Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[Cl:23][C:24]1[C:29](F)=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:27]=[CH:26][N:25]=1>O>[Cl:23][C:24]1[C:29]([O:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:28]([C:31]([F:32])([F:33])[F:34])[CH:27]=[CH:26][N:25]=1
Reactant: Fc1c(C(F)(F)F)ccnc1Cl
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccnc(Cl)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a round bottom flask charged with 3,5-dichlorophenol (1.23 g, 7.52 mmol) and potassium carbonate (1.04 g, 7.52 mmol) was added N-methylpyrrolidinone (5 mL). To this suspension under N2 was added 2-chloro-3-fluoro-4-(trifluoromethyl)pyridine (1.50 g, 7.52 mmol) and the reaction mixture was placed in an oil bath at 120° C. After 60 minutes, the reaction mixture was allowed to cool to room temperature, water (20 mL) was added and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (3×25 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on a pre-packed silica gel Redi Sep 80 gram column, eluting with 0-75% CH2Cl2 in hexanes to afford the title compound. 1H NMR (DMSO-d6) δ 8.52 (d, J=4.5 Hz, 1H), 7.60 (d, J=4.6 Hz, 1H), 7.14-7.10 (m, 1H), 6.72-6.68 (m, 2H). HRMS (M+1)=341.9465.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH3:15][NH:16][C:17](=[O:20])[CH:18]=[CH2:19].Cl>>[CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][N:11]([CH2:19][CH2:18][C:17]([NH:16][CH3:15])=[O:20])[CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: C=CC(=O)NC
Reactant: CC1=C2CCNCC2c2ccccc21
Agent: Cl
Product: CNC(=O)CCN1CCC2=C(C)c3ccccc3C2C1

Procedure:
1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-C]pyridine and N-methyl acrylamide are reacted in accordance with the process described in Example 6. Reaction period 15 hours. M.P. of the hydrochloride of the title compound 200°-201° from ethanol.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19](O)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:34]1([CH2:40][CH2:41][NH2:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.O>O1CCCC1>[C:1]1([CH:7]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:42][CH2:41][CH2:40][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCN1CCCCC1
Reactant: O=C(O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCN1CCCCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C

Procedure:
To a suspension of 6-[(2,2-diphenylethyl)amino]-9-(tetrahydro-2H-pyran-2-yl) 9H-purine-2-carboxylic acid (249 g, 0.561 moles) (Preparation 21) in anhydrous tetrahydrofuran (2500 ml) was added N,N′-carbonyldiimidazole (109 g, 0.672 moles) in two portions over 10 minutes. The resulting mixture was stirred at ambient temperature under an atmosphere of nitrogen whereupon the solid gradually dissolved to give a cloudy pale orange solution. After stirring for 2.5 h, the reaction mixture was cooled in an ice-bath, and a solution of 2-(1-piperidinyl)ethylamine (86.4 g, 0.674 moles) in anhydrous tetrahydrofuran (100 ml) was added over a period of 55 minutes during which time a clear orange solution formed. The reaction mixture was stirred at room temperature for a further 17.5 hours. Deionised water (10 ml) was then added and the reaction mixture was then distilled at atmospheric pressure until approximately 2400 ml of distillate had collected. To the resultant amber oil was added isopropanol (2000 ml) and distillation at atmospheric pressure was continued until approximately 50 ml of distillate had collected. The resultant dark orange solution was allowed to cool to ambient temperature and further isopropanol (600 ml) was added to give a solution of the title compound in isopropanol that may be used directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: COc1cnc(Cl)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.08 %

Procedure:
2,4-Dichloro-5-methoxy-pyrimidin (3.2 g, 1.0 eq) was stirred in toluene (20 ml) and a solution of morpholine (2.34 ml, 1.5 eq) in toluene (20 ml) was added dropwise at −10˜0° C. After stirring the resulting solution overnight at r.t., NH4Cl (aq) was added and the solution was extracted with EA. The combined organic layers were washed with brine, dried and evaporated in vacuo. A product was obtained as a white solid (3.80 g, 93.08%)
Reaction SMILES: [C:1]([N:5]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]I.Cl>CN(C)C=O.O>[CH3:25][N:6]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CI
Reactant: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)c1ccccc1)N(C(=O)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N'-t-butyl-N,N'-dibenzoylhydrazine (2.5 g, 0.008M) in dimethylformamide (DMF) (30 ml) at room temperature under nitrogen was added portionwise sodium hydride (60% oil dispersion) (0.4 g, 0.009M). The mixture was stirred at room temperature for 0.5 hours, and then methyl iodide (1.0 g, 0.008M) was added dropwise. The reaction mixture was allowed to stir for 1 hour. The mixture was then diluted with water (50 ml), neutralized with 10% HCl and the product extracted into methylene chloride (50 ml). The methylene chloride layer was washed with water (5×20 ml), dried over anhydrous magnesium sulfate and the methylene chloride removed under vacuum to afford N-methyl-N'-t-butyl-N,N'-dibenzoylhydrazine as an oil.
Reaction SMILES: Cl[CH:2]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[N:15][CH:16]=2)[O:6][C:7]=1[CH2:8][O:9][CH3:10].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH:19]1([CH:2]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:3]2[CH:4]=[C:5]([C:11]3[CH:16]=[N:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[O:6][C:7]=2[CH2:8][O:9][CH3:10])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COCc1oc(-c2ccc(OC)nc2)cc1C(Cl)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCc1oc(-c2ccc(OC)nc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 14.9 %

Procedure:
A mixture of 5-{4-[chloro(cyclohexyl)methyl]-5-(methoxymethyl)furan-2-yl}-2-methoxypyridine (0.4 g), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.4 g), sodium carbonate (0.2 g) and sodium iodide (0.2 g) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 70% ethyl acetate/hexane). To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.45 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (91 mg, 14%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)=[C:11]2[C@H:25]([CH3:28])[CH2:26][NH2:27])([CH3:7])[CH3:6])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl-].C([N+]1(C)[CH2:44][CH2:43][C:42](=[O:45])[CH2:41][CH2:40]1)C>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:29])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([CH3:23])[CH:22]=1)=[C:11]2[C@H:25]([CH3:28])[CH2:26][N:27]1[CH2:44][CH2:43][C:42](=[O:45])[CH2:41][CH2:40]1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CC[N+]1(C)CCC(=O)CC1
Reactant: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c([C@H](C)CN)c2c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c([C@H](C)CN3CCC(=O)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a solution of (S)-2-[3-(2-amino-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid ethyl ester (EXAMPLE 1, Step 1B, 0.50 g in 2 mL ethanol) was added 18 mg potassium carbonate followed by the dropwise addition of a solution of 1-ethyl-1-methyl-piperidinium-4-one chloride (513 mg in 0.80 mL water) and the mixture heated to reflux on an oil bath. After 1 hour, the mixture was cooled to room temperature, diluted with ethyl acetate and washed successively with 10% aqueous sodium bisulfate, water, saturated aqueous sodium bicarbonate and brine. The organic portion was dried over sodium sulfate, concentrated in vacuo and the residue purified by flash chromatography on silica gel (hexane:ethyl acetate, 7:3) to give the title compound (356 mg).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB(/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]1([C:24]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH2:23])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: CC1(C)OB(/C=C/c2ccccc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(c1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
To a solution of tert-butyl 4-bromobenzoate (616 mg, 2.4 mmol) in 1,4-dioxane and water (4:1, 10 mL) were added (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (553 mg, 2.4 mmol), tetrakis(triphenylphosphine)palladium (58.9 mg, 0.05 mmol) and sodium carbonate (164 mg, 1.55 mmol). The mixture was stirred at 90° C. under nitrogen atmosphere for 18 hours. Once the start material was consumed, the resultant mixture was concentrated to give a residue and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=30:1) to give tert-butyl 4-(1-phenylvinyl)benzoate (0.59 g, 87.5%). 1H NMR (300 MHz, CDCl3): δ 7.96 (d, J=4.8 Hz, 2H), 7.41-7.26 (m, 7H), 5.55-5.53 (m, 2H), 1.61 (s, 9H).
Reaction SMILES: Cl.CO.[OH:4][C:5]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:6]=1[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]([S:16][CH3:17])=[S:15])[CH2:10][CH2:9]1>O>[C:5]1(=[O:4])[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[C:6]1[CH2:7][N:8]1[CH2:9][CH2:10][N:11]([C:14]([S:16][CH3:17])=[S:15])[CH2:12][CH2:13]1
Reactant: CSC(=S)N1CCN(Cc2cc(O)ccc2O)CC1
Agent: Cl
Solvent: CO
Solvent: O
Product: CSC(=S)N1CCN(CC2=CC(=O)C=CC2=O)CC1
Reaction time: 0.17 h
Yield: 34.6 %

Procedure:
In a mixture of 6.8 ml of 1-N hydrochloric acid and 6.8 ml of methanol was dissolved 680 mg of methyl 4-(2,5-dihydroxybenzyl)-1-piperazinecarbodithioate. The resulting solutionwas chilled with ice, and to this was drowpise added a solution of 1.24 g (5.3 mmol.) of FeCl3.6H2O in 4.3 ml of water for 15 min. To this was further added 25 ml of methanol. To thus obtained homogeneous solution was again added a solution of 2.2 g of FeCl3.6H2O in 10 ml of water. The mixture was then stirred for 10 min. and placed under reduced pressure to distill off methanol. To the residue was added 50 ml of chloroform, and to this was added a saturated sodium hydrogen carbonateto adjust pH of the mixture to 7. Insolubles were removed by filtration. The organic solvent portion was taken out, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. Theresidue was then purified by silica gel column chromatography to give 234 mg of the desired compound as a yellow powder, m.p. 115°-116° C. (decomp.), yield 38.9%.
Reaction SMILES: [Na].[C:2]([OH:5])(=[S:4])[CH3:3].[CH3:6][O:7][C:8](=[O:15])/[CH:9]=[C:10](/[O:13][CH3:14])\[CH2:11]Cl>CO>[CH3:6][O:7][C:8](=[O:15])/[CH:9]=[C:10](/[O:13][CH3:14])\[CH2:11][O:5][C:2](=[S:4])[CH3:3]
Reactant: COC(=O)/C=C(\CCl)OC
Reactant: CC(O)=S
Agent: [Na]
Solvent: CO
Product: COC(=O)/C=C(\COC(C)=S)OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
4.07 g (0.177 mol) of sodium is dissolved in 180 ml of methanol and cooled to 0° C. 13.47 g (0.171 mol) of thioacetic acid is instilled in this solution. Then this solution is mixed at 0° C. with a solution of 29.15 g (0.150 mol) of 3-methoxy-4-chloro-2E-butenoic acid methyl ester in 'ml of methanol. It is stirred again overnight at room temperature. The precipitated salt is filtered off, the solvent is evaporated on the rotary evaporator and mixed with a little methylene chloride for precipitation of the remaining salt. After filtering off, evaporation of the solvent and drying of the residue in a high vacuum, 36.53 g of a yellow-colored liquid with a content according to GC of 82.8 percent is obtained. This corresponds to 30.25 g of 100 percent product ≐98.7 percent yield. Further data concerning the compound is:
Reaction SMILES: ClC1C=C(C=CC=1)C(O[CH:8]1[C:13](=[O:14])[NH:12][C:11]([CH3:15])=[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[S:9]1)=O.[O:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1>C(#N)C>[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:8]1[C:13](=[O:14])[NH:12][C:11]([CH3:15])=[C:10]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)[S:9]1
Reactant: c1ccoc1
Reactant: CC1=C(c2ccncc2)SC(OC(=O)c2cccc(Cl)c2)C(=O)N1
Solvent: CC#N
Product: CC1=C(c2ccncc2)SC(c2ccco2)C(=O)N1
Temperature: 50 °C
Reaction time: 35 h
Yield: 38.6 %

Procedure:
Silica gel (Wakogel C-200, 0.03 g) was added as catalyst to a solution of 2-(3-chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (0.79 g) and furan (0.30 g) in acetonitrile (30 ml) and the mixture was stirred at 50° C. for 35 hours. The mixture was chromatographed on silica gel (Wakogel C-200) column, using acetonitrile as an eluant. The residue was recrystallized from acetonitrile to give the titled compound (0.23 g, yield 37.7%) as pale orange crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7].[I-:15].[Na+]>CC(C)=O>[I:15][CH2:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7]
Reactant: C=CCOC(=O)c1cccc(CCl)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCOC(=O)c1cccc(CI)c1

Procedure:
A solution of allyl 3-(chloromethyl)-benzoate (54.5 g, 0.259 mmol) and sodium iodide (46.56 g, 0.311 mol) in acetone (500 mL) is stirred at room temp. for 6.5 hours, after which time the mixture is filtered. The filtrate is evaporated and the residue is dissolved in diethyl ether (500 mL), then washed with water (1×200 mL), 5% sodium sulfite solution (1×200 mL) and brine (1×200 mL), dried over magnesium sulfate, and evaporated to yield allyl 3-(iodomethyl)-benzoate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([F:12])[CH3:11])=[CH:6][C:5]=1[N+:13]([O-])=O>CO.CCO.[Ni]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([F:12])[CH3:11])=[CH:6][C:5]=1[NH2:13]
Reactant: COC(=O)c1ccc(C(C)F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Solvent: CO
Product: COC(=O)c1ccc(C(C)F)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
A solution of 4-(1-fluoro-ethyl)-2-nitro-benzoic acid methyl ester (0.6 g, 2.64 mmol) in MeOH (15 mL) was treated with Nickel-raney in EtOH (254 mL) and the mixture was stirred at r.t. for 3 h under H2 (0.1 bar). The mixture was then filtered and concentrated in vacuo to give 2-amino-4-(1-fluoro-ethyl)-benzoic acid methyl ester (334 g, 1.69 mmol, 93%) as a yellow oil. ESI-MS: m/z 198 [M+H]+, rt 4.86 min.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[C:21]1([CH3:38])[CH:26]=[CH:25][C:24](S(OCC2CCCCC2)(=O)=O)=[CH:23][CH:22]=1>>[CH:21]1([CH2:38][N:7]2[C:8]([C:9](=[O:18])[C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]2=[O:19])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCCC2)cc1
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(CC2CCCCC2)c(=O)[nH]c1=O
Yield: 63.2 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and (cyclohexyl)methyl para-toluenesulfonate were reacted by the same way with the example 1 to obtain the titled compound (233 mg, yield: 63.2%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][P:6]([O-:10])[O:7][CH2:8][CH3:9])[CH3:4].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17]Cl>CCCCC>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][P:6]([O:7][CH2:8][CH3:9])([O:5][CH2:3][CH3:4])=[O:10]
Reactant: CCOP([O-])OCC
Reactant: ClCOCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Product: CCOP(=O)(COCCCCBr)OCC
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a slurry of 6.26 g (149 mmol) of 57% NaH and 300 mL of n-pentane at 0° C. was added 17.14 g (124 mmol) of diethylphosphite and the mixture was stirred for 1 hour at 0°. The mixture was then cooled to -70° and 25 g (124 mmol) of 1-bromo-4-(chloromethoxy)butane was added and the reaction mixture warmed to 0° and stirred for 1 hour. The mixture was then filtered and evaporated. The residue was purified by SiO2 chromatography to give 26 g (70%) of 1-bromo-4-(diethylphosphonomethoxy)butane as a colorless oil.
Reaction SMILES: [CH:1](OC)(OC)OC.[Cl:8][C:9]1[C:10]([NH:22][NH2:23])=[N:11][CH:12]=[C:13]([CH:21]=1)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[Cl:8][C:9]1[C:10]2[N:11]([CH:1]=[N:23][N:22]=2)[CH:12]=[C:13]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH:21]=1
Reactant: COC(OC)OC
Reactant: CC(C)(C)OC(=O)c1cnc(NN)c(Cl)c1
Product: CC(C)(C)OC(=O)c1cc(Cl)c2nncn2c1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
Trimethyl orthoformate (19 mL, 172 mmol) was added neat to tert-butyl 5-chloro-6-hydrazinonicotinate (1.9 g, 7.8 mmol). The mixture was heated to 85° C. After 4 h, the mixture was cooled to ambient temperature and concentrated to dryness: LC-MS [M+1]=254.1.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH3:32].C(OCC)(=O)C>CN(C=O)C>[CH2:29]([N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCBr
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 95 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.350 g, 1.24 mmol), K2CO3 (0.427 g, 3.09 mmol), and 1-bromobutane (0.178 g, 1.30 mmol) in DMF (6.2 mL). Heat at 95° C. for 5.5 hours, then at 50° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL) and brine (1×30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 20% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 340.2 (M+H)+, HRMS calcd for C20H26N3O2 340.2025 (M+H)+, found 340.2019, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min. 20-95% over 18 min], tR=9.6 min, 98.3% purity.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1.O>C1COCC1>[NH2:3][C:4]1[C:9]([Br:1])=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1
Reactant: BrBr
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncc([N+](=O)[O-])cc1Br
Reaction time: 1 h
Yield: 81.1 %

Procedure:
Bromine (62.6 mλ; 1.2 mole) was dropwise added to 2-amino-5-nitropyridine (154.1 g; 1.1 mole) in THF (300 mλ) at room temperature. The resulting mixture was stirred for one hour and then poured into water (3 λ). The crystals thus formed were recrystallized from acetonitrile (500 mλ) to give 2-amino-3-bromo-5-nitropyridine (A) (194.4 g; 80%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]#[CH:11])[C:7]([CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]=1[NH2:15].[N:17]1[CH:22]=[CH:21]N=N[N:18]=1>ClCCCl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]2[CH:21]=[CH:22][N:17]=[N:18][CH:11]=2)[C:7]([CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]=1[NH2:15]
Reactant: c1cnnnn1
Reactant: C#Cc1cc(C(=O)OC)c(N)cc1C(C)C
Solvent: ClCCCl
Product: COC(=O)c1cc(-c2ccnnc2)c(C(C)C)cc1N
Yield: 26.4 %

Procedure:
A solution of 2-amino-5-ethynyl-4-isopropyl-benzoic acid methyl ester (718 mg, 3.3 mmol) and tetrazine (406.8 mg, 5.0 mmol) in 1,2-dichloroethane (15 mL) in a sealed tube was heated in the microwave at 130° C. for 45 min. The reaction mixture was then concentrated in vacuo and the residue was purified by flash chromatography (50 g silica gel, hexanes→EtOAc:hexanes (1:1)) to provide the title compound (236 mg, 26%). API-ES: m/z 272 [M+H]+, rt 3.38 min.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=O)=[CH:4][CH:3]=1.[NH2:14][OH:15]>C(O)C>[Br:1][C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[N:14][OH:15])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(Br)c2cnccc12
Solvent: CCO
Product: ON=Cc1ccc(Br)c2cnccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 8-bromo-5-isoquinolinecarboxaldehyde (i.e. a product from Step A) (75 mg, 0.3 mmol) in ethanol (7 mL) was added an aqueous solution of hydroxylamine (0.5 mL, 50% in water). After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure to provide the title compound as a yellow solid (70 mg).