Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:2]([CH2:10][N:11]([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[I:18]N1C(=O)CCC1=O.O>C(#N)C>[I:18][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][C:2]=1[CH2:10][N:11]([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)CN(C)Cc1cn2ccccc2n1
Solvent: O
Solvent: CC#N
Product: COC(=O)CN(C)Cc1nc2ccccn2c1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.4 %

Procedure:
0.107 g (0.459 mmol) of methyl 2-((imidazo[1,2-a]pyridin-2-ylmethyl)(methyl)amino)acetate were dissolved in 4 ml of acetonitrile with magnetic stirring, to this solution were added 0.112 g (0.482 mmol) of N-iodosuccinimide. The mixture was stirred at r.t. for 16 h. The reaction mixture was treated with 10 ml of water and then extracted with 3×10 ml of ethyl acetate. The combined organic phases were washed with 20 ml of a saturated NaCl aqueous solution, and then dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: ethyl acetate 100%). 0.093 g (yield=46%) of methyl 2-(((3-iodoimidazo[1,2-a]pyridin-2-yl)methyl)(methyl)amino)acetate were obtained as a yellow oil. LC-MS: m/z=360 (MH+); UV purity at 254 nm=82%. 1H NMR (300 MHz, DMSO) δ 8.30 (d, J=6.8 Hz, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.41-7.23 (m, 1H), 7.03 (t, J=6.7 Hz, 1H), 3.79 (s, 2H), 3.62 (s, 3H), 3.37 (s, 2H), 2.34 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([O-:9])=[O:8].[CH2:17]([O:19][C:20](=[O:29])[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)Br)[CH3:18]>CN(C=O)C>[CH2:17]([O:19][C:20](=[O:29])[CH:21]([O:16][C:13]1[CH:14]=[CH:15][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:18]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of cesium carbonate (2.51 g, 7.70 mmol) in DMF (30 mL) was added 4-nitrophenol(1.07 g, 7.70 mmol). After stirring at room temperature under argon for 30 minutes, ethyl-alpha-bromophenylacetate (1.70 g, 7.00 mmol) was added to the suspension and the resulting mixture was stirred at room temperature overnight. The reaction was then quenched with water and extracted with EtOAc. The organic extracts were washed with water, brine, and dried over Na2SO4. After removing the solvent under reduced pressure, the crude product was used in the next reaction without further purification. 1H NMR (400 MHz, CDC3) δ8.20 (d, 2H) 7.60-7.37 (m, 5H), 7.05 (d, 2H), 5.70 (s, 1H), 4.20 (m, 2H), 1.22 (t, 3H). MH+ 303.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>C(OCC)C>[C:1]([Cl:12])(=[O:9])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccncc1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: O=C(Cl)c1ccncc1

Procedure:
123 g (1 mol) of isonicotinic acid are placed in a 1 liter round-bottomed flask equipped with a condenser and a calcium chloride drying tube, and 250 ml of thionyl chloride are added all at once, whilst cooling with an ice bath. The exothermic reaction lasts about ten minutes. The mixture is then heated under reflux on an oil bath for one and a half hours. The excess thionyl chloride is driven off and the crystalline residue is taken up in 100 ml of dry diethyl ether. The mixture is stirred and the white precipitate which forms is filtered off, washed again with 50 ml of diethyl ether and dried to yield 171 g of isonicotinoyl chloride in the form of the hydrochloride. 92 g (0.516 mole) of this are placed in a 2 liter three-necked flask equipped with a thermometer, a stirrer, a condenser and a calcium chloride drying tube, and 300 ml of anhydrous toluene are added. The mixture is cooled to 10° C., 262 g (1.96 mol) of ground aluminium chloride are added in small portions and the mixture is stirred for 2 hours at ambient temperature. The dark red solution is then transferred to a dropping funnel and added dropwise to 2.5 liters of iced water cooled with an ice bath. 800 ml of ethyl acetate are then added, followed by the addition of 1 liter of sodium carbonate solution (d=1.33), with cooling. This gives a solution from which the organic phase is decanted. The aqueous phase is extracted a further three times with 500 ml of ethyl acetate, the organic phases are combined, washed with water and dried and the solvent is evaporated off in vacuo in a water bath. The residue is triturated with 100 ml of ethanol, whilst cooling in an ice bath. It is isolated by filtration and dried to give 80 g of 4-(4-methylbenzoyl)-pyridine. 42.6 ml of hydrazine hydrate and 18.4 ml of water are then added, followed by 420 ml of ethylene glycol and then by 103.5 g of sodium hydroxide pellets. The mixture is heated under reflux for 2 hours and cooled and 1 liter of water is added. The supernatant oil is extracted with diethyl ether (4×250 ml). The ether phase is washed with water, dried and evaporated. This gives 72 g of 4-(4-methylbenzyl)-pyridine in the form of an oil which crystallises.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:37]4[CH2:38][CH2:39][C@H:35]([F:34])[CH2:36]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1
Reactant: F[C@H]1CCNC1
Reactant: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CC[C@H](F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-cyclohexylmethyl)-amide, DIPEA and (S)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.75 (m, 1H), 7.55 (2H), 7.05 (1H), 5.43-5.56 (1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 426 [M+H]
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[CH:16]=[C:15]([F:17])[C:14]([N+:18]([O-:20])=[O:19])=[CH:13]C=1C(O)=O.C(Cl)Cl>CN(C)C=O>[F:7][C:8]1[CH:16]=[C:15]([F:17])[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1F
Temperature: 25 °C
Yield: 101.8 %

Procedure:
Oxalyl chloride (94.0 g, 0.739 mol) is added dropwise to a mixture of 2,4-difluoro-5-nitrobenzoic acid (100.0 g, 0.492 mol), methylene chloride and N,N-dimethylformamide (0.600 ml). The resultant mixture is stirred 3.25 hours at reflux, cooled to room temperature, and concentrated in vacuo to afford the title compound as a brown oil (111 g, 95.2%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C@@H:13]([CH3:23])[CH2:12][N:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[NH:30][C:31]([C:33]2[C:42]([NH:43]C(=O)OCC3C=CC=CC=3)=[CH:41][C:40]3[C:35](=[CH:36][C:37]([C:54]4[CH2:55][CH2:56][O:57][CH2:58][CH:59]=4)=[CH:38][CH:39]=3)[N:34]=2)=[O:32])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:43][C:42]1[C:33]([C:31]([NH:30][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][C:24]=2[N:11]2[CH2:12][C@H:13]([CH3:23])[C@@H:14]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10]2)=[O:32])=[N:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[C:37]([CH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)[CH:36]=2
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(C4=CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(C4CCOCC4)ccc3cc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 62 %

Procedure:
A mixture of benzyl [2-({[4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)pyridin-3-yl]amino}carbonyl)-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-3-yl]carbamate (0.023 g, 0.028 mmol) in 1.5 mL of MeOH was hydrogenated in the presence of 10% Pd on carbon (10 mg) under a balloon of hydrogen at room temperature for 1 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford a hydrogenated intermediate tert-butyl ((3R,4R,5S)-1-[3-({[3-amino-7-(tetrahydro-2H-pyran-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (0.012 g, 62%). LCMS calc. for C37H55N6O5Si [M+H]+: m/z=691.4. found: 691.5.
Reaction SMILES: C(O[CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:7][CH:6]=1)C.[O-]S([O-])(=O)=O.[Na+].[Na+].Cl.[NH2:32][OH:33]>CC1OCCC1.CC(OC)(C)C>[OH:33][N:32]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:7][CH:6]=1
Reactant: NO
Reactant: CCOC(OCC)c1ccc(CN(C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: COC(C)(C)C
Product: CN(Cc1ccc(C=NO)cc1)C(=O)OC(C)(C)C
Temperature: 30 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
A biphasic solution of tert-butyl N-[[4-(diethoxymethyl)phenyl]methyl]-N-methyl-carbamate (50.0 g, 154.6 mmol) in 2-MeTHF (400.0 mL) and Na2SO4 (100.0 mL of 10% w/v, 70.40 mmol) was stirred at 8-10° C. in a 1-L, glass-jacketed reactor. Hydroxylamine hydrochloride (46.38 mL of 5.0 M, 231.9 mmol) was added and the biphasic solution was stirred at 30° C. for 16 hours. The reaction was diluted with MTBE (200.0 mL) and the layers separated. The organic phase was washed with water (200.0 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was diluted with heptane (200.0 mL) and the resultant suspension was stirred at ambient temperature for 30 minutes. The solid was collected by filtration to give the title compound as a white solid (36.5 g, 89% Yield); 1H NMR (400 MHz, CDCl3) δ 1.50 (s, 9H), 2.88 (br s, 3H), 4.60 (s, 2H), 7.26 (d, 2H), 7.52 (d, 2H) and 8.15 (s, 1H) ppm.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1)[NH2:2].[CH3:13][O:14][C:15]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.Cl>>[CH3:13][O:14][C:15]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[N:2][NH:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1
Reactant: NNC1=NCCc2ccccc21
Reactant: COc1cccc(C=O)c1OC
Agent: Cl
Product: COc1cccc(C=NNC2=NCCc3ccccc32)c1OC

Procedure:
In a manner similar to that of Example 4, condensation of 1-hydrazino-3,4-dihydroisoquinoline (5.7 g.) and 2,3-dimethoxybenzaldehyde (6.17 g.) and treatment of the reaction mixture with hydrochloric acid gave a solid, which was recrystallized twice from ethanol, affording 1-[2-(2,3-dimethoxybenzylidene)-hydrazino]-3,4-dihydroisoquinoline (I: X=2,3-(CH3O)2C6H3, X'=Y=Y'=Z=Z'=H) hydrochloride (8.2 g., m.p. 222°-223° C.).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].Br[C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[N:36]([CH3:38])[CH3:37]>>[CH3:37][N:36]([CH3:38])[C:35]1[CH:34]=[C:33]([C:9]2[C:10]3[O:14][CH2:13][CH:12]([C:15]4[CH:20]=[CH:19][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:17][CH:16]=4)[C:11]=3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[C:8]=2[CH3:29])[CH:41]=[CH:40][CH:39]=1
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Reactant: CN(C)c1cccc(Br)c1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cccc(N(C)C)c1)OCC2c1ccc(C(C)C)cc1
Yield: 77 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 3-bromo-N,N-dimethylaniline, the title compound was obtained in the same manner as in Example 107. Yield: 77%. Melting point: 197-199° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11](=[O:14])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:18][C:19]#[C:20][CH2:21][CH3:22]>CN(C=O)C>[CH2:18]([N:10]1[C:11](=[O:14])[CH:12]=[N:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)[C:19]#[C:20][CH2:21][CH3:22]
Reactant: O=c1cnc(-c2ccc(Cl)cc2)n[nH]1
Reactant: CCC#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC#CCn1nc(-c2ccc(Cl)cc2)ncc1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The 0.4 g of 3-(4-chlorophenyl)-1,2,4-triazin-6-one (1.9 mmol) was placed in 10 mL of DMF and cooled in an ice bath. Sodium hydride (NaH) (0.8 g of 60% dispersion, 2 mmol) was added, and the reaction mixture was held for 15 minutes. Excess 1-chloro-2-pentyne was added, the bath was removed, and the reaction mixture was allowed to warm to room temperature. Water and ethyl acetate were added. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and stripped. The crude product was chromatographed on silica gel to give 0.05 g of 1-(2-pentynyl)-3-(4-chlorophenyl)-1,2,4-triazin-6-one.
Reaction SMILES: C([NH:8][C@H:9]([C:17]([CH:19]1[CH:26]2[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:28][C:20]1([NH2:29])[CH2:21]3)[CH2:25]2)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(OC(C)(C)C)=O.ClCCl>FC(F)(F)C(O)=O>[NH2:8][C@H:9]([C:17]([CH:19]1[CH:26]2[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:28][C:20]1([NH2:29])[CH2:21]3)[CH2:25]2)=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2CC3CC(C2)CC1(N)C3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C(=O)C1C2CC3CC(C2)CC1(N)C3
Reaction time: 0.75 h

Procedure:
Under a nitrogen atmosphere a solution of 9.5 g of Boc-L-phenylalanyl-1-aminoadamantane in 25 ml of cold, dry dichloromethane is diluted with 25 ml of trifluoroacetic acid. The reaction is allowed to proceed for 45 minutes then the solution is concentrated and 50 ml of methylene chloride is added. The solution is washed with 25 ml portions of ice cold water, 2 M potassium carbonate solution, and saturated sodium chloride solution then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is rubbed with ethyl ether and the solid isolated and dried over potassium hydroxide under reduced pressure to give L-phenylalanyl-1-aminoadamantane which is represented by the following formula ##STR33##
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:13][O:14][C:15]=3[CH3:16])[N:10]=2)[CH:7]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>>[N:23]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([C:11]4[C:12]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)=[N:13][O:14][C:15]=4[CH3:16])[N:10]=3)[CH:7]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: c1c[nH]cn1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(I)ccc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(-n3ccnc3)ccc2n1
Yield: 29 %

Procedure:
As described for Example 60, 6-iodo-2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine (47 mg, 0.13 mmol) was converted, using imidazole instead of benzamide, to the title compound (13 mg, 29%) which was obtained as a brown foam. MS: m/e=342.3 [M+H]+ as the most polar component.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[C:18]([O:25][CH3:26])[C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[CH:12]2.[Cl-].O.NN>CO>[NH2:22][C:21]1[C:3]([O:2][CH3:1])=[C:4]([C:18]([O:25][CH3:26])=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[CH:12]2
Reactant: COc1ccc([N+](=O)[O-])c(OC)c1COc1cccc2ccc(C)nc12
Agent: NN
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: COc1ccc(N)c(OC)c1COc1cccc2ccc(C)nc12
Yield: 63.7 %

Procedure:
To a mixture of 8-[2,6-dimethoxy-3-nitrobenzyloxy]-2-methylquinoline (2.28 g), ferrric chloride (68 mg), carbon (68 mg) and methanol (34 ml) was added hydrazine monohydrate (1.25 ml) at 60° C., and the mixture was refluxed for 4 hours. Ferric chloride (68 mg), carbon (68 mg), hydrazine monohydrate (1.25 ml) and methanol (10 ml) was further added, and the mixture was refluxed overnight. Insoluble materials were filtered off, and the filtrate was concentrated. The residue was dissolved in chloroform, and the solution was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) and crystallized with methanol to give 8-[3-amino-2,6-dimethoxybenzyloxy]-2-methylquinoline (1.33 g) as pale brown crystals.
Reaction SMILES: [CH:1]12[N:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:6]1[CH2:5][CH2:4][N:3]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:2]2.[CH:25]1([CH2:29][Mg]Br)[CH2:28][CH2:27][CH2:26]1.C1COCC1.[NH4+].[Cl-]>[Cu]I>[C:11]([O:10][C:8]([NH:7][C@H:1]1[C@H:6]([CH2:29][CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH2:5][CH2:4][N:3]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:2]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: Br[Mg]CC1CCC1
Reactant: CC(C)(C)OC(=O)N1C2CCN(C(=O)OCc3ccccc3)CC21
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1CC1CCC1
Temperature: 25 °C
Reaction time: 0.13 h
Yield: 19 %

Procedure:
(±)-3-benzyl 7-tert-butyl 3,7-diaza-bicyclo[4.1.0]heptane-3,7-dicarboxylate (62 mg, 0.187 mmol), CuI (8 mg, 0.2 equiv), and a stirring bar were put in a 100-mL flask. The flask was evacuated and backfilled with N2 gas (3×). Dry THF (5 mL) was added and the mixture was cooled to −40° C. (Cyclobutylmethyl)magnesium bromide in THF (620 μL, 3 equiv., ˜0.89 M) was added slowly. After 8 min, the reaction mixture was allowed to warm slowly to rt. After 20 min, the reaction mixture turned black. After stirring a further 2 h the reaction was complete. Satd aq NH4Cl solution (5 mL) was added to quench the reaction. The reaction mixture was partitioned between EtOAc (50 mL) and satd aq NH4Cl solution (20 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined EtOAc layers were washed with water (15 mL), brine (15 mL), and dried over Na2SO4. After concentration, the residue was purified by Gilson to afford (±)-trans-benzyl 3-(tert-butoxycarbonylamino)-4-(cyclobutylmethyl)piperidine-1-carboxylate (14 mg, 19% yield). MS ESI +ve m/z 425 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[CH:11](O)=[O:12].Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:11]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)=[O:12]
Reactant: O=CO
Reactant: Nc1ccc2c(c1)CCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=CNc1ccc2c(c1)CCC2
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of 5-aminoindane (7.53 g, 56.5 mmol) in DMF (100 mL) was added formic acid (2.2 mL, 58.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.94 g, 57 mmol) and diisopropylethylamine (19.7 mL, 0.11 mol). The resulting solution was stirred overnight and then partitioned between saturated aqueous citric acid (100 mL) and ethyl acetate (200 mL). The organic layer was separated and washed with aqueous sodium bicarbonate solution (100 mL) and water (3×100 mL), then concentrated under reduced pressure to give the formamide as a thick oily solid (8.5 g, 93%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][NH:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1.ClC[CH2:26][O:27][CH2:28]CCl>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[N:14]=[CH:13][N:12]([CH2:26][O:27][CH3:28])[C:11]=2[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)=[CH:17][CH:18]=1
Reactant: ClCCOCCCl
Reactant: COc1ccc(-c2nc[nH]c2-c2ccc(OC)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COCn1cnc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Reaction time: 0.5 h

Procedure:
Incremental portions of 3.6 g of sodium hydride (50% strength in white oil) is added to a solution of 21 g of 4,5-bis(4-methoxyphenyl)imidazole in 75 ml of absolute dimethylformamide. The mixture is stirred for another 30 minutes, and then 6.3 ml of 1-chloromethylmethyl ether in 35 ml of dimethylformamide is added dropwise. After 30 minutes the mixture is poured on ice water, the product is taken up in chloroform, the organic solution is washed with water, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is crystallized from benzene/hexane, thus obtaining 18.31 g of 4,5-bis(4-methoxyphenyl)-1-methoxymethylimidazole, mp 99°-101°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([NH:13][NH:14][C:15](=[O:23])[CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:12])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.FC(F)(F)C(O)=O>C(OCC)(=O)C.FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([NH:13][NH:14][C:15](=[O:23])[CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:12])[C:5]2[CH:6]=[N:7][N:8]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][O:24]3)[C:9]=2[CH:10]=1
Reactant: O=C(CN1CCOCC1)NNC(=O)c1cc(Br)cc2[nH]ncc12
Reactant: C1=COCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(CN1CCOCC1)NNC(=O)c1cc(Br)cc2c1cnn2C1CCCCO1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 70.3 %

Procedure:
6-Bromo-N′-(4-morpholinylacetyl)-1H-indazole-4-carbohydrazide (0.232 g, 0.607 mmol) in ethyl acetate (3 ml) was treated with 3,4-dihydro-2H-pyran (0.111 ml, 1.214 mmol) then heated to 50° C. under nitrogen. Trifluoroacetic acid (4 drops) was added and heating continued for 1.5 h at 50° C. A further portion of 3,4-dihydro-2H-pyran (0.111 ml, 1.214 mmol) and trifluoroacetic acid (0.047 ml, 0.607 mmol) were added and heating continued for a further 1.5 h. The solution was left to stand at room temperature for 18 h. The clear solution was diluted with ethyl acetate (5 ml), washed with saturated aqueous sodium bicarbonate (2×10 ml), filtered through a phase separator cartridge then blown to dryness and left under vacuum. The crude product was dissolved in dichloromethane (2 ml) and purified on a silica (5 g) cartridge which was eluted with a gradient of methanol and chloroform and the appropriate fractions evaporated to give the title compound as a beige gummy solid (0.199 g).