)2 (650 mg, 930 μmol, 0.05 eq.). The resulting solution was stirred for 14 hours while the temperature was maintained at reflux in an oil bath. The resulting solution was diluted with EtOAc (100 mL), then washed with saturated aqueous NaCl (2×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:20) to yield 3′,6′-dihydro-2′H-[3,4]bipyridinyl-2,1′-dicarboxylic acid 1′-t-butyl ester 2-methyl ester (3.8 g) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]=1[O:16][CH3:17])[C:6]([O:8][N:9]=[C:10]([NH2:12])[CH3:11])=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:9]=[C:10]([CH3:11])[N:12]=2)[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]=1[O:16][CH3:17]
Reactant: COc1cc(C(=O)ON=C(C)N)cc([N+](=O)[O-])c1OC
Solvent: CC(=O)O
Product: COc1cc(-c2nc(C)no2)cc([N+](=O)[O-])c1OC

Procedure:
2.0 g of N'-[(3,4-dimethoxy-5-nitrobenzoyl)oxy]acetamidine are held at reflux temperature for 1 hour in 20 ml of glacial acetic acid. After distillation of the acetic acid, the crystalline residue is recrystallized from ether/hexane. There is obtained 5-(3,4-dimethoxy-5-nitrophenyl)-3-methyl-1,2,4-oxadiazole in the form of colorless crystals of m.p. 111°.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([Cl:15])[CH:10]=2)[C:5]([NH2:16])=[CH:4][CH:3]=1.[C:17](O)(=O)C.C(N)=N>CCO.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([Cl:15])[CH:10]=3)[CH:17]=[N:16][C:5]2=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(Br)nc1Nc1ccnc(Cl)c1
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Clc1cc(-n2cnc3ccc(Br)nc32)ccn1
Temperature: 25 °C

Procedure:
6-Bromo-N*2*-(2-chloro-pyridin-4-yl)-pyridine-2,3-diamine (step 2)(1 eq, 1.22 mmol, 634 mg) is dissolved in EtOH (15 mL) and treated formamidine acetate (5 eq, 6.105 mmol, 634 mg). The reaction is heated at reflux for 3 hours allowed to cool to room temperature. The mixture is diluted with saturated aqueous sodium bicarbonate and extracted with EtOAc (3×10 ml). The organic portions are combined, dried (MgSO4) and concentrated in vacuo. Purification of the residue by flash chromatography on silica eluting at 5-10% EtOAc in hexane affords the title compound; [M+H]+=310.
Reaction SMILES: [N:1]1[C:5]2[C:6]3[C:11]([CH2:12][CH2:13][C:4]=2[S:3][C:2]=1[NH:14][C:15](=O)[CH2:16][CH3:17])=[CH:10][CH:9]=[CH:8][CH:7]=3.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:15]([NH:14][C:2]1[S:3][C:4]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:1]=1)[CH2:16][CH3:17]
Reactant: CCC(=O)Nc1nc2c(s1)CCc1ccccc1-2
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCCNc1nc2c(s1)CCc1ccccc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
Under ice-cooling, to a solution of N-(4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-yl)propanamide (1.70 g, 6.6 mmol) in tetrahydrofuran (30 mL) was added lithium aluminum hydride (749 mg, 20 mmol), and the mixture was stirred at room temperature for 3 hrs. Sodium sulfate 10 hydrate (9.6 g, 30 mmol) was added, and the mixture was stirred at room temperature for 1 hr. Insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4:1) to give the title compound (1.32 g, yield 82%) as a yellow powder.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]([O:19][CH3:20])=[O:18])[CH:7]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:9]=1[O:10]C)([CH3:3])[CH3:2].B(Br)(Br)Br.C(OCC)C.CCCCCC>ClCCl>[CH3:20][O:19][C:17](/[CH:16]=[CH:15]/[C:6]1[CH:7]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:10])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1)=[O:18]
Reactant: COC(=O)C=Cc1cc(C(C)C)c(OC)c(C(C)C)c1
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)/C=C/c1cc(C(C)C)c(O)c(C(C)C)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 72.5 %

Procedure:
Methyl 3-(3,5-diisopropyl-4-methoxyphenyl)acrylate (610 mg) and boron tribromide (10 mL) were combined in dichloromethane (10 mL) and the mixture was allowed to stir at 0° C. for 5 hours. The reaction was quenched with water and extracted with dichloromethane. The organics were washed (brine), dried (sodium sulfate), filtered, and condensed. Chromatography, with ethyl ether:hexane (gradient 10:90 to 20:80) as the eluent, provided material that was recrystallized from hexane to give the title compound as a white solid (420 mg); 1H-NMR (CDCl3) δ=1.28 (d, 12H, CH(CH3)2), 3.16 (m, 2H, CH(CH3)2), 3.80 (S, 3H, OCH3), 5.10 (S, 1H, OH), 6.32 (d, 2H, CH═CH), 7.24 (S, 2H, Ar—H), 7.66 (d, 2H, CH═CH).
Reaction SMILES: [CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]([CH:13]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=O)[CH2:14][CH3:15])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]3=[C:13]([CH2:14][CH3:15])[N:16]=[C:17]([CH:19]4[CH2:21][CH2:20]4)[N:8]3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(NC(=O)C1CC1)c1nnc(C2CCCC2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C2CC2)n2nc(C3CCCC3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 200 mg (0.66 mmol) crude N-[1-(3-cyclopentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]cyclopropanecarboxamide, 165 mg (1.1 mmol) phosphoric trichloride are stirred at reflux for 4 hours, proportionate amounts of the solvents are used. The product is purified by chromatography (preparative HPLC).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][N:56]1[CH:60]=[C:59]([C:61](Cl)=[O:62])[CH:58]=[N:57]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:61]([C:59]2[CH:58]=[N:57][N:56]([CH3:55])[CH:60]=2)=[O:62])[CH2:49][CH2:48]1
Reactant: Cn1cc(C(=O)Cl)cn1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cn1
Yield: 42 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1-methyl-1H-pyrazole-4-carbonyl chloride as starting materials in 42% yield. LCMS for C29H31ClN9O2 (M+H)+: m/z=572.2.