Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3]I.[Cl:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:13]([C:15]3[C:19]4=[N:20][C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=[C:18]4[NH:17][CH:16]=3)=[CH:14][C:7]=12>CN(C=O)C.CCOC(C)=O>[Cl:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:29])=[O:30])[C:13]([C:15]3[C:19]4=[N:20][C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=[C:18]4[N:17]([CH3:3])[CH:16]=3)=[CH:14][C:7]=12
Reactant: CI
Reactant: COc1cc2[nH]cc(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)c2nc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reaction time: 1.5 h
Yield: 104.3 %

Procedure:
Add KOH (5.0 equiv., 21.6 mg) then MeI (5.0 equiv., 55.0 mg, 24 μL) to bisazaindole 28 (37.3 mg, 0.0772 mmol) stirred in DMF (5.0 mL) at 0° C., and stir the reaction medium at for 1.5 h. Then allow the reaction medium to return to room temperature, dilute it with EtOAc, wash it with saturated NaHCO3, dry (MgSO4) and concentrate, to obtain 29 (40 mg, 100%) as an amorphous solid: TLC (EtOAc at 40%/heptane) Rf=0.10.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[C:21]([CH:20]=[CH:19][N:18]=2)[C:23]#[N:24])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2cc(C#N)ccn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccnc(Oc2ccc(CCN)cc2)c1
Reaction time: 3 h
Yield: 179.4 %

Procedure:
{2-[4-(4-Cyanopyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (5.57 g, 8.2 mmol) was dissolved with magnetic stirring in CH2Cl2 (100 mL) in a 250 mL round bottom flask equipped with a dry nitrogen line at 25° C. To this solution was added trifluoroacetic acid (10 mL), and the reaction mixture was kept at 25° C. for 3 h. The solution was concentrated in vacuo. The residue was taken up in H2O (50 mL) and EtOAc (75 mL) and treated with conc. ammonium hydroxide (NH4OH) to adjust the pH to 9-10. The layers were separated, and the aqueous fraction was extracted twice with EtOAc. The pooled organic fractions were filtered and concentrated in vacuo to afford 2-[4-(2-aminoethyl)-phenoxy]-isonicotinonitrile (3.52 g, 89%) as a beige waxy solid: 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J=5.1 Hz, 1H), 7.27 (m, 2H), 7.19 (d, J=5.1 Hz, 1H), 7.15 (s, 1H), 7.07 (d, J=8.4 Hz, 2H), 3.00 (t, J=6.9 Hz, 2H), 2.78 (t, J=6.9 Hz, 2H), 1.63 (s, 2H); ESIMS m/z 240.1 ([M+H]+).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([I:16])=[CH:14][N:13]=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH3:23][C:24](OC(C)=O)=[O:25]>C1COCC1.O.C1COCC1>[CH:1]1([C:4]2[N:8]([C:24](=[O:25])[CH3:23])[N:7]=[C:6]([NH:9][C:10]3[C:15]([I:16])=[CH:14][N:13]=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: Ic1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)n1nc(Nc2nc(-c3ccccc3)ncc2I)cc1C1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.4 %

Procedure:
To the solution of N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-iodo-2-phenylpyrimidin-4-amine (3 g, 7.44 mmol) in THF/H2O (50 mL/25 mL), a solution of Ac2O (1.5 g, 14.88 mmol, 2.0 equiv.) in THF (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was filtered to afford compound 1-(5-cyclopropyl-3-(5-iodo-2-phenylpyrimidin-4-ylamino)-1H-pyrazol-1-yl)ethanone (2.2 g, 66%). LC-MS (m/z): 446.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:19][N:20]([CH3:22])[CH3:21])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)N1CCN(CC(=O)OC)CC1
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=CN(C)C)C(=O)OC)CC1
Reaction time: 48 h

Procedure:
To a solution of the product of step (i) (10 g) in dry DMF (80 ml) was added dimethylformamide dimethyl acetal (DMFDMA) (30 ml) and the reaction mixture was heated to reflux. After 2 days a further quantity of DMFDMA (30 ml) was added and refluxing was continued for a further 2 days. The reaction mixture was evaporated and the residue partitioned between aqueous ammonium chloride solution and ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica by elution with ethyl acetate to yield 1-ethoxycarbonyl-4-(1-dimethylamino-2-methoxycarbonylethen-2-yl)piperazine (7 g) as an orange oil: NMR (CDCl3) δ1.28 (3H, t), 2.90 (4H, m), 3.14 (6H, s), 3.50 (4H, m), 3.64 (3H, s), 4.12 (2H, q), 7.01 (1H, s); m/Z 286 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25](Br)=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:9])([F:11])[F:10])[C:2]2=[O:1])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1ncccc1C(F)(F)F
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2cccc(C(F)(F)F)c2=O)sc1C(=O)NCc1ccccc1
Yield: 37 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 2-hydroxy-3-(trifluoromethyl)pyridine in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 37% yield: mp 203-204° C.; 1H NMR (300 MHz, CDCl3) δ 9.01 (d, J=7.2 Hz, 1H), 7.87 (d, J=7.2 Hz, 1H), 7.36-7.23 (m, 5H), 6.53 (t, J=7.2 Hz, 1H), 6.10 (s, 1H), 4.57 (d, J=5.4 Hz, 2H), 2.69 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.7, 156.6, 152.2, 152.1, 139.3, 139.2, 137.4, 135.1, 128.9, 128.8, 127.8, 123.8, 121.9, 106.0, 44.2, 17.2; MS (ES+) m/z 394.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=O)[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23](O)=[O:24].B(F)(F)F.CCOCC.[BH4-].[Na+]>C1COCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:11][N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][CH2:23][OH:24])=[C:2]2[CH3:1])=[CH:14][CH:15]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(c1)c(CCO)c(C)n2Cc1ccc(Cl)cc1
Temperature: 12.5 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
A solution of indomethacin (10 g, 28 mmol) in THF (90 mL) was immersed in an ice bath to maintain an internal temperature of 10-15° C. To this solution was added BF3-Et2O (30 mL, 230 mmol) over 5 min, resulting in the formation of a precipitate. Sodium borohydride (4.2 g, 110 mmol) was added portionwise over 10 min resulting in vigorous effervescence. After gas evolution subsided the flask was stoppered and allowed to warm to room temperature. After 1 hour the pressure was vented through a needle. The heterogeneous mixture was stirred for 6 hours. The mixture was cooled in an ice bath and was quenched by adding saturated NaHCO3. To break the resultant emulsion the mixture was made acidic with 1N HCl and extracted with a 3:1 mixture of Et2O:Hexane (270 mL). The organic layer was washed with brine, dried over Na2SO4, and evaporated. The residue was taken up in a 3:1 mixture of hot Hex:EtOAc (80 mL). Upon cooling to room temperature, crystals began to form. Crystallization was completed by cooling to −20° C. The solid was removed by filtration, washed with cold 3:1 Hex:EtOAc (2×25), Hexane (1×25) and dried in vacuo. This gave the title compound (4.5 g, 49%) as a white solid. mp 113-115° C. 1H-NMR (300 MHz, CDCl3) δ 7.24 (d, J=8.4 Hz, 2H), 7.06 (d, J=9.1 Hz, 1H), 7.03 (d, J=3.5 Hz, 1H), 6.87 (d, J=8.3 Hz, 2H), 6.78 (dd, J=2.4 and 8.7 Hz, 1H), 5.23 (s, 2H), 3.86 (s, 3H), 3.84 (t, J=6.5 Hz, 2H), 2.99 (t, J=6.5 Hz, 2H), 2.29 (s, 3H); mass spectrum (API-TIS) m/z 330 (MH+). Anal calcd for C19H20ClNO2: C, 69.19; H, 6.11; N, 4.25; Cl, 10.75. Found: C, 68.98; H, 6.30; N, 4.08; Cl, 10.60.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=3)[C:20]([C:30]([F:33])([F:32])[F:31])=[CH:19][N:18]=2)=[CH:4][C:5]([CH3:15])=[C:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:7]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:13][CH2:12][C@H:11]([N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:10][CH2:9]2)[C:5]([CH3:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[C:20]([C:30]([F:33])([F:32])[F:31])=[CH:19][N:18]=1
Reactant: C1CCNCC1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCC(=O)CC4)cc3F)ncc2C(F)(F)F)n[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c([C@H]4CC[C@H](N5CCCCC5)CC4)cc3F)ncc2C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(5-fluoro-2-methyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone (30 mg, 0.065 mmol), piperidine (30 μL, 0.174 mmol) and acetic acid (75 μL, 0.13 mmol) was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (27.4 mg, 0.13 mmol) was added to the reaction and the reaction mixture was stirred overnight. The mixture was concentrated and purified by silica chromatography (MeOH/DCM 8:92) to afford N2-(2-fluoro-5-methyl-4-(trans-4-(piperidin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine; Rf: 0.32 (Silica; MeOH/DCM 8:92); ESMS m/z 532.3 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13](=[N:15][O:16][CH:17](O)[CH3:18])[CH3:14])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:20][C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13](=[N:15][O:16][CH2:17][CH2:18][O:20][C:21]3[CH:22]=[CH:23][C:24]([CH2:25][CH:26]4[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C:27]4=[O:51])=[CH:52][CH:53]=3)[CH3:14])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOC(C)O)c1ccc(-c2ccccc2)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(-c2ccccc2)cn1

Procedure:
Following a procedure similar to that described in Example 1(a), but using 513 mg of 2-[(1-(5-phenyl-2-pyridyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 39), 1.02 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 577 mg of triphenylphosphine and 383 mg of diethyl azodicarboxylate, 1.40 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([C:18]#[N:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])[CH:14]=[C:15]([C:18]#[N:19])[C:16]=1[OH:17]
Reactant: N#Cc1cc(C=O)cc(O)c1O
Reactant: O=C1CSC(=S)N1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: N#Cc1cc(C=C2SC(=S)NC2=O)cc(O)c1O
Temperature: 100 °C

Procedure:
A solution containing 0.61 g of rhodanine, 0.72 g of 3,4-dihydroxy-5-cyanobenzaldehyde and 0.1 ml of piperidine in 10 ml of acetic acid was heated for 4 h at 100° C. The product was filtered and washed with 2-propanol. Yield 0.35 g, mp>350° C.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:20])C2C=C(C)C(O)=C(C)C=2)[CH2:7][C:6](=[O:21])[C:5]2[CH:22]=[CH:23][CH:24]=[CH:25][C:4]=2[N:3]1[CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].[C:37]1(C(O)=O)[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][N:38]=1>>[O:1]=[C:2]1[C@@H:8]([NH:9][C:10]([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][N:38]=2)=[O:20])[CH2:7][C:6](=[O:21])[C:5]2[CH:22]=[CH:23][CH:24]=[CH:25][C:4]=2[N:3]1[CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28]
Reactant: Cc1cc(C(=O)N[C@H]2CC(=O)c3ccccc3N(CC(=O)OCc3ccccc3)C2=O)cc(C)c1O
Reactant: O=C(O)c1nccc2ccccc12
Product: O=C(CN1C(=O)[C@@H](NC(=O)c2nccc3ccccc23)CC(=O)c2ccccc21)OCc1ccccc1
Yield: 92 %

Procedure:
Was prepared by the method reported in 14a by reaction of 12 and isoquinoline-1-carboxylic acid to afford 930 mg (92%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]=[C:15]=[N:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[O:27][CH3:28])=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:14]=[C:15]([N:39]1[CH2:38][CH2:37][N:36]([C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=3)[CH2:41][CH2:40]1)[N:16]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[O:27][CH3:28])[CH:8]2[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: COC(=O)/C=C/c1cccc(F)c1N=C=Nc1cc(C(F)(F)F)ccc1OC
Solvent: ClCCl
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3ccc(F)cc3)CC2)N1c1cc(C(F)(F)F)ccc1OC
Reaction time: 90 h

Procedure:
550 mg (1.39 mmol) of methyl (2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]-imino}methylene)amino]phenyl}-2-propenoate (Example 18A) and 251 mg (1.39 mmol) of 1-(4-fluorophenyl)piperazine are stirred in the presence of a spatula tip of silica gel in 15 ml of dichloromethane for 1 hour. After 90 hours of stirring under reflux, the product is purified by chromatography on silica gel (dichloromethane, dichloromethane/ethyl acetate 10:1).
Reaction SMILES: [I:1]C1C=C(C=C(OC)C=1)N.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)N>>[I:1][C:15]1[CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=[C:13]([O:12][CH3:11])[CH:14]=1
Reactant: COc1cc(N)cc([N+](=O)[O-])c1
Reactant: COc1cc(N)cc(I)c1
Product: COc1cc(I)cc([N+](=O)[O-])c1

Procedure:
Certain 5-alkoxy-3-aminophenyl substituted olefinic amine compounds, such as (E)-N-methyl-5-(5-methoxy-3-aminophenyl)-4-penten-2-amine, can be synthesized by coupling a 3-halo-5-alkoxyaniline such as 3-bromo-5-methoxyaniline or 3-iodo-5-methoxyaniline (protected by a phthaloyl functionality) with an olefin containing a secondary alcohol functionality, 4-penten-2-ol, under Heck reaction conditions. The resulting secondary alcohol intermediate can be converted to its p-toluenesulfonate ester, followed by treatment with methylamine (which also removes the protecting group). Alternatively, certain 5-alkoxy-3-aminophenyl substituted olefinic amine compounds can be synthesized by coupling a 3-halo-5-alkoxyaniline such as 3-bromo-5-methoxyaniline or 3-iodo-5-methoxyaniline (protected by a phthaloyl functionality) with an olefinic side chain compound, such as N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine, followed by removal of the protecting groups. The required 3-halo-5-alkoxyaniline compounds such as 3-bromo-5-methoxyaniline and 3-iodo-5-methoxyaniline can be prepared using the techniques of T. A. Emokpae et al., J. Chem. Soc., Perkin Trans 2 (1):14-17 (1977) and B. Liedholm, Acta Chem. Scand., Ser. B 38:877-884 (1984). In the former method, 3-bromo-5-methoxyaniline and 3-iodo-5-methoxyaniline can be prepared starting from commercially available 1,3,5-trinitrobenzene. Treatment of the latter compound with refluxing sodium methoxide produces 3,5-dinitroanisole. One of the nitro groups is then reduced to give 3-methoxy-5-nitroaniline. The latter compound can be diazotized and treated with copper(I) bromide to give 1-bromo-3-methoxy-5-nitrobenzene. Reduction with tin and hydrochloric acid gives 3-bromo-5-methoxyaniline. In a similar manner, 3-iodo-5-methoxyaniline can be prepared by diazotizing 3-methoxy-5-nitroaniline to give 1-iodo-3-methoxy-5-nitrobenzene. The latter compound can be reduced with iron filings and hydrochloric acid to give 3-iodo-5-methoxyaniline. Other 3-halo-5-alkoxyanilines such as 3-bromo-5-ethoxyaniline, 3-bromo-5-isopropoxyaniline, and 3-bromo-5-sec-butoxyaniline can be prepared using similar techniques. As such, compounds of the present invention such as (E)-N-methyl-5-(5-ethoxy-3-aminophenyl)-4-penten-2-amine, (E)-N-methyl-5-(5-isopropoxy-3-aminophenyl)-4-penten-2-amine, and (E)-N-methyl-5-(5-sec-butoxy-3-aminophenyl)-4-penten-2-amine can be similarly prepared.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][C:31](=[O:37])[CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:17][CH:18]=2)[C:13]1=[O:38])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][C:31](=[O:37])[CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:17][CH:18]=2)[C:13]1=[O:38]
Reactant: COC(=O)CC(=O)Nc1ccc2c3c(n(CCCNC(=O)OC(C)(C)C)c(=O)c2c1)-c1ccccc1C3=O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CC(=O)Nc1ccc2c3c(n(CCCN)c(=O)c2c1)-c1ccccc1C3=O

Procedure:
Compound 18 (0.080 g, 0.145 mmol) was treated with TFA (0.5 mL) in chloroform (5 mL) for 2 h at room temperature. The solvent was removed on a rotary evaporator and the residue was then basified with 2 N NH3 in methanol to get the free amine, which was purified by silica gel column chromatography, eluting with chloroform-methanol, 8.8:1.2, to yield the product 23 (0.040 g, 62%) as a brown solid: mp 225-227° C. IR (KBr) 3067, 1739, 1673, 1574, 1535, 1511, 1202, 1134, 722 cm−1; 1H NMR (CD3OD, 300 MHz) 8.52 (d, J=2.1 Hz, 1H), 8.29 (d, J=6.8 Hz, 1H), 7.43 (m, 5H), 4.50 (t, J=2.1 Hz, 2H), 3.78 (s, 3H), 3.10 (m, 2H), 2.22 (m, 2H); 13C NMR (CD3OD, 125 MHz) δ 191.6, 169.9, 166.8, 164.9, 155.4, 138.8, 137.9, 135.7, 134.9, 132.2, 129.6, 127.2, 125.0, 124.8, 124.1, 123.9, 118.6, 109.6, 52.9, 42.5, 38.2, 28.6; ESIMS m/z (relative intensity) 420 (MH+, 100); HRESIMS calcd for C23H21N3O5 420.1559 (MH+). found 420.1554 (MH+); HPLC purity: 100% (1% TFA in MeOH—H2O, 50:50).
Reaction SMILES: CO[C:3](OC)(OC)[CH2:4][CH2:5][CH3:6].[NH2:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[NH:22][CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[N:19][CH:18]=[CH:17][CH:16]=2>C1(C)C=CC=CC=1.Cl.N1C=CC=CC=1>[CH2:4]([C:3]1[N:22]([CH2:23][C:24]2([OH:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=1)[CH2:5][CH3:6]
Reactant: Nc1cnc2cccnc2c1NCC1(O)CCOCC1
Reactant: CCCC(OC)(OC)OC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCc1nc2cnc3cccnc3c2n1CC1(O)CCOCC1
Yield: 69.2 %

Procedure:
Trimethylorthobutyrate (1.9 mL, 12.0 mmol) and pyridine hydrochloride (23 mg, 0.2 mmol) were added to a suspension of 4-[(3-amino[1,5]naphthyridin-4-ylamino)methyl]tetrahydropyran-4-ol (10.0 mmol) in toluene (50 mL). The reaction mixture was heated at reflux overnight and then concentrated under reduced pressure. The residue was triturated with acetonitrile and the resulting solid was isolated by filtration to provide 2.26 g of 4-[(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]tetrahydro-2H-pyran-4-ol as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[NH3:14]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[NH2:14]
Reactant: N
Reactant: FC(F)(F)c1cc(Cl)c(Cl)c(Cl)c1
Solvent: O
Product: Nc1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
Into a 1000 ml high-pressure reaction vessel add 200 g 3,4,5-Trichlorobenzotrifluoride and 145 g water, enclose the reaction vessel, fill liquid ammonia 380 g, close the valve, start agitation, slowly increase temperature to 160° C. and pressure to 10.0 MPa, make timed temperature-retention under controlled temperature 165° C. and controlled pressure 11.5 MPa for 8 h, then release the pressure and discharge ammonia.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[CH2:31][CH2:32][CH2:33][OH:34])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:35][O:36][CH2:37]OC>C[Si](I)(C)C.O>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=5)=[CH:18]4)=[CH:13][C:12]=3[CH2:31][CH2:32][CH2:33][O:34][CH2:35][O:36][CH3:37])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COC(=O)c1ccc(-c2ccc3cc(CCCO)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Reactant: COCOC
Agent: C[Si](C)(C)I
Solvent: O
Product: COCOCCCc1cc2ccc(-c3ccc(C(=O)OC)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
541 mg (1.2 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxypropyl-2-naphthyl]benzoate and 5 ml of dimethoxymethane were introduced into a round-bottomed flask and 5 drops of trimethylsilyl iodide were added. The reaction mixture was stirred at room temperature for 24 hours, was poured into water and extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([CH2:7][CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6])[CH3:3].[H-].[Na+].[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH3:31])[CH:30]=1)[CH2:26]Br.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[CH2:17]([O:16][C:14]([C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH2:22][C:23]1[CH:24]=[C:25]([CH3:26])[CH:28]=[C:29]([CH3:31])[CH:30]=1)[CH2:7][C:5]([O:4][C:2]([CH3:1])([CH3:3])[CH3:19])=[O:6])=[O:15])[CH3:18]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)C(=O)OCC
Reactant: Cc1cc(C)cc(CBr)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)OC(C)(C)C)(Cc1cc(C)cc(C)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 13.8 g (50.2 mMol) of diethyl [(1,1-dimethylethoxycarbonyl)methyl]-malonoate in 400 ml of anhydrous tetrahydrofuran, 2.3 g (52.7 mMol) of sodium hydride was added whilst being externally cooled with iced water. After stirring for 30 minutes, and maintaining a reaction temperature of 0 to +5° C., the solution of 10.0 g (50.2 mMol) of 3,5-dimethylbenzylbromide in 80 ml tetrahydrofuran was added dropwise and the mixture allowed to warm to room temperature within 14 hours. The reaction mixture was freed from the solvent in vacuo, 200 ml of 10% citric acid was added to the residue and the resulting mixture was thoroughly extracted with ethyl acetate. After the usual working up, the combined extracts yielded 19.7 g (100% of theory) of a colourless oil of Rf=0.67 (eluant: dichloromethane), which was used in the following steps without further purification.