Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(OCC)(=O)C>O1CCCC1.O>[O:14]=[C:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:21](=[O:22])[O:23][CH2:24][CH3:25])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)Nc1ccc(N2CCC(=O)CC2)cc1

Procedure:
4.9 g of 1-(4-aminophenyl)-4-piperidinone were suspended in a mixture of 30 ml of tetrahydrofuran and 9 ml of water under argon and treated with 3.3 g of sodium hydrogen carbonate. Then, a solution of 2.7 ml of ethyl chloroformate in 20 ml of tetrahydrofuran was added dropwise at room temperature while stirring vigorously and, after completion of-the addition, the mixture was stirred for a further 1 h. After adding water and ethyl acetate the phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulfate and concentrated. The residue (6.6 g) was chromatographed over silica gel 60 with ethyl acetate/hexane mixtures (1:2-1:0). Crystallization from diethyl ether yielded 3.8 g of ethyl 4-(4-oxo-piperidin-1-yl)-phenylcarbamate as grey crystals. M.p.: 145°-146°.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CN(C)C=O>[O:1]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][C:7]1=[CH:17][N:18]([CH3:20])[CH3:19]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CN(C)C=O
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O

Procedure:
A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (8.73 g, 44 mmol) and N,N-dimethylformamide dimethyl acetal (5.8 mL, 44 mmol) in 80 mL of dry N,N-dimethylformamide was warmed at 80° C. for 18 h. The solution was cooled and concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The mixture was filtered through a pad of Celite, and the organic layer was separated, washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].F[C:12]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:15]=[CH:14][C:13]=1[C:24]1[N:29]=[C:28]([CH3:30])[N:27]=[C:26]([N:31]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[N:25]=1>>[CH3:49][O:48][C:45]1[CH:44]=[CH:43][C:42]([CH2:41][N:31]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[C:26]2[N:27]=[C:28]([CH3:30])[N:29]=[C:24]([C:13]3[CH:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[N:17][C:12]=3[NH:10][C:4]3[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)[N:25]=2)=[CH:47][CH:46]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccc(-c4ccncc4)nc3F)n2)cc1
Reactant: COc1ncc(N)cc1F
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccc(-c4ccncc4)nc3Nc3cnc(OC)c(F)c3)n2)cc1
Yield: 39.6 %

Procedure:
The title compound was prepared in an analogous manner to that described in Example 164 using 5-fluoro-6-methoxypyridin-3-amine (Anichem) and 4-(6-fluoro-2,4′-bipyridin-5-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine. Purification using an ISCO Combiflash Companion (12 g column and sample loader, 30-100% EtOAc in hexanes over 20 min; the product eluted with 82% EtOAc) afforded the title compound as a brown oil (39.6%). 1H NMR (400 MHz, d6-DMSO) δ 11.86 (s, 1H); 8.91 (d, J=8.2 Hz, 1H); 8.70-8.76 (m, 2H); 8.21 (d, J=2.2 Hz, 1H); 8.09 (dd, J=12.4, 2.2 Hz, 1H); 7.94-7.99 (m, 2H); 7.66 (d, J=8.0 Hz, 1H); 7.26 (dd, J=18.4, 8.6 Hz, 4H); 6.89 (dd, J=18.7, 8.7 Hz, 4H); 4.83 (d, J=9.2 Hz, 4H); 3.95 (s, 3H); 3.74 (s, 3H); 3.70 (s, 3H); 2.59 (s, 3H). m/z (ESI, +ve ion) 645.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]4[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][C:35]=4[F:44])=[O:32])=[C:26]([Cl:45])[CH:25]=3)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.C(OCC)(=O)C>ClCCCl>[NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]4[CH:39]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:37]=[CH:36][C:35]=4[F:44])=[O:32])=[C:26]([Cl:45])[CH:25]=3)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(Cl)c3)c3c(N)ncnn23)CC1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(Cl)c3)c12
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
A suspension of Example 266 (1.64 g, 2.53 mmol) in 50 mL 1,2-dichloroethane was treated with 10 mL TFA at rt. The reaction quickly became homogeneous and at 10 min no starting material remained by RP-HPLC. The reaction mixture was concentrated in vacuo, and the residue taken up again in fresh 1,2-dichloroethane and concentrated again; this was repeated 2 times. The residue was taken up in THF (15 mL) and EtOAc (85 mL) and washed with aq. sodium carbonate. The organic layer was dried with sodium sulfate and concentrated in vacuo to provide a tan solid. Trituration with ethyl acetate provided the title compound (1.2 g, 87%) as a tan solid. 1H-NMR (DMSO-d6) δ 8.64 (dd, 1H), 8.23 (d, 1H), 7.88 (s, 1H), 7.46-7.54 (m, 2H), 7.34-7.43 (m, 2H), 6.55 (s, 1H), 3.17 (tt, 2H), 2.96-3.05 (m, 2H), 2.60 (dd, 2H), 1.60-1.85-1.95 (m, 2H), 1.56 (ddd, 2H); MS [M+H]+=548.3; LCMS RT=2.94 min.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=[O:7]>O.CC#N>[C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][C:1]#[N:2])=[CH:9][CH:10]=1
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#CCC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 118.6 %

Procedure:
To a solution of 105 mg (1.6 mmol) of KCN in 1 mL of water, 220 mg (0.8 mmol) of 2-bromo-4′-phenylacetophenone in 3 mL of MeCN was added. The mixture was warmed in a 50° C. bath to dissolve some of the halide. After ˜20 min the solids dissolved. The reaction was stirred for 30 min, then partitioned between 1.2 N HCl and EtOAc. The organic layer was washed with brine, dried and concentrated leaving 210 mg of the title compound which was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[CH:8][C:7](=[O:11])[C:6]=2[CH:12]=1.C[Si]([C:17]#[N:18])(C)C.CO>CCOCC.[I-].[Zn+2].[I-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:17]#[N:18])[CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1
Reactant: O=c1ccoc2ccc(F)cc12
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: CO
Solvent: CCOCC
Product: N#CC1CC(=O)c2cc(F)ccc2O1
Yield: 94.8 %

Procedure:
To a mixture of 72.2 g (0.44 mol) of 6-fluoro-4H-1-benzopyran-4-one obtained through the process as described in said Item b and 1.39 g (4.4 mmol) of zinc iodide in 610 ml of dry ether, 101 g (1.0 mol) of trimethylsilylcyanide were added under stirring. The mixture was heated at reflux temperature for 24 hours. After cooling the reaction mixture, the solution was poured into 500 ml of methanol, stirred for one hour at room temperature and evaporated in vacuo to dryness. Resulting residue was chromatographed on silica gel, eluting with dichloromethane to give 79.7 g (94.9%) of the desired compound.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=2[F:22])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].[CH:26](I)([CH3:28])[CH3:27]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([C:14]2[C:15]([F:22])=[CH:16][C:17]([O:21][CH:26]([CH3:28])[CH3:27])=[CH:18][C:19]=2[F:20])[O:11][CH2:12][CH3:13])=[CH:24][CH:25]=1)#[N:2]
Reactant: CC(C)I
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(O)cc1F
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(OC(C)C)cc1F

Procedure:
In analogy to example 16.4 (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-4-hydroxy-phenyl)-2-ethoxy-acetamide was reacted with isopropyl iodide to give (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-4-isopropoxy-phenyl)-2-ethoxy-acetamide. Colorless oil. MS 387.1 ([M−H]−)
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24]C)=[O:23])[CH:17]=2)[CH2:10][C@H:9]1[C:27]([N:29]1[CH2:33][CH2:32][S:31][CH2:30]1)=[O:28])=O)(C)(C)C.[OH-].[Na+].Cl>O1CCCC1.C(O)C>[S:31]1[CH2:32][CH2:33][N:29]([C:27]([C@H:9]2[NH:8][CH2:12][C@@H:11]([CH2:13][NH:14][C:15](=[O:26])[C:16]3[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=3)[C:22]([OH:24])=[O:23])[CH2:10]2)=[O:28])[CH2:30]1
Reactant: COC(=O)c1cccc(C(=O)NC[C@H]2C[C@@H](C(=O)N3CCSC3)N(C(=O)OC(C)(C)C)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cccc(C(=O)NC[C@@H]2CN[C@H](C(=O)N3CCSC3)C2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 18A (100 mg) in tetrahydrofuran (0.5 mL) and ethanol (0.5 mL) was added 2 M NaOH (1 mL) and the resulting mixture was stirred at room temperature for 16 hours. The mixture was adjusted to a pH 2-3 by the addition of 1 M HCl, extracted with ethyl acetate (3×15 mL) and the combined organic layers washed with brine (15 mL), dried (Na2SO4), filtered and concentrated to provide a white solid which was processed as described in Example 18 to provide the titled compound as a pale yellow solid. MS (ESI) m/e 364 (M+H)+; 1H NMR (500 MHz, CD3OD) δ ppm 1.82 (m, 1 H), 2.74 (m, 1 H), 2.83 (m, 1 H), 3.09 (m, 1 H), 3.17 (q, 1 H), 3.24 (dd, 1 H), 3.33 (m, 1 H), 3.55 (m, 2 H), 3.64 (m, 1 H), 3.75 (m, 1 H), 3.88 (m, 1 H), 4.52 (m, 1 H), 4.66 (m, 2 H), 7.60 (m, 1 H), 8.06 (t, 1 H), 8.20 (d, 1 H), 8.49 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8](OC)[O:9]C)=[C:6]([O:13][CH:14]([F:16])[F:15])[CH:5]=[CH:4][C:3]=1[F:17]>CC(C)=O.O>[Cl:1][C:2]1[C:3]([F:17])=[CH:4][CH:5]=[C:6]([O:13][CH:14]([F:16])[F:15])[C:7]=1[CH:8]=[O:9]
Reactant: COC(OC)c1c(OC(F)F)ccc(F)c1Cl
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1c(OC(F)F)ccc(F)c1Cl
Yield: 39.9 %

Procedure:
To a solution of crude 2-chloro-4-difluoromethoxy-3-dimethoxymethyl-1-fluorobenzene (181 g, 670 mmol) in acetone (650 mL) and water (150 mL) was added Amberlyst-15 resin (540 g, pre-washed with water) and the mixture was stirred using mechanical stirrer for 40 h at RT. The Amberlyst-15 resin was removed by filtration using celite bed on sintered funnel, and the filtrate was evaporated on a rotary evaporator at RT (Note: aldehyde evaporates at higher temperatures under reduced pressure). The residue was purified by column chromatography on silica gel using ethyl acetate/hexanes (5% to 10%) to obtain the title compound (60 g, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][N:32]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:23][N:24]([CH:25]([CH3:26])[CH3:27])[C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([C:30]([F:41])([F:29])[F:40])=[N:32][CH:33]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28]
Reactant: CC(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Product: CC(C)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(=O)c1ccc(C(F)(F)F)nc1

Procedure:
2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol (compound 132) was coupled with 6-trifluoromethyl-nicotinic acid following procedure D2. LC-MS showed the product had the expected M+H+ of 570. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 9.5 (s, 1H)) 8.6 (d, 1H) 8.5 (s, 1H) 8.2 (d, 1H) 8.1 (s, 1H) 7.9 (m, 2H) 7.5 (m, 1H) 7.4 (m, 2H) 7.2 (s, 1H) 6.9 (d, 1H) 5.7 (s, br, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 3.1 (m, 1H) 3.0 (m, 2H) 1.2 (d, 6H).
Reaction SMILES: O[C:2]1[CH:10]=C(O)C=C[C:3]=1C(N)=O.[OH:12][C:13]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(Br)C=C>>[OH:12][C:13]1[CH:22]=[C:21]([O:23][CH2:10][CH:2]=[CH2:3])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: NC(=O)c1ccc(O)cc1O
Reactant: COC(=O)c1ccc(O)cc1O
Solvent: C=CCBr
Product: C=CCOc1ccc(C(=O)OC)c(O)c1

Procedure:
Scheme B shows methods for the preparation of the 2,4-dihydroxybenzamide starting materials. Methyl 2,4-dihydroxybenzoate (X) is reacted with allyl bromide to give methyl 2-hydroxy-4-allyloxybenzoate (XI) which is heated to produce methyl 2,4-dihydroxy-3-(2-propenyl) benzoate (XII). Reaction of XII with an appropriate amine in the presence of ammonium chloride gives the 2,4-dihydroxy-3-(2-propenyl)benzamide (XIII) which can be hydrogenated to the 3-propyl compound (XIV). Alternatively XII may be reacted with methylene iodide and triisobutylaluminum to give methyl 3-(cyclopropylmethyl)-2,4-dihydroxybenzoate (XV) which is then reacted with an appropriate amine in the presence of ammonium chloride to give the 2-(cyclopropylmethyl)-2,4-dihydroxybenzamide (XVI).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][N:14]([CH2:22][CH2:23]Cl)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[H-].[Na+]>CN(C)C=O>[C:9]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:23][CH2:22][N:14]([C:15]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:21])[CH2:13][CH2:12]1)#[N:10]
Reactant: N#CCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(F)cc2)CC1
Temperature: 0 °C

Procedure:
2-(4-Fluorophenyl)acetonitrile (1.35 g, 10.0 mmol) and tert-butyl bis(2-chloroethyl)carbamate (2.42 g, 10.0 mmol) were combined in dimethylformamide (30 mL) and cooled to 0° C. The reaction was treated with sodium hydride (760 mg, 30.0 mmol) in several portions. The ice bath was removed and the reaction heated at 60° C. for 24 h. After cooling to room temperature, the mixture was poured into ice water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (15% ethyl acetate/hexanes) gave 1.65 g (54%). 1H-NMR (CDCl3, 500 MHz) δ 7.39-7.44 (m, 2H), 7.04-7.10 (m, 2H), 4.23-4.27 (m, 2H), 3.12-3.21 (m, 2H), 2.03-2.07 (m, 2H), 1.82-1.92 (m, 2H), 1.45 (s, 9H). Mass spec.: 327.11 (MNa)+.
Reaction SMILES: C(N1C2C=CN[C:12](=[O:17])[C:11]=2C=C1C)C1C=CC=CC=1.C(N1C(C)=CC=C1C=C[C:34](O)=[O:35])C1C=CC=CC=1.[CH2:37]([N:44]1[C:48]2=[N:49][CH:50]=[CH:51][C:52]([O:53][CH3:54])=[C:47]2[CH:46]=[C:45]1[CH3:55])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O.C(N(CC)CC)C>[CH2:37]([N:44]1[C:48]2=[N:49][CH:50]=[CH:51][C:52]([O:53][CH2:54][C:34]([O:17][CH2:12][CH3:11])=[O:35])=[C:47]2[CH:46]=[C:45]1[CH3:55])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Cc1ccc(C=CC(=O)O)n1Cc1ccccc1
Reactant: COc1ccnc2c1cc(C)n2Cc1ccccc1
Reactant: Cc1cc2c(=O)[nH]ccc2n1Cc1ccccc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccnc2c1cc(C)n2Cc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
1-Benzyl-2-methyl-1,5-dihydro-pyrrolo[3,2-c]pyridin-4-one, 9: 3-(1-Benzyl-5-methyl-1H-pyrrol-2-yl)-acrylic acid, 6 (26.72 g, 110.9 mmol) was dissolved in a dry acetone (1050 mL). To the suspension mixture triethylamine (35 mL) was added to form a clear solution. The reaction mixture was cooled to 0° C. and then to the cooled reaction mixture a solution of ethyl chlorofomate (30 mL, 304 mmol) in dry acetone (650 mL) was added dropwise over 1 hour. After addition the reaction mixture was stirred for 4 h at 0° C. Then to the reaction mixture was added dropwise the solution of sodium azide (14.52 g, 223 mmol) in H2O (175 mL) over 30 minutes. The reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was poured into ice-water (1 L). Then the mixture was extracted with dichloromethane (3×1 L). The organic layers were combined and dried over MgSO4. The mixture was filtered and concentrated to afford a crude 8 as a yellow solid (32 g). To the mixture of diphenyl ether (175 mL) and tributylamine (31 mL) which was preheated to 205° C. was added dropwise the solution of crude 8 in diphenyl ether (250 mL) at 205° C. for 1 hour. After addition the mixture was stirred for another hour at 205° C. The mixture was cooled to room temperature and solid was formed. Diethyl ether (500 mL) was added into the reaction mixture to form more solid. The mixture was filtered and the solid was washed with diethyl ether to afford the product (8.81 g). The filtrate was concentrated and the residue was purified by silica gel chromatography (hexane to hexane:ethyl acetate, gradient 1:1 to 1:3; then methanol in dichloromethane, 1% to 5%) to afford 1-benzyl-2-methyl-1,5-dihydro-pyrrolo[3,2-c]pyridin-4-one, 9 as a yellow solid (4.7 g). Yield: 13.51 g, (51%)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=1)=O.[Br-].[O:27]([CH2:34][CH2:35][CH2:36][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[H-].[Na+]>O1CCCC1.CS(C)=O>[CH2:19]([O:18][C:6]1[CH:5]=[C:4]([C:2]([CH3:1])=[CH:36][CH2:35][CH2:34][O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(OCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(=CCCOc1ccccc1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
Under a nitrogen atmosphere a mixture of 3,5-dibenzyloxyacetophenone (50.0 g., 0.15 M) in tetrahydrofuran (175 ml.) and 3-phenoxypropyltriphenylphosphonium bromide (7.18 g., 0.15 M) in dimethylsulfoxide (450 ml.) is added dropwise over 1.75 hours to a suspension of 50% sodium hydride (7.89 g., 0.165 M) (previously washed with pentane) in tetrahydrofuran (75 ml.) maintained at 0°-5° C. After stirring for 4 hours at 0°-5° C. the reaction is allowed to warm to room temperature and is then carefully stirred into ice water (2000 ml.), acidified with concentrated hydrochloric acid, and extracted with ethyl acetate (5×400 ml.). The combined organic phases are washed with saturated sodium chloride solution (3×300 ml.), dried over sodium sulfate and concentrated under vacuum to yield an oil which is triturated with ether to precipitate triphenylphosphine oxide. Filtration, followed by concentration of the filtrate, gives an oily residue which is chromatographed over silica gel (1300 g.) eluting with benzene-hexane consisting of 30% to 100% benzene. From the middle fractions 51 g. (75%) of 4-(3,5-dibenzyloxyphenyl)-1-phenoxypent-3-ene is isolated as an oil; Rf =0.8 (silica gel, 2-benzene:1-hexane); m/e--450 (m+).
Reaction SMILES: C(C1[NH:5][C:6]2[C:11](C=1)=[C:10]([C:13]([NH:15][C:16]1[CH:47]=[CH:46][C:19]([C:20]([N:22]([CH3:45])[C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=3[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([N:38]3[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)=[O:37])=[O:21])=[CH:18][C:17]=1[O:48][CH3:49])=[O:14])[CH:9]=[CH:8][CH:7]=2)(O)=O.Cl.CNC.[OH:54]N1C2C=CC=CC=2N=N1.Cl.[CH3:65][N:66]([CH3:75])[CH2:67][CH2:68][CH2:69]N=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH3:75][N:66]([CH3:65])[C:67]([C:68]1[NH:5][C:6]2[C:11]([CH:69]=1)=[C:10]([C:13]([NH:15][C:16]1[CH:47]=[CH:46][C:19]([C:20]([N:22]([CH3:45])[C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=3[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([N:38]3[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]3)=[O:37])=[O:21])=[CH:18][C:17]=1[O:48][CH3:49])=[O:14])[CH:9]=[CH:8][CH:7]=2)=[O:54]
Reactant: On1nnc2ccccc21
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(C(=O)O)cc12
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(C(=O)N(C)C)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
To a mixture of 4-[(2-carboxyindol-4-yl)-carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (60 mg), N,N-dimethylamine hydrochloride (7.7 mg) and 1-hydroxybenzotriazole (14.5 mg) in N,N-dimethylformamide (3.0 ml) was added a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20.6 mg) in N,N-dimethylformamide (1.0 ml) and the mixture was stirred at ambient temperature for 4 hours. The resulting mixture was diluted with ethyl acetate and the organic layer was washed successively with saturated aqueous sodium bicarbonate solution and brine. Drying, filtering and removal of solvents afforded 4-[(2-dimethylaminocarbonylindol-4-yl)-carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (60 mg) as a yellow amorphous powder.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[N:32]1C2C(=CC=CC=2)[CH:35]=[CH:34][CH:33]=1>P(Cl)(Cl)(Cl)=O.N1C=CC=CC=1>[NH2:32][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:33]([NH2:32])[CH2:34][CH3:35]
Reactant: Oc1ccnc2cccnc12
Reactant: c1ccc2ncccc2c1
Agent: CS(=O)(=O)Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCCN
Product: Nc1ccnc2cccnc12

Procedure:
4-Hydroxy-1,5-naphthyridines can be prepared from 3-aminopyridine derivatives by reaction with diethyl ethoxymethylene malonate to produce the 4-hydroxy-3-carboxylic acid ester derivative with subsequent hydrolysis to the acid, followed by thermal decarboxylation in quinoline (as for example described for 4-Hydroxy-[1,5]naphthyridine-3-carboxylic acid, J. T. Adams et al., J. Amer. Chem. Soc., 1946, 68, 1317). A 4-hydroxy-[1,5]naphthyridine can be converted to the 4-chloro derivative by heating in phosphorus oxychloride, or to the 4-methanesulphonyloxy or 4-trifluoromethanesulphonyloxy derivative by reaction with methanesulphonyl chloride or trifluoromethanesulphonic anhydride, respectively, in the presence of an organic base. A 4-amino 1,5-naphthyridine can be obtained from the 4-chloro derivative by reaction with n-propylamine in pyridine.