Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[I:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].[CH3:15][NH2:16]>C1(C)C=CC=CC=1>[I:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:16][CH3:15])=[O:9]
Reactant: O=C(O)c1ccccc1I
Reactant: CN
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1ccccc1I
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Thionyl chloride (29.4 mL, 404 mmol) is added to a solution of (2-iodo-benzoic acid (50.0 g, 202 mmol) in dry toluene (600 mL). The mixture is heated to reflux for 4 hours and the solvent is removed in vacuo. The remanence is redissolved in dry toluene (600 mL) and cooled to 0° C. 40% methylamine (aq., 94.1 mL, 1.21 mol) is added dropwise at 0-5° C. during 30 minutes. The mixture is then stirred at ambient temperature for 16 hours, poured onto water (300 mL) and extracted with ethyl acetate (3×300 mL) The combined organic fractions are washed successively with saturated sodium bicarbonate solution (250 mL) and brine (250 mL), dried (MgSO4) and concentrated in vacuo. This gives 50.8 g (96%) of crystalline 2-iodo-N-methyl-benzamide.
Reaction SMILES: N1C(C)=CC=CC=1C.B(Br)(Br)Br.COC(C1C=C(OC)C2CC(C)OC=2C=1)=O.[CH3:29][O:30][C:31]([C:33]1[CH:34]=[C:35]([O:43]C)[CH:36]=[C:37]2[O:41][CH:40]([CH3:42])[CH2:39][C:38]=12)=[O:32]>C(Cl)Cl>[CH3:29][O:30][C:31]([C:33]1[CH:34]=[C:35]([OH:43])[CH:36]=[C:37]2[O:41][CH:40]([CH3:42])[CH2:39][C:38]=12)=[O:32]
Reactant: COC(=O)c1cc(OC)cc2c1CC(C)O2
Agent: BrB(Br)Br
Agent: COC(=O)c1cc(OC)c2c(c1)OC(C)C2
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)c1cc(O)cc2c1CC(C)O2
Temperature: 0 °C
Yield: 23.2 %

Procedure:
2,6-Lutidine (2.64 mL, 22.7 mmol) and BBr3 (22.7 mL, 22.7 mmol, 1.0 M solution in CH2Cl2) were added to a mixture of 4-methoxy-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester and 6-methoxy-2-methyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (1d) (1.68 g, 7.58 mmol) in CH2Cl2 (30 mL) at 0° C. The mixture was stirred at 0° C. and the warmed to room temperature overnight. The mixture was quenched with H2O (80 mL) and extracted with CH2Cl2 (2×80 mL). The organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 20-30% EtOAc in hexanes to give a pale brown colored solid (366 mg, 23% yield). 1H NMR (400 MHz, CDCl3) δ 6.99 (d, J=2.27 Hz, 1 H) 6.49 (d, J=2.27 Hz, 1 H) 5.46 (s, 1 H) 4.86-5.07 (m, 1 H) 3.89 (s, 3 H) 3.57 (dd, J=16.93, 8.84 Hz, 1 H) 3.03 (dd, J=16.93, 7.33 Hz, 1 H) 1.46 (d, J=6.32 Hz, 3 H); LCMS for C11H12O4 m/z 209.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])[C:15]([OH:17])=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][N:35]1[CH2:39][CH3:40]>>[CH2:39]([N:35]1[CH2:36][CH2:37][CH2:38][CH:34]1[CH2:33][NH:32][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:20]([O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])=[C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])[CH:13]=1)[CH3:40]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1OC/C=C(\C)CCC=C(C)C
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1ccc(OC/C=C(\C)CCC=C(C)C)c(OC/C=C(\C)CCC=C(C)C)c1
Yield: 72 %

Procedure:
In a manner identical to Example 15, 3,4-digeranyloxybenzoic acid(2.13 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.93 g(72%) of the aimed compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.Br[CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]1[C:41](=[O:42])[C:40]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:39]2[C:38]1=[O:47])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C>C(#N)C>[CH2:27]([O:26][C:24]([C@H:23]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]1[C:38](=[O:47])[C:39]2=[CH:46][CH:45]=[CH:44][CH:43]=[C:40]2[C:41]1=[O:42])=[O:25])[CH3:28]
Reactant: CCOC(=O)C(Br)CCCCCCCCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](CCCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 80 °C
Yield: 25 %

Procedure:
In 100 ml of acetonitrile are dissolved 1.7 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 2.4 g of ethyl 2-bromo-10-phthalimidodecanoate, and 0.75 g of triethylamine is added to the solution. The mixture is heated at 80° C. for 3 days, concentrated under reduced pressure, diluted with 100 ml of water and extracted with 150 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is separated and purified by silicagel column chromatography (hexane:ethyl acetate=3:1-2:1) to give from the first fraction 0.9 g of tert-butyl 3(R)-[1(R)-ethoxycarbonyl-9-phthalimidononyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([OH:14])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15]>CO.[C].[Pd]>[BrH:1].[NH2:11][C:9]1[C:8]([OH:14])=[C:7]2[C:3]([CH2:4][CH2:5][C:6]2=[O:15])=[CH:2][CH:10]=1
Reactant: O=C1CCc2c(Br)cc([N+](=O)[O-])c(O)c21
Agent: [Pd]
Solvent: CO
Product: Br
Product: Nc1ccc2c(c1O)C(=O)CC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.9 %

Procedure:
4-Bromo-7-hydroxy-6-nitroindan-1-one (2.90 g, 10.66 mmol) was dissolved in methanol (53 mL), a 10% palladium-carbon powder (290 mg) was added, and the mixture was stirred at room temperature for 6 hr under a hydrogen atmosphere. The catalyst was filtered off using celite, and the filtrate was concentrated under reduced pressure to give the title compound (2.08 g, yield 80%).
Reaction SMILES: CN(C)CCN(C)C.C(=O)=O.C([Li])(CC)C.C1CCCCC1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[F:33])[C:27]([OH:29])=[O:28].[Cl:34]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1.O>[Cl:34][C:25]1[C:24]([Cl:23])=[C:32]([F:33])[CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: O
Product: O=C(O)c1ccc(F)c(Cl)c1Cl
Temperature: -85 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To an oven-dried, N2-purged 1-L, round-bottomed flask containing a large magnetic stir bar were added via syringe anhydrous tetrahydrofuran (200 mL) and tetramethylethylenediamine (11.3 mL, 8.72 g, 75.0 mmol). The flask was cooled to −85° C. (dry ice/anhydrous ether slurry) and the sec-butyllithium/cyclohexane solution (53.6 mL of 1.4 M solution, 75.0 mmol) was added via syringe. A solution of commercially available 3-chloro-4-fluorobenzoic acid (5.24 g, 30 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise to the reaction via syringe. The resulting orange/brown slurry was stirred at −85° C. for 2 hours. A solution of hexachloroethane (28.4 g, 120 mmol) in anhydrous tetrahydrofuran (30 mL) was added dropwise to the reaction mixture. The mixture was stirred at −85° C. for 1 hour and then allowed to warm to room temperature over 4 hours. The solvents/volatiles were removed by rotary evaporator to give a brown semi-solid. Water (150 mL) was added. The mixture was transferred to a separatory funnel and washed with ether (2×100 mL). Hydrochloric acid (1 N) was added via pipet to adjust the pH to ˜1. The mixture was extracted with ethyl acetate (4×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporator to give a tan solid. The product was recrystallized from ethyl acetate/hexanes to give 4.36 g (70%) of the title compound as a fine white powder. MS (ESI−) m/z 206.9 (M−H); 1H NMR (DMSO-d6) δ 7.54 (dd, J=8.8, 8.8 Hz, 1H), 7.85 (dd, J=8.8, 5.8 Hz, 1H), 13.72 (br s, 1H).
Reaction SMILES: O.NN.[Br:4][C:5]1[CH:6]=[C:7]([CH3:31])[C:8]([CH2:11][CH2:12][CH2:13][NH:14][C:15]2[C:20]([N+:21]([O-])=O)=[CH:19][C:18]([CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:17][N:16]=2)=[N:9][CH:10]=1>[Ni].CO.C(O)C>[Br:4][C:5]1[CH:6]=[C:7]([CH3:31])[C:8]([CH2:11][CH2:12][CH2:13][NH:14][C:15]2[C:20]([NH2:21])=[CH:19][C:18]([CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:17][N:16]=2)=[N:9][CH:10]=1
Reactant: Cc1cc(Br)cnc1CCCNc1ncc(Cc2cccnc2)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Solvent: CO
Product: Cc1cc(Br)cnc1CCCNc1ncc(Cc2cccnc2)cc1N

Procedure:
Hydrazine hydrate (5.3 ml in 25 ml methanol) was added dropwise over 25 minutes to a stirred and cooled suspension under nitrogen of 2-[3-(5-bromo-3-methylpyrid-2-yl)propylamino]-3-nitro-5-(pyrid-3-ylmethyl)pyridine (5.07 g) and Raney nickel (10 g) in methanol (600 ml) and ethanol (100 ml) keeping the temperature at 5°-10° C. Reaction was allowed to stir at 5° C. for a further 45 minutes. Raney nickel was filtered off and the filtrate was concentrated to dryness to give an oil which was re-evaporated with n-propanol giving the title compound, theoretical yield, crude product used directly in next reaction.
Reaction SMILES: CC(C)=[O:3].[CH2:5]1[O:15][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(=O)(=O)(O)O>>[CH2:5]([OH:15])[CH:6]([OH:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCC1CO1
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Product: CCCCCCCCC(O)CO

Procedure:
A homogeneous clear solution is prepared by adding 3 moles of acetone to 1 mole of 1-decene oxide at room temperature. After adding 50 grams of 5% aqueous sulfuric acid to the solution, the acetone is evaporated off and the resulting solution is neutralized by adding an aqueous sodium hydroxide. The neutralized solution is extracted with pet ether and the extract dried over anhydrous magnesium sulfate. The pet ether is stripped off and 1,2-decanediol is obtained by distilling under vacuo.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:17][CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23](Cl)[C:22]=1[N+:29]([O-:31])=[O:30])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>COCCOCCOC.C(OCC)(=O)C>[CH2:10]([O:17][CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:22]=1[N+:29]([O-:31])=[O:30])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Oc1ccccc1
Reactant: Cc1cc(NCCOCc2ccccc2)c([N+](=O)[O-])c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOCCOC
Solvent: O
Product: Cc1cc(NCCOCc2ccccc2)c([N+](=O)[O-])c(Oc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Under a nitrogen atmosphere, diglyme (20 mL) was added to sodium hydride (0.548 g, 13.7 mmol), which is available as a 60% dispersion in mineral oil, and the mixture was cooled to 0° C. A solution of phenol (1.35 g, 14.4 mmol) in diglyme (20 mL) was added, and the addition flask was rinsed with additional diglyme (2×5 mL), which was added to the reaction flask. The reaction became homogeneous and was stirred for 30 minutes. Solid [2-(benzyloxy)ethyl]-(2-chloro-6-methyl-3-nitropyridin-4-yl)amine (4.2 g, 13 mmol) was added, and the resulting dark solution was heated at 60° C. for 90 minutes. The reaction was allowed to cool and then slowly poured into water (500 mL) and stirred rapidly for 90 minutes. A yellow solid formed, which was isolated by filtration and dissolved in ethyl acetate. The solution was then dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a yellow oil, which began to crystallize over three days. The product was triturated with hexane, and the resulting solid was isolated by filtration and dried for two hours under high vacuum at 55° C. to provide 4.44 g of [2-(benzyloxy)ethyl]-(6-methyl-3-nitro-2-phenoxy-pyridin-4-yl)amine as a yellow solid.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([O:11][C:12]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)=[O:13])([CH3:10])([CH3:9])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:7]([O:11][C:12]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[CH2:1])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)Oc1cccc(C=O)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1cccc(OC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 48.7 %

Procedure:
m-Hydroxybenzaldehyde (819 mmol, 100.0 g) was placed in a 5 L 3-necked round bottom flask equipped with a mechanical stirrer and an argon gas inlet, to which was added THF (4.5 L). Potassium t-butoxide (834 mmol, 93.7 g) was slowly added to the solution over 3 min. After 15 min, di-t-butyl dicarbonate (834 mmol, 182.3 g) was added over 15 min. After 2.5 hr at room temperature the reaction mixture was poured into 4 L of water and the product was extracted with 2 L of a mixture of hexanes and ether (1:1). The organic layers were combined, washed with saturated NaCl (2 L), saturated NaHCO3 (1 L), and H2O (2 L), and dried over MgSO4 (ca. 100 g). The organic phase was filtered and condensed to give m-(t-butoxycarbonyloxy)benzaldehyde (792 mmol, 176 g) in 97% crude yield. Methyl(triphenyl)phosphonium bromide (848 mmol, 303 g) was placed in a 2 L 3-necked round bottom flask containing 1.5 L of THF. The mixture was cooled to 0° C. under nitrogen and potassium t-butoxide (830 mmol, 93.1 g) was added slowly to the mixture over 10 min. m-(t-Butoxycarbonyloxy)benzaldehyde (792 mmol, 176 g) was added and the mixture was stirred for another 6 h, upon which the solvent was removed on a rotary evaporator and hexanes (1.5 L) added. The mixture was stirred for 2 h and filtered through a small bed of silica. The hexane layer was concentrated to give 120 g of the crude product. Purification by column chromatography gave 85 g of pure m-(t-butoxycarbonyloxy)styrene (47% yield based on m-hydroxybenzaldehyde).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.CCO.O>[Cl:18][C:15]([F:17])([F:16])[O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:19]=[CH:20][C:21]([N:22]3[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]3)=[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)[CH:3]=2)=[CH:9][CH:10]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)benzamide (Stage 244.1, 80 mg, 0.167 mmol), pyrimidin-5-ylboronic acid (41.5 mg, 0.335 mmol), Pd(PPh3)2Cl2 (11.76 mg, 0.017 mmol) and Na2CO3 (71.0 mg, 0.670 mmol) were added to a MW vial and treated with a mixture of DME (710 μL), water (203 μL) and EtOH (101 μL). The vial was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 10 min, diluted with MeOH (1 mL) and DCM (2 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 69.8 mg, 0.1 mmol). The solvent was evaporated off under reduced pressure to give a crude product that was purified by flash chromatography (RediSep® Silica gel column, 12 g, DCM/(MeOH-1% NH4OH), from 2% to 12% (MeOH-1% NH4OH). Product was further purified by preparative SFC (Column DEAP, from 25% to 30% in 10 min) to yield the title product as a white solid. UPLC-MS (Condition 3) tR=0.90 min, m/z=476.9 [M+H]+, m/z=521.0 [M+ formic acid-H]; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.75 (d, J=10.39 Hz, 2H) 3.27 (dd, J=10.33, 3.61 Hz, 2H) 3.88 (br. s, 2H) 5.09 (d, J=3.18 Hz, 2H) 6.97 (d, J=8.93 Hz, 1H) 7.33 (d, J=9.05 Hz, 2H) 7.82-7.90 (m, 3H) 7.94 (dd, J=8.80, 2.20 Hz, 1H) 8.86 (s, 2H) 9.17 (s, 1H) 10.11 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([CH2:12][C:13]#[N:14])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[C:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:22][C:23]#[N:24].O>O1CCCC1>[NH2:24][C:23]1[N:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]2[C:12]([C:13]#[N:14])=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=1
Reactant: N#CCc1n[nH]c(-c2ccccc2)n1
Reactant: N#CC=C(Br)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(-c2ccccc2)cc(N)n2nc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 1.2 %

Procedure:
A solution of 0.18 g (0.001 mol) 5-phenyl-1H-1,2,4-triazole-3-acetonitrile in 7 ml tetrahydrofuran was treated at −70° C. with 1.56 ml (0.0025 mol) butyllithium (1.6 M in hexane). After one hour 0.21 g (0.001 mol) 3-bromo-3-phenyl-2-propenenitrile was added, stirring was continued for one hour, the mixture warmed to room temperature over night and water was added. Extraction with diethylether, chromatography on silicagel with dichloromethane/methanol 99/1 and crystallisation from diethylether gave 3.6 mg 5-amino-2,7-diphenyl-[1,2,4]triazolo[1,5-a]pyridine-8-carbonitril as white cystals. MS m/e (%): 312 (M+H+, 100).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[NH2:5][C:6]1[N:14]=[C:13]([O:15][CH2:16][CH2:17][O:18][CH3:19])[N:12]=[C:11]2[C:7]=1[N:8]=[C:9](Br)[N:10]2[CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>CO.C(COC)OC>[NH2:5][C:6]1[N:14]=[C:13]([O:15][CH2:16][CH2:17][O:18][CH3:19])[N:12]=[C:11]2[C:7]=1[N:8]=[C:9]([O:2][CH3:1])[N:10]2[CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1
Reactant: C[O-]
Reactant: COCCOc1nc(N)c2nc(Br)n(Cc3ccc(C#N)cc3)c2n1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: COCCOC
Product: COCCOc1nc(N)c2nc(OC)n(Cc3ccc(C#N)cc3)c2n1
Temperature: 100 °C

Procedure:
Sodium methoxide is generated by reaction of sodium metal (81 mg) in dry methanol (30 mL). The product of example 4 (700 mg) is dissolved in dry dimethoxyethane and the temperature raised to 100° C. After overnight reaction, the mixture is concentrated in vacuo and the residue is chromatographed on silica using 5% methanol in dichloromethane. Yield 120 mg. NMR is consistent with structure assignment.
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:8][CH:7]1[C:6](=[O:9])[NH:5][C:4]2=[O:10].I[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CN(C)C=O>O1CCCC1.ClCCl>[CH2:12]([N:5]1[C:6](=[O:9])[CH:7]2[CH:3]([CH2:8]2)[C:4]1=[O:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCI
Reactant: O=C1NC(=O)C2CC12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCN1C(=O)C2CC2C1=O
Reaction time: 0.08 h

Procedure:
Sodium hydride (0.11 g) was added to a solution of 3-azabicyclo[3.1.0]hexane-2,4-dione (0.3 g) in dry tetrahydrofuran (10 ml) under a nitrogen atmosphere at room temperature. The suspension was stirred for 5 minutes and 1-iodoheptane (0.61 g) was then added in one portion to the reaction mixture. After stirring for two hours at room temperature, dimethylformamide (5 ml) was added and the reaction mixture was stirred for a further 16 hours at room temperature. The reaction mixture was diluted with dichloromethane and then partitioned with water (20 ml). The aqueous phase was extracted with dichloromethane (20 ml) and the combined organic extracts were washed with water (2×20 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by chromatography on silica gel (50 g) using 25-30% ethyl acetate/hexane as eluant to give the title compound as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH3:11][O:12][CH:13]([O:18][CH3:19])[C:14](OC)=[O:15].C(N(CC)CC)C.CO>CCOC(C)=O>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:14](=[O:15])[CH:13]([O:18][CH3:19])[O:12][CH3:11]
Reactant: COC(=O)C(OC)OC
Reactant: NCc1cccc(F)c1Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(OC)C(=O)NCc1cccc(F)c1Cl
Temperature: 80 °C

Procedure:
A mixture of 2-chloro-3-fluorobenzylamine (575 mg, 3.53 mmol), methyl dimethoxyacetate (512 mg, 3.78 mmol), triethylamine (0.62 mL, 4.4 mmol) and MeOH (1 mL, 20 mmol) in a sealed tube was heated at 80° C. for 20 h. After cooling to rt, the mixture was diluted with EtOAc (40 ml), washed with HCl (2N, 2×30 ml), water (2×30 ml), brine (30 ml), dried over MgSO4, filtered, and concentrate vacuo to give the title compound as a brown oil. 1H NMR (400 MHz, CDCl3): δ=3.40 (s, 6H), 4.59 (d, J=6.0 Hz, 2H), 4.74 (s, 1H), 6.99 (brs, 1H), 7.07-7.12 (m, 1H), 7.17-7.25 (m, 2H). MS(ES+): m/z=262.06/264.04 (100/62) [MH+]. HPLC: tR=2.91 min (ZQ3, polar—5 min).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH:9]1[CH2:28][C:29]([OH:31])=O)=O)(C)(C)C.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[ClH:27].[Cl:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([S:14]([N:11]1[CH2:12][CH2:13][NH:8][CH:9]([CH2:28][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:31])[CH2:10]1)(=[O:16])=[O:15])[CH:26]=[CH:25]2
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CC(=O)O
Reactant: C1COCCN1
Product: Cl
Product: O=C(CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1)N1CCOCC1

Procedure:
In the same manner as in Referential Example 319, an amid bond was formed using 1-tert-butoxycarbonyl-2-carboxymethyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine and morpholine as starting materials, followed by deprotection In the same manner as in Referential Example 1, whereby the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:19]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C1Nc2cc(Cl)ccc2C1c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1ccccc1)c1cccc(Cl)c1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (0.17 g, 0.6 mmol) (from Example 5b supra), benzyl bromide (0.12 g, 0.7 mmol) (Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 5 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, dichloromethane, then 5% ethyl acetate in dichloromethane as solvent) to give two products. Lower Rf sample was recrystallized from dichloromethane-hexanes to give rac-3-benzyl-6-chloro-3-(3-chloro-phenyl)-1,3-dihydro-indol-2-one as white needles. (Yield 0.17 g, 76.9%).