Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:14][C:5]2=[N:6][C:7]([CH3:13])=[C:8]([CH2:11][CH3:12])[C:9]([CH3:10])=[C:4]2[C:3]=1[C:15]#[N:16].[CH:17]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]1.O>N1C=CC=CC=1>[C:15]([C:3]1[C:4]2[C:5](=[N:6][C:7]([CH3:13])=[C:8]([CH2:11][CH3:12])[C:9]=2[CH3:10])[S:14][C:2]=1[NH:1][C:22]([CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:23])#[N:16]
Reactant: O=C(Cl)C1CCCC1
Reactant: CCc1c(C)nc2sc(N)c(C#N)c2c1C
Solvent: c1ccncc1
Solvent: O
Product: CCc1c(C)nc2sc(NC(=O)C3CCCC3)c(C#N)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of 2-amino-5-ethyl-4,6-dimethylthieno[2,3-b]pyridine-3-carbonitrile (23 mg, 0.10 mmol) in pyridine (2.5 mL) was added cyclopentanecarbonyl chloride (15 mg, 0.11 mmol). The mixture was stirred at room temperature overnight, poured into water (10 mL) and extracted with DCM (10 mL). The organic layer was separated and washed with HCl (2 N, 2×3 mL), water (3×3 mL) and brine (3 mL), dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to provide essentially pure cyclopentanecarboxylic acid (3-cyano-5-ethyl-4,6-dimethyl-thieno[2,3-b]pyridin-2-yl)amide (28 mg, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.CS(O)(=O)=O.[N-:17]=[N+]=[N-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:17][CH2:6][CH2:5]2
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCc2cc(Br)ccc21
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1NCCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
5-bromo-2,3-dihydro-1H-inden-1-one (1K1) (9.48 mmol, 2 g) was dissolved in DCM (35 ml) and methane sulfonic acid (95 mmol, 9.11 g) was added. The reaction mixture was cooled to 0° C. before portionwise addition of sodium azide (28.4 mmol, 1.85 g). Once addition was complete the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was partitioned between DCM and NaOH (2M, 50 ml). The phases were separated and the aqueous layer was extracted twice more with DCM. The combined organics were washed with water and brine, dried (MgSO4) and evaporated to dryness before purification on silica eluting with 75-100% EtOAc/heptane to give 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (1K2) 919 mg (42%) 1H NMR (400 MHz, CDCl3) δ 7.93 (d, 1H) 7.49 (d, 1H) 7.40 (s, 1H) 6.36 (bs, 1H) 3.58 (t, 2H) 2.99 (t, 2H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([F:10])[CH:4]=1.[CH3:11][C:12]1([CH3:25])[O:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2OC)=[N:14][CH2:13]1>O1CCCC1>[CH3:11][C:12]1([CH3:25])[O:16][C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=2[C:3]2[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([F:10])[CH:4]=2)=[N:14][CH2:13]1
Reactant: Cc1ccc(Br)cc1F
Reactant: COc1ccccc1C1=NCC(C)(C)O1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccccc2C2=NCC(C)(C)O2)cc1F
Reaction time: 2 h

Procedure:
14.7 g (605.7 mol) of magnesium filings are initially introduced into 50 ml of analytical grade tetrahydrofuran under argon, and 117.7 g (623 mmol) of 4-bromo-2-fluorotoluene in 500 ml of analytical grade tetrahydrofuran are added, while stirring. A clear solution forms at 35°-40° C. within 2 hours. A solution of 74.0 g (360.5 mmol) of the compound from Example II in 500 ml of analytical grade tetrahydrofuran is added dropwise at room temperature and the mixture is subsequently stirred at about 25° C. for 16 hours, initially with gentle cooling. The solvent is evaporated off and the crude product is subsequently rinsed in 600 ml of ethyl acetate and 800 ml of saturated ammonium chloride solution at 10° C., dried with sodium sulphate and evaporated in vacuo. For purification, the product is taken up in 600 ml of ether, any solid residue is filtered off with suction and the crude product is extracted into the aqueous phase by several extractions with 2M hydrochloric acid. This aqueous phase is covered with a layer of ether and brought to pH 13 with sodium hydroxide solution. After three extractions with ether, the product phase is dried with sodium sulphate and evaporated and the residual solvent is removed under a high vacuum.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[O:19][CH3:20])=[O:7].[K].CC(C)([O-])C>CN(C=O)C>[CH3:20][O:19][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:9]=1[N:8]1[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1=[O:7])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccc(NC(=O)CCCCCl)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCCCC2=O)c(OC)c1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
2.25 g (7.51 mmol) methyl 4-(5-chloro-pentanoyl-amino)-3-methoxy-benzoate dissolved in 60 ml DMF are combined with 1.26 g (11.2 mmol) potassium-tert.-butoxide and stirred for 2.5 hours at 60° C. Then the mixture is evaporated down i. vac., the residue is combined with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate, evaporated down i. vac. and the residue obtained is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate 3:2->0:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[C:9](Br)[CH:10]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:24]1(B2OC(C)(C)C(C)(C)O2)[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[C:9]([C:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=2)[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OCC(F)(F)F)c(C2=CCCCC2)c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 85.8 %

Procedure:
5-Bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid methyl ester (500 mg, 1.59 mmol, CAN 1211589-51-3), potassium carbonate (660 mg, 4.78 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (65.0 mg, 79.6 μmol) were combined to give a light red solid. To this solid was added a solution of 2-(1-cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (331 mg, 1.59 mmol, CAN 141091-37-4) in DMF (12.0 ml), that had been thoroughly degassed and flushed with argon. The reaction mixture was heated to 80° C. and stirred for 48 h. Subsequently the reaction mixture was cooled to ambient temperature and poured into 75 mL brine and extracted with isopropyl acetate (2×150 mL). The organic layers were washed with brine (2×50 mL), combined and dried with Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 50 g, 0% to 10%, n-heptane/isopropyl acetate) to give the title compound (0.43 g, 60%) as white solid; MS (EI) 316.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH2:21][CH:20]([O:22][CH2:23][C:24](N4CCOCC4)=[O:25])[CH2:19][CH2:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[CH3:32][Mg]Br.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH2:21][CH:20]([O:22][CH2:23][CH:24]([OH:25])[CH3:32])[CH2:19][CH2:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][CH2:12]1
Reactant: C[Mg]Br
Reactant: O=C(COC1CCc2nc(-c3ccc(OCC4CC4)c(Cl)c3)oc2C1)N1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)COC1CCc2nc(-c3ccc(OCC4CC4)c(Cl)c3)oc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-((2-(3-chloro-4-(cyclopropylmethoxy)phenyl)-4,5,6,7-tetrahydro-1,3-benzoxazol-6-yl)oxy)-1-(morpholin-4-yl)ethanone (9.24 g) in THF (25 mL) was added methylmagnesium bromide (1 M THF solution, 31.0 mL). To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the obtained residue in a mixed solvent of THF (10 mL)-methanol (10 mL) was added sodium tetrahydroborate (782 mg), and the mixture was stirred at room temperature for 10 min. the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.51 g).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][CH2:21][CH2:22][C:23]1[O:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:28]([C:26]3[N:27]=[C:23]([CH2:22][CH2:21][O:20][CH3:19])[O:24][C:25]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:29])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COCCc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: COCCc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)c(-c2ccccc2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-(2-methoxy-ethyl)-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.97 min; [M+H]+=435.13.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1CCC([N:29]=C=NC2CCCCC2)CC1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C(Cl)Cl>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[N:38]1([NH-:29])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: C1COCCN1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: ClCCl
Product: [NH-]N1CCOCC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 4.49 g of Z-(L)-Phe-OH in 190 ml of methylene chloride is cooled to 0° C. and 3.09 g of DCC are added. After stirring for 20 minutes at 0° C., a solution of 1.31 ml of morpholine in 10 ml of methylene chloride is added dropwise thereto over a period of 15 minutes. The reaction mixture is stirred for a further 24 hours at room temperature and, after the precipitated dicyclohexylurea has been filtered off, is washed in succession with methylene chloride, aqueous sodium hydrogen carbonate solution and brine. Drying over sodium sulfate and concentration yield the crude title compound which crystallises from ether. TLC Rf (C)=0.55.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([O:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:38]C1C=CC(S(CC2C(C(OC)=O)=C(O)C(C3C=COC=3)=CC=2)(=O)=O)=CC=1.C(OC(NCCBr)=O)(C)(C)C>>[C:29]([O:28][C:26]([NH:25][CH2:24][CH2:23][O:22][C:15]1[C:14]([C:33]2[CH:37]=[CH:36][O:35][CH:34]=2)=[CH:13][CH:12]=[C:11]([CH2:10][S:7]([C:1]2[CH:6]=[CH:5][C:4]([F:38])=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:16]=1[C:17]([O:19][CH3:20])=[O:18])=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCNC(=O)OC(C)(C)C
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(-c2ccoc2)c1O
Agent: CC(C)(C)OC(=O)NCCBr
Product: COC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(-c2ccoc2)c1OCCNC(=O)OC(C)(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 10, starting from methyl 6-(4-fluorobenzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 38) and 2-[N-(t-butoxycarbonyl)amino]ethyl bromide.
Reaction SMILES: NOS(O)(=O)=O.C[N:8](C)[CH:9]=[CH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[O:12].C(=O)(O)[O-].[Na+]>CO.O>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:12][N:8]=[CH:9][CH:10]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(C(=O)C=CN(C)C)cc1
Agent: NOS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2ccno2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
At 0° C. a solution of hydroxylamine-O-sulfonic acid (93 g) in dry methanol (700 ml) is added over 2 min to a solution of crude 3-dimethylamino-1-p-tolylprop-2-en-1-one (148 g) in dry methanol (1 l). The mixture is stirred at ambient temperature for 20 min, then carefully poured into a solution of sodium bicarbonate (150 g) in water (1 l). After standing at room temperature over night (for convenience) the precipitate is collected and dried to give crude 5-(4-methylphenyl)-isoxazole. In order to obtain purer product, the material can be purified by flash cromatography on silica gel, using hexane/ethyl acetate (4:1) as eluent.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:16]=[CH:15][C:8]([C:9]([O:11]C(C)C)=[O:10])=[CH:7][C:6]=1[C:17]([F:20])([F:19])[F:18])[CH3:3].[OH-].[Na+]>C(O)C>[CH3:3][CH:2]([O:4][C:5]1[CH:16]=[CH:15][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[C:17]([F:18])([F:20])[F:19])[CH3:1]
Reactant: CC(C)OC(=O)c1ccc(OC(C)C)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Yield: 93.3 %

Procedure:
To a mixture of 1-methylethyl 4-[(1-methylethyl)oxy]-3-(trifluoromethyl)benzoate (D70) (704 mg, 2.43 mmol) in ethanol (110 mL) was added aqueous sodium hydroxide (2M, 12.2 mL, 24.3 mmol) and the reaction heated to reflux for 1 h. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (100 mL) and water (100 mL) and acidified with aqueous hydrochloric acid (2M, 13 mL). The aqueous layer was extracted further with ethyl acetate (100 mL) and the combined organic layers dried and concentrated in vacuo to give the title compound as a yellow solid (563 mg). δH (methanol-d4, 400 MHz): 8.21-8.17 (2H, m), 7.26 (1H, d), 4.84 (1H, septet), 1.38 (6H, d). MS (ES): C11H11F3O3 requires 248; found 247 (M−H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C@@H:12]1[CH2:18][CH2:19][S:20][CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SiH](CC)(CC)CC.C(C(O)=O)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C@@H:12]1[CH2:18][CH2:19][S:20][CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSCC[C@H]1C(=O)NC=CN1C(=O)OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCC[C@H]1C(=O)NCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 44.7 %

Procedure:
To a solution of 4-benzyloxycarbonyl-3-(S)-(2-methylsulfanyl-ethyl)-3,4-dihydro-1H-pyrazine-2-one (0.3 g, 1 mmol) in CH2Cl2 is added Et3SiH (1.57 ml, 10 mmol). The resulting solution is cooled to 0° C. and CF3CO2H (2.2 ml, 30 mmol) is added dropwise. The mixture is stirred 16 hours at room temperature, washed with a saturated aqueous NaHCO3 solution, brine. The solution is dried over MgSO4, concentrated. The resulting crude product is purified by column chromatography on silica gel eluting with a gradient of 50% AcOEt:Hexane to 100% AcOEt. The title compound (0.138 g, 46% yield) is obtained as an oil.
Reaction SMILES: C[N:2]([CH3:19])/[CH:3]=[C:4](/[C:10](=[O:18])[C:11]1[C:16](Cl)=[CH:15][CH:14]=[CH:13][N:12]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1CN.O>CC(N(C)C)=O>[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:19][N:2]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:18])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3]1
Reactant: NCc1ccccc1Br
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1ncccc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cn(Cc2ccccc2Br)c2cccnc2c1=O
Temperature: 74 °C
Reaction time: 15 h
Yield: 49.2 %

Procedure:
To a brown solution of (Z)-ethyl 2-(3-chloropicolinoyl)-3-(dimethylamino)acrylate (35) (850 mg, 3.01 mmol) in DMA (dimethylacetamide) (50 mL) were added a solid powder of tribasic potassium phosphate (1.4 g, 6.61 mmol) and then (2-bromophenyl)methanamine (615 mg, 3.31 mmol) at room temperature under a nitrogen atmosphere. The resulting brown suspension was heated to 74° C. and stirred for 15 h at which time LCMS analysis indicated the absence of starting material. Then, it was cooled to room temperature and poured slowly into water (100 mL). Then, the organic compound was extracted into dichloromethane (2×200 mL). The combined extracts were washed with water, brine solution, and dried over anhydrous MgSO4. Filtration and concentration gave a crude brown oil which was purified using an ISCO (120 g) column, eluting with ethyl acetate in hexanes (0 to 100%) and then 5 to 10% methanol in dichloromethane. The pure fractions were combined and the solvent was removed under vacuum to obtain ethyl 1-(2-bromobenzyl)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (36) (574 mg, 46.8% yield) as a light brown solid.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:24][N:23](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:22][CH2:21][CH2:20][N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:18][CH2:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11]2)(=O)=O)=CC=1.OS(O)(=O)=O.C(O)C>C(OCC)C>[NH:10]1[CH2:24][NH:23][CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)N2CCCN(S(=O)(=O)c3ccc(C)cc3)CN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOCC
Product: C1CNCCNCCNCCNCNC1
Temperature: 100 °C
Yield: 39 %

Procedure:
A mixture of 1,4,7,10,14-penta(p-toluenesulfonyl)-1,4,7,10,14-pentaazacyclopentadecane prepared as in Example 12 A (28.5 g, 0.0279 mole) and concentrated H2SO4 (100 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 72 H. To the resulting brown solution, ethanol (100 ml) was added dropwise with stirring at 0° C. followed by ethyl ether (1 l). The tan solid was filtered and washed thoroughly with ethyl ether. The solid was then dissolved in H2O (100 ml) and the resulting solution filtered and washed with ethyl ether. The pH of the solution was adjusted to 11 with 10N NaOH and the solvent was removed in vacuo. The resulting brown oily solid was extracted with hot THF (2×500 ml) and the THF extracts were filtered. The filtrates were combined and the solvent was removed in vacuo. The oily residue was dissolved in hot hexane and the insoluble impurities were removed by filtration. The solvent was removed in vacuo and the residual oil was purified by vacuum distillation to give 2.68 g (39% yield) of the product as a light yellow oil: bp 140-5° C. (0.10 mm Hg); 1H NMR (CDCl3) δ 1.51 (br s, 5 H), 1.68 (quint, J=6.1 Hz, 4 H), 2.73 (m, 20 H); Exact mass (M+H)+ : calcd., 244.2501; Found: 244.2555 (C12H30N5).
Reaction SMILES: [C:1]1([OH:7])C=CC=CC=1.[C:8]1([CH:15]=[CH:14][CH:13]=[C:11](O)[CH:10]=1)[OH:9].C1(C=CC(O)=CC=1)O.OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.BrC1C=C(C(C2C=C(Br)C(O)=C(Br)C=2)(C)C)C=C(Br)C=1O.C1C(O)=CC=C(S(C2C=CC(O)=CC=2)(=O)=O)C=1>>[CH2:1]=[O:7].[C:8]1([OH:9])[CH:15]=[CH:14][CH:13]=[CH:11][CH:10]=1
Reactant: Oc1cccc(O)c1
Agent: CC(C)(c1cc(Br)c(O)c(Br)c1)c1cc(Br)c(O)c(Br)c1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: Oc1ccccc1
Product: C=O

Procedure:
The epoxy compounds can also derive from mononuclear phenols, for example from phenol, resorcinol, or hydroquinone; or they can be based on polynuclear phenols, for example on bis(4-hydroxyphenyl)methane, 2,2-bis(4-hydroxyphenyl)propane, 2,2-bis(3,5-dibromo-4-hydroxyphenyl)propane, 4,4′-dihydroxydiphenyl sulfone, or condensates obtained under acidic conditions from phenols with formaldehyde, e.g. phenol novolacs.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([NH2:13])[CH:10]=[N:11][CH:12]=2)[CH2:3][CH2:2]1>CCOC(C)=O.CCO.[Pd]>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([NH2:13])[CH:10]=[N:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: Nc1cncc(C2=CCOCC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cncc(C2CCOCC2)c1
Temperature: 23 °C
Reaction time: 19 h

Procedure:
To a flask containing 5-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-amine (61.6 mg, 0.35 mmol) in EtOAc (3.0 mL) and EtOH (1.0 mL) was added 10% palladium on activated carbon (75.7 mg, 0.071 mmol). After purging, the mixture was stirred under an atmosphere of hydrogen at 23° C. The reaction was monitored with TLC and LC-MS. After 19 h, the reaction was filtered through Celite™. After concentration, the residue was identified as 5-(tetrahydro-2H-pyran-4-yl)pyridin-3-amine that was used without purification. Mass Spectrum (pos.) m/e: 179.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[Br:22])(=[O:13])=[O:12])[CH:6]=[C:5]2[CH2:23]Cl.[NH:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[Br:22])(=[O:13])=[O:12])[CH:6]=[C:5]2[CH2:23][N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1
Reactant: C1CNCCNC1
Reactant: COc1ccc(S(=O)(=O)n2cc(CCl)c3cc(Br)ccc32)c(Br)c1
Product: COc1ccc(S(=O)(=O)n2cc(CN3CCCNCC3)c3cc(Br)ccc32)c(Br)c1

Procedure:
Using essentially the same procedure as described in example 127, 5-Bromo-1-(2-Bromo-4-methoxybenzenesulfonyl)-3-chloromethyl-1H-indole was reacted with homopiperazine to obtain the above derivative.
Reaction SMILES: [NH:1]1[C:5]([NH2:6])=[CH:4][CH:3]=[N:2]1.O.[N+:8]([CH:11]([CH:14]=O)[CH:12]=O)([O-:10])=[O:9].[Na].O>C(O)(=O)C>[N+:8]([C:11]1[CH:12]=[C:4]2[CH:3]=[N:2][NH:1][C:5]2=[N:6][CH:14]=1)([O-:10])=[O:9]
Reactant: Nc1ccn[nH]1
Reactant: O=CC(C=O)[N+](=O)[O-]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cnc2[nH]ncc2c1
Temperature: 90 °C
Yield: 90 %

Procedure:
A suspension of 1H-pyrazol-5-amine (0.804 g, 9.48 mmol) and sodium nitromalonaldehyde monohydrate (1.56 g, 9.96 mmol) in acetic acid (12 mL) was heated to 90° C. overnight. The reaction mixture was cooled to room temperature and poured into water (50 mL). The resulting solids were collected by filtration. The solids were washed with water (3×20 mL) and dried in vacuo to give 5-nitro-1H-pyrazolo[3,4-b]pyridine (1.40 g, 84%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[CH2:19]([SnH:23]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22]>C1COCC1.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>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[Sn:23]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9]\[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:6][CH:7]=1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CC(C)(C)OC(=O)NCC#Cc1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)/C(=C/CNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
To a solution of tert-butyl [3-(4-chlorophenyl)prop-2-yn-1-yl]carbamate (5.97 g, 22.5 mmol) in THF (240 mL) under an atmosphere of argon was added bis(triphenylphosphine)palladium(II) chloride (0.788 g, 1.12 mmol) and tri-n-butyltin hydride (9.55 mL, 35.5 mmol). The solution was stirred at room temperature for 90 minutes. The solvent was evaporated and the residue was purified using column chromatography on silica gel (220 g Analogix column, gradient hexane to 20% EA in hexane over 30 minutes) to give the product (11.2 g, 90%). LCMS: (AA) ES+ 556, 558. 1H NMR (400 MHz, d6-DMSO) δ: 7.37-7.31 (m, 2H), 6.96 (m, 2H), 5.83-5.60 (m, 1H), 3.60-3.37 (m, 2H), 1.44-1.36 (m, 6H), 1.34 (m, 9H), 1.26-1.15 (m, 6H), 0.89-0.77 (m, 15H).