Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7]([O:9][C:10](=[O:11])[C:2]=12)=[O:8].[Al+3].[Cl-].[Cl-].[Cl-].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:7]([C:3]2[C:2]([C:10]([OH:9])=[O:11])=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:8])=[CH:19][CH:18]=1
Reactant: O=C1OC(=O)c2ncccc21
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(F)cc1)c1cccnc1C(=O)O

Procedure:
A mixture of 2,3-pyridinedicarboxylic anhydride (9.0 g, 60.36 mmol) in 75 mL of fluorobenzene is warmed and stirred mechanically while AlCl3 (17.7 g, 0.132 mol) is added portionwise from a powder addition funnel over 20 m. The resulting mixture is heated to reflux for 24 hours, then allowed to cool and the excess fluorobenzene decanted. Quenching of the residue with ice water and 5% aqueous HCl generates a solid which is filtered and washed with hot H2O. The combined filtrates are evaporated to a final volume of ca. 250 mL, then heated to boiling and treated with a hot solution of 15% aqueous CuSO4 solution to precipitate a blue solid. The suspension is filtered and the resulting solid resuspended in H2O (75 mL) and treated with a stream of H2S gas until the initial blue color of the suspension subsides and is replaced by a black suspension. The solid is filtered with the aid of Celite and the filtrate evaporated to produce a tan solid which is recrystallized from H2O to obtain 3-(4-fluorobenzoyl)pyridine-2-carboxylic acid. M.P. 153.5°-155° C.
Reaction SMILES: [Cl-:1].C(OC([NH:12][C:13]([CH3:24])([CH3:23])[CH2:14][CH2:15][N+:16]([CH2:19][CH2:20][O:21][CH3:22])([CH3:18])[CH3:17])=O)C1C=CC=CC=1>[Pd].CO>[Cl-:1].[NH2:12][C:13]([CH3:24])([CH3:23])[CH2:14][CH2:15][N+:16]([CH2:19][CH2:20][O:21][CH3:22])([CH3:17])[CH3:18]
Reactant: COCC[N+](C)(C)CCC(C)(C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: [Cl-]
Solvent: CO
Product: COCC[N+](C)(C)CCC(C)(C)N
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.1 %

Procedure:
Under a nitrogen atmosphere, palladium on carbon (10%, 280 mg) was added to a solution of 3-(((benzyloxy)carbonyl)amino)-N-(2-methoxyethyl)-N,N,3-trimethylbutan-1-aminium chloride (1.3 g, 3.5 mmol) in 12 mL of methanol. The flask was degassed and placed under a hydrogen atmosphere, stirring for 18 hours at room temperature. The suspension was filtered through a pad of Celite® washing with methanol, and the filtrate was concentrated under reduced pressure to give about 835 mg of a clear oil. 1H NMR (D2O, 400 MHz) δ 1.15 (s, 6H), 1.87-1.92 (m, 2H), 3.06 (s, 6H), 3.30 (s, 3H), 3.39-3.43 (m, 2H), 3.49-3.51 (m, 2H), 3.79-3.80 (m, 2H); LRMS (ESI/APCI) m/z 189 [M]+
Reaction SMILES: C1(C)C=CC(C=O)=CC=1.CC1[CH:12]=[CH:13][C:14]([C:17]([OH:19])=[O:18])=[CH:15][CH:16]=1.[C:20]([OH:23])(=[O:22])[CH3:21]>C([O-])(=O)C.[Co+2].C([O-])(=O)C.[Co].CC1C=CC=CC=1C(O)=O.[Co]>[C:17]([OH:19])(=[O:18])[C:14]1[CH:15]=[CH:16][C:21]([C:20]([OH:23])=[O:22])=[CH:12][CH:13]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)O
Agent: [Co+2]
Agent: [Co]
Agent: CC(=O)[O-]
Product: O=C(O)c1ccc(C(=O)O)cc1
Reaction time: 2.67 h
Yield: 95.1 %

Procedure:
All the same operations as in Example 1 were carried out except that a stock solution consisting of 1000 g of glacial acetic acid, 108 g of p-tolualdehyde, 122 g of p-toluic acid and 10 g of cobalt acetate (cobalt concentration 0.24% by weight based on the weight of the solvent) was charged into the reactor at a rate of 160 ml/hr. The value of toluic acid/cobalt in the reaction solution at a steady state was 1.34 and the average residence time of the reaction solution was 160 minutes. As a result, terephthalic acid having an acid value of 672 and a purity of 99.1% was obtained in a yield of 95.1% by mole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:18]2[CH2:19][CH2:20][CH:15]([F:14])[CH2:16][CH2:17]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: FC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CCC(F)CC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.1 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (1 g, 5.84 mmol), 4-fluoropiperidine hydrochloride (0.97 g, 6.42 mmol) and 4 Å molecular sieves (10 g) in DCE (50 mL). The reaction mixture was stirred for 4 h at room temperature. Sodium triacetoxyborohydride (2.48 g, 11.68 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc:cyclohexane, gradient 0:100 to 100:0) then (Si—PPC, MeOH: DCM, 0:100 to 5:95) to give 3-(4-Fluoropiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil (0.59 g, 39%). 1H NMR (CDCl3, 400 MHz) δ 4.80-4.58 (m, 1H); 3.97-3.89 (m, 2H); 3.85-3.76 (m, 2H); 3.08 (t, J=6.4 Hz, 1H); 2.50-2.28 (m, 4H); 1.99-1.82 (m, 4H); 1.48-1.38 (m, 9H).
Reaction SMILES: [BH4-].[Na+].[N:3]1[N:4]([CH2:12][CH2:13][C:14]#[C:15][C:16]2[N:21]=[C:20]([C:22](=[O:24])[CH3:23])[CH:19]=[CH:18][CH:17]=2)[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12>CO>[N:3]1[N:4]([CH2:12][CH2:13][C:14]#[C:15][C:16]2[N:21]=[C:20]([CH:22]([OH:24])[CH3:23])[CH:19]=[CH:18][CH:17]=2)[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12
Reactant: CC(=O)c1cccc(C#CCCn2nc3ccccc3n2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cccc(C#CCCn2nc3ccccc3n2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
NaBH4 (99 mg, 1.6 mmol) was added to a solution of 1-[6-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-yl]-ethanone (380 mg, 1.31 mmol) in MeOH (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 30 min, quenched by the addition of water at 0° C. and extracted twice with DCM. The organic phase was washed with water, dried over Na2SO4, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 202 mg (0.69 mmol, 53%) of 1-[6-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-yl]-ethanol as a colorless oil.
Reaction SMILES: [CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]2[CH2:13]O)[CH2:3][CH2:2]1.S(Cl)([Cl:17])=O>>[CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]2[CH2:13][Cl:17])[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: OCC1c2ccccc2CN1C1CC1
Product: ClCC1c2ccccc2CN1C1CC1

Procedure:
2-Cyclopropyl-1-hydroxymethylisoindoline (3.8 g) was stirred with thionyl chloride (35 ml) for 3 hr. Thionyl chloride was evaporated to give crude 2-cyclopropyl-1-chloromethylisoindoline (as an oil) which was dissolved in chloroform (50 ml) and treated with diethylamine (15 ml). The reaction mixture was left for 12 hr, evaporated to dryness and the residue was partitioned between aqueous sodium hydroxide and ether. The ether layer was washed (water), evaporated to dryness in vacuo, and the residue was redissolved in ether and extracted with aqueous hydrochloric acid. The acidic extract was evaporated to dryness and the residue was recrystallised from iso-propanol/ethyl acetate to give 2-cyclopropyl-1-diethylaminomethylisoindoline dihydrochloride, (0.35 g, m.p. 150°).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=O.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.CN(C)C=O>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:9])[NH:10][C:14]([C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[Cl:11])=[N:1][C:2]=2[CH:6]=1
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: O=C(Cl)c1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=c1[nH]c(-c2ccccc2Cl)nc2cc(Br)sc12
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-amino-5-bromothiophene-2-carboxamide (100 mg), 2-chlorobenzoylchloride (57 μL), N,N-dimethylpyridin-4-amine (55 mg), pyridine (1.0 mL) and N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1.5 hr. The reaction system was concentrated under reduced pressure, 2M aqueous sodium hydroxide solution was added to the residue, and the mixture was heated to 120° C. After 1 hr, insoluble material was removed by filtration, and the filtrate was neutralized with 1M hydrochloric acid. The precipitate was collected by filtration and washed with water to give the title compound (120 mg) as a dark orange solid.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12].CS([Cl:17])(=O)=O>CO>[Cl:17][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12]
Reactant: Cc1cccc(CCCO)c1O
Reactant: CS(=O)(=O)Cl
Solvent: CO
Product: Cc1cccc(CCCCl)c1O
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A solution of N,N-dimethylaniline (24.0 mL) in toluene (20.0 mL) was bubbled with hydrochloride gas to prepare the corresponding hydrochloride. To the mixture were added 2-(3-hydroxypropyl)-6-methylphenol (20.0 g) and methanesulfonyl chloride (10.2 mL), and the resulting mixture was stirred at 110° C. for 1.5 hours. After cooling, methanol (2.4 mL) was added to the reaction mixture. The mixture was washed with distilled water, an aqueous sodium bicarbonate solution, distilled water and brine successively and then evaporated to give a solution of 2-(3-chloropropyl)-6-methylphenol (19.9 g) in toluene (21 g). NMR spectrum of this compound was identical with that of Reference Example 12.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([NH2:20])=O)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:21][C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]#[N:20])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C(N)=O)cc3c2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C#N)cc3c2)cc1
Reaction time: 2 h
Yield: 82 %

Procedure:
To a mixture of 7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide (840 mg), pyridine (0.23 mL) and N,N-dimethylformamide (20 mL) was added dropwise oxalyl chloride (0.25 mL) under ice-cooling, and the mixture was stirred for 2 hr. Pyridine (0.23 mL) and oxalyl chloride (0.25 mL) were successively added, and the mixture was further stirred for 30 min. Water was added to the reaction solution, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed successively with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained solid was washed with a mixed solvent of diethyl ether-hexane to give the title compound (660 mg, yield 92%) as yellow crystals. The obtained yellow crystals were recrystallized from ethanol-hexane to give yellow crystals. melting point 209-210° C.
Reaction SMILES: [Cl:1]Cl.[C:3]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4].O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:1][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([C:3](=[O:5])[CH3:4])[CH2:7][CH2:8]2
Reactant: ClCl
Reactant: CC(=O)N1CCc2ccccc21
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1CCc2cc(Cl)ccc21

Procedure:
74.5 g (1.05 moles) of chlorine were added with stirring at 20° to 30° C. to a mixture of 161 g (1 mole) of 1-acetyl-indoline in 1,050 ml of glacial acetic acid and the mixture was stirred for 15 minutes after which 8500 ml of water were added thereto with stirring. The mixture was stirred for 30 minutes and sodium bisulfite was added to destroy excess chlorine and was then vacuum filtered. The recovered product was dissolved in 250 ml of hot isopropanol and the mixture was cooled with stirring and then vacuum filtered. The product was rinsed with 250 ml of isopropanol to obtain 5-chloro-1-acetyl-indoline which was saponified as in Example 1 to obtain 70 g (45% yield) of 5-chloro-indoline.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][C:22]3[N:21]4[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]4)=[CH:15][C:14]=3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1Br)(=[O:3])[CH3:2].[CH3:28][N:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][N:54]([CH:57]4[CH2:60][O:59][CH2:58]4)[CH2:53][C@@H:52]3[CH3:61])=[CH:47][N:46]=2)[C:30]1=[O:62].CC(O[Na])=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CC#N>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][C:22]3[N:21]4[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]4)=[CH:15][C:14]=3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:33]1[CH:32]=[C:31]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][N:54]([CH:57]4[CH2:58][O:59][CH2:60]4)[CH2:53][C@@H:52]3[CH3:61])=[CH:47][N:46]=2)[C:30](=[O:62])[N:29]([CH3:28])[CH:34]=1)(=[O:3])[CH3:2]
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCc2c(cc3n2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)O[Na]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(cc3n2CCCC3)C1=O
Temperature: 100 °C
Yield: 59 %

Procedure:
A mixture of 101h (300 mg, 0.70 mmol), (S)-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (332 mg, 0.70 mmol), CH3COONa (114 mg, 1.4 mmol), K3PO4 (368 mg, 1.4 mmol), PdCl2(dppf) (56 mg, 0.07 mmol), CH3CN (25 mL), and H2O (1 mL) was heated at 100° C. for 3 hours. It was then evaporated and the residue was purified by silical-gel column eluting with methylene chloride/methanol (30:1) to afford 101i (293 mg, yield 41%) as a brown solid. MS: (M+H)+ 710.
Reaction SMILES: [OH:1][N:2]1[CH:10]=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].O[CH2:23][CH2:24]/[CH:25]=[CH:26]\[P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:32]([O:31][P:27](/[CH:26]=[CH:25]\[CH2:24][CH2:23][O:1][N:2]1[CH:10]=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([O:28][CH2:29][CH3:30])=[O:34])[CH3:33]
Reactant: CCOP(=O)(/C=C\CCO)OCC
Reactant: O=C1c2ccccc2C(=O)N1c1ncnc2c1ncn2O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(/C=C\CCOn1cnc2c(N3C(=O)c4ccccc4C3=O)ncnc21)OCC
Temperature: 0 °C
Yield: 59.5 %

Procedure:
To a mixture of 9-hydroxy-6-phthalimidopurine (320 mg, 1.14 mmol) , diethyl (Z)-4-hydroxybut-1-enylphosphonate (250 mg, 1.20 mmol) and triphenyl phosphine (448 mg, 1.71 mmol) in dry tetrahydrofuran (11 ml) stirred at 0° C. under dry nitrogen was added diethyl azodicarboxylate (296 mg, 170 mmol). The mixture was allowed to warm to r.t. and stirred for 2.3 hr. The solvent was removed and the residue was purified by column chromatography on silica gel eluting with acetone-hexane (1:1, 4:3) to give (Z)-9-[4-(diethoxyphosphoryl)but-3-enyloxy]-6-phthalimidopurine as a light brown gum (320 mg, 60%); λmax (EtOH) 271 (14,680)nm; υmax (KBr) 2980, 1735, 1595, 1575, 1360, 1330, 1245 and 1025 cm-1 ; δH [(CD3)2SO] 1.23 (6H, t, J 7 Hz, CH3), 3.05 (2H, m, CH2), 3.98 (4H, dq, J 7 Hz and 8Hz, CH2CH 3), 4.63 (2H, t, J 6 Hz, CH2O ), 5.90 (1H, dd, J 14 Hz and 20 Hz, PCH=CH), 6.75 (1H, ddt, J 7 Hz, 14 Hz and 52 Hz, PCH=CH), 8.05 (4H, m, C6H4), 9.05 (1H, s, H-2/H-8), 9.10 (1H, s, H-2/H-8) (Found: C, 53.77; H, 4.87; N, 14.52%; MH+ 472.1384. C21H22N5O6P requires C, 53.50; H, 4.70; N, 14.86%; MH+ 472.1386).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]=[CH2:14])[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH3:16][C:17]1([CH3:43])[CH2:22][CH:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][CH:31]2[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][C:33]([CH3:40])([CH3:39])[CH2:32]2)[CH2:20][C:19]([CH3:42])([CH3:41])[NH:18]1.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:1]([NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]=[CH2:14])[N:8]=[C:7]([N:23]([CH:21]2[CH2:22][C:17]([CH3:43])([CH3:16])[NH:18][C:19]([CH3:42])([CH3:41])[CH2:20]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]([C:7]2[N:8]=[C:9]([NH:11][CH2:12][CH:13]=[CH2:14])[N:10]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[N:6]=2)[CH:31]2[CH2:32][C:33]([CH3:40])([CH3:39])[NH:34][C:35]([CH3:38])([CH3:37])[CH2:36]2)[N:6]=1)[CH:2]=[CH2:3]
Reactant: CC1(C)CC(NCCCCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: C=CCNc1nc(Cl)nc(NCC=C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: C=CCNc1nc(NCC=C)nc(N(CCCCCCN(c2nc(NCC=C)nc(NCC=C)n2)C2CC(C)(C)NC(C)(C)C2)C2CC(C)(C)NC(C)(C)C2)n1
Reaction time: 2.5 h

Procedure:
46.5 g (0.206 mole) of 2,4-bis-allylamino-6-chloro-1,3,5-triazine and 39.5 g (0.1 mole) of N,N'-bis-(2,2,6,6-tetramethylpiperid-4-yl)-hexamethylenediamine are dissolved rapidly by stirring in 200 ml of xylene in an atmosphere of nitrogen, a clear solution being formed initially. A precipitate of the hydrochlorides begins to form after approx. 10-15 minutes. The mixture is stirred for a further 2.5 hours at reflux temperature. A total of 8.8 g (0.22 mole) of finely powdered solid sodium hydroxide is then added in 5 portions in the course of 5 hours, and stirring is continued for a further 10 hours at reflux temperature. The reaction mixture is worked up by being filtered while hot (approx. 125°) through a preheated suction filter, the residue is washed with a little warm xylene, and the filtrate is induced to crystallise by stirring and cooling (0°-5°). The crystalline precipitate is filtered off and recrystallised from special boiling point gasoline (boiling point 110°-140°), which gives N,N'-bis-[2,4-di-(allylamino)-1,3,5-triazin-6-yl]-N,N'-bis-(2,2,6,6-tetramethylpiperid-4-yl)-hexamethylenediamine of melting point 161°-163°. This product is identical with the product prepared in accordance with Example 1b) (stabiliser No. 1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Al](Cl)(C)C.[CH3:13][C:14]1[O:15][C:16]2[CH:22]=[C:21]([C:23](OCC)=[O:24])[CH:20]=[C:19]([O:28][C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=3)[C:17]=2[CH:18]=1>ClCCCl>[CH3:13][C:14]1[O:15][C:16]2[CH:22]=[C:21]([C:23]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=3)=[O:24])[CH:20]=[C:19]([O:28][C:29]3[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][CH:34]=3)[C:17]=2[CH:18]=1
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(C)oc2c1
Reactant: Cc1ccc(N)nc1
Agent: C[Al](C)Cl
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3cc(C)oc3c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
2-Amino-5-methylpyridine (289 mg, 2.67 mmol) was dissolved in DCE (10 mL) at 0° C., then Al(CH3)2Cl (2.67 mL, 1M in hexanes) was added drop wise. After the addition, the ice-bath was removed, and the mixture was stirred for 30 min at room temperature. Ethyl 2-methyl-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxylate (100 mg, 0.267 mmol) was added and the stirring was continued for 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl3, washed with brine and dried over MgSO4. The crude product was purified by gradient silica gel chromatography using CHCl3/MeOH (100/0 to 98/2) to give the title compound (100 mg, 86%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.32 (s, 3 H) 2.48 (s, 3 H) 3.07 (s, 3 H) 6.24 (s, 1 H) 7.08-7.16 (m, 2 H) 7.48 (d, J=1.32 Hz, 1 H) 7.57 (dd, J=8.29, 2.35 Hz, 1 H) 7.81-7.97 (m, 3 H) 8.12 (d, J=2.35 Hz, 1 H) 8.25 (d, J=8.29 Hz, 1 H) 8.44 (s, 1 H). LCMS for C23H20N2O5S m/z 437.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=[C:4]2[CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH2:20]([N:27]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([NH2:36])[C:30]=2[CH:29]=[N:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>ClCCl.CO.CN(C=O)C>[CH2:20]([N:27]1[C:35]2[C:30](=[C:31]([NH:36][C:11]([C:8]3[N:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]4=[N:10][CH:9]=3)=[O:13])[CH:32]=[CH:33][CH:34]=2)[CH:29]=[N:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Reactant: O=C(O)c1cnc2cc(Br)ccn12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cccc2c1cnn2Cc1ccccc1)c1cnc2cc(Br)ccn12
Yield: 69.9 %

Procedure:
To a solution of 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (42 mg; 0.17 mmol) in dichloromethane (1 mL) was added oxalyl chloride (1.1 equivalents; 2M solution in dichloromethane) followed by a catalytic amount of DMF. The mixture was stirred in a sealed container stirred until effervescence stopped, venting occasionally to release gas. 1-Benzyl-1H-indazol-4-amine (Example 155, Steps A-B; 39 mg; 0.17 mmol) was added followed by diisopropylethylamine (2 equivalents). The mixture was stirred at ambient temperature for 2 days. The mixture was diluted with methanol and the solids were collected by filtration and washed twice with 2M aqueous sodium carbonate solution, water and ether. The solids were then dried to give the desired product as an off-white solid (53 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:41](O)=[O:42])=[N:11][C:12]([C:15]2[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[C:20]([C:30](=[O:33])[NH:31][CH3:32])[C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[F:75][C:76]1[CH:81]=[CH:80][C:79]([CH2:82][NH2:83])=[CH:78][CH:77]=1>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[C:10]([C:41]([NH:83][CH2:82][C:79]2[CH:80]=[CH:81][C:76]([F:75])=[CH:77][CH:78]=2)=[O:42])=[N:11][C:12]([C:15]2[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:37])=[O:38])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[C:20]([C:30](=[O:33])[NH:31][CH3:32])[C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)O)n3)cc12
Reactant: NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)NCc4ccc(F)cc4)n3)cc12
Reaction time: 3 h
Yield: 95.9 %

Procedure:
A mixture of 3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinic acid (200 mg, 0.33 mmol), HATU (252 mg, 0.66 mmol) and Et3N (111 mg, 1 mmol) was stirred in DMF (5 mL) at RT for 1 h, and then (4-fluorophenyl)methanamine (124 mg, 1 mmol) was added. After being stirred for 3 h, the mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated and purified by column chromatography (DCM:MeOH=100:1 to 50:1) to get the product of 3-(benzyloxy)-N-(4-fluorobenzyl)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinamide (225 mg, yield: 96%). 1H-NMR (Methanol-d4, 400 MHz) δ 7.90˜7.94 (m, 2H), 7.83 (s, 1H), 7.76 (s, 1H), 7.65˜7.72 (m, 2H), 7.43˜7.45 (m, 2H), 7.28˜7.34 (m, 5H), 7.22 (t, J=8.6 Hz, 2H), 6.91 (t, J=8.6 Hz, 2H), 5.20 (s, 2H), 4.50 (s, 2H), 3.14 (s, 3H), 2.89 (s, 3H), 2.87 (s, 3H). MS (M+H)+: 711.