Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][NH:19][S:20]([C:23]3[N:24]=[CH:25][N:26]([CH3:28])[CH:27]=3)(=[O:22])=[O:21])[CH:16]=2)[CH2:11][CH2:10][CH:9]1[NH:29][C:30]([C@H:32]1[CH2:34][C@H:33]1[C:35](O)=[O:36])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>O1CCCC1.O>[CH2:1]([CH:8]1[C:17]2[CH:16]=[C:15]([CH2:18][NH:19][S:20]([C:23]3[N:24]=[CH:25][N:26]([CH3:28])[CH:27]=3)(=[O:21])=[O:22])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH:9]1[N:29]1[C:35](=[O:36])[CH:33]2[CH:32]([CH2:34]2)[C:30]1=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cnc(S(=O)(=O)NCc2ccc3c(c2)C(Cc2ccccc2)C(NC(=O)[C@H]2C[C@H]2C(=O)O)CC3)c1
Solvent: O
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Product: Cn1cnc(S(=O)(=O)NCc2ccc3c(c2)C(Cc2ccccc2)C(N2C(=O)C4CC4C2=O)CC3)c1

Procedure:
cis-2-{[1-Benzyl-7-({[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}methyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamoyl}cyclopropanecarboxylic acid (382 mg, 0.731 mmol) was dissolved in tetrahydrofuran (10 mL) and acetyl chloride (5 mL, 88 mmol) was added. The reaction mixture was heated under reflux for 2 h. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic extracts were washed with aqueous sodium bicarbonate solution, dried (sodium sulfate) and concentrated in vacuo. The crude product was used for the next step without further purificiation. Yield: 377 mg (light orange oil).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:34]=[CH:33][C:8]([CH2:9][C:10]2[N:18]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]3[C:16](=[O:27])[NH:15][C:14](=[O:28])[N:13]([CH2:29][CH2:30][CH2:31][CH3:32])[C:12]=3[N:11]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:42][C:43]1[CH:56]=[CH:55][CH:54]=[CH:53][C:44]=1[O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47].O>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>[C:1]([NH:4][C:5]1[CH:34]=[CH:33][C:8]([CH2:9][C:10]2[N:18]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:24])([CH3:25])[CH3:23])[C:17]3[C:16](=[O:27])[N:15]([CH2:42][C:43]4[CH:56]=[CH:55][CH:54]=[CH:53][C:44]=4[O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C:14](=[O:28])[N:13]([CH2:29][CH2:30][CH2:31][CH3:32])[C:12]=3[N:11]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1CBr
Reactant: CCCCn1c(=O)[nH]c(=O)c2c1nc(Cc1ccc(NC(C)=O)cc1)n2COC(=O)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(Cc2ccccc2O[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Cc1ccc(NC(C)=O)cc1)n2COC(=O)C(C)(C)C
Temperature: 50 °C
Yield: 63.4 %

Procedure:
A solution of 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-3-butyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (100 mg, 0.21 mmol) in N,N-dimethylformamide (2.0 mL) was treated with sodium carbonate (68 mg, 0.64 mmol), (2-bromomethyl-phenoxy)-tert-butyl-dimethyl-silane (70.6 mg, 0.23 mmol) in N,N-dimethylformamide (0.5 mL), and tetrabutylammonium iodide (24 mg, 0.06 mmol). The reaction was heated at 50° C. for 4 h. At this time, the reaction was poured onto a solution of water (125 mL) and a IN aqueous hydrochloric acid solution (1.28 mL). The product was extracted into ethyl acetate. The organics were washed with water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1:4 ethyl acetate/petroleum ether) afforded 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-3-butyl-1-[2-(tert-butyl-dimethyl-silanyloxy)-benzyl]-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (91.9 mg, 63%) as an off-white foam: FAB-HRMS m/e calcd for C37H51N5O6Si (M+H)+ 690.3687, found 690.3685.
Reaction SMILES: [ClH:1].[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.[C:21]1(NN)C=CC=CC=1>>[ClH:1].[CH3:21][C:9]1[C:8]2[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3[CH2:5][CH2:4][NH:3][CH2:2][C:14]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Reactant: NNc1ccccc1
Agent: Cl
Product: CCOC(=O)Cn1c2c(c3cccc(C)c31)CNCC2

Procedure:
The title compound is prepared using a procedure analogous to Intermediate 1, substituting 2-methylphenylhydrazine for phenylhydrazine in Step 1a).
Reaction SMILES: C([C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH:9]([CH3:20])[N:10]3[C:15]=2[C:14]=1[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11]3)#N.NC1C=CC2CCC(C)N3C=2C=1C(=O)C(C(O)=O)=C3>>[CH3:20][CH:9]1[N:10]2[C:15]3[C:14](=[CH:3][CH:4]=[CH:5][C:6]=3[CH2:7][CH2:8]1)[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11]2
Reactant: CC1CCc2ccc(C#N)c3c(=O)c(C(=O)O)cn1c23
Agent: CC1CCc2ccc(N)c3c(=O)c(C(=O)O)cn1c23
Product: CC1CCc2cccc3c(=O)c(C(=O)O)cn1c23

Procedure:
U.S. Pat. Nos. 3,896,131 and 3,985,882 describe the synthesis of substituted benzo[ij]quinolizine-2-carboxylic acids. The synthesis of the compound 10-cyano-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid is described in Example 71 of said U.S. Pat. No. 3,896,131. That synthetic process utilizes 10-amino-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as an intermediate, which intermediate is prepared from the corresponding 10-nitro compound. The 10-nitro compound is obtained by nitration of 6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]-quinolizine-2-carboxylic acid. The 10-nitro compound is the predominant isomer obtained by such nitration. Accordingly, when preparing the 8-cyano final product, it would be desirable to employ a synthetic sequence which avoids such a nitration step.
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:25][CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][NH2:37])[CH2:30]2)[CH2:24][CH2:23][CH2:22][CH2:21]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:50].Cl.N>ClCCl.C(O)C>[ClH:1].[ClH:50].[N:20]1([CH2:25][CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][NH:37][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:30]2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: NCCN1CCCC(CCCCN2CCCC2)C1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Agent: Cl
Agent: N
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCO
Solvent: ClCCl
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCCC(CCCCN3CCCC3)C2)c2ccccc21
Yield: 35 %

Procedure:
Prepared analogously to Example 46 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[4-(pyrrolidin-l-yl)butyl]-piperidin-l-yl]ethanamine in a yield of 35% of theory. The colourless dihydrochloride melted at 170°-172° C.; RF 0.69 (HPTLC ready-made silica gel plates 60 F254 for Nano-TLC, Messrs Merck; eluant: dichloromethane/ethanol/conc. ammonia 65/30/5 v/v/v).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.Cl[CH2:16][CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:19][CH2:18][CH2:17][CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:14])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: OCCCCl
Reactant: CCOC(=O)C(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C(=O)O)c1ccc(OCCCO)cc1

Procedure:
Ethyl 2-[4-hydroxyphenyl]propionate [20 mmole] was combined with 3-chloropropanol [22 mmole] and potassium carbonate [24 mmole] in acetone [100 ml], then refluxed for 18 hours. After removal of the acetone under reduced pressure, the reaction mixture was extracted with 1N sodium hydroxide solution to remove acidic components. These were chromatographed on silica gel/toluene to isolate the product, 2-[4-(3-hydroxypropoxy)phenyl]propionic acid, as an amorphous solid. Mass spectral, proton nuclear magnetic resonance, and elemental analysis data are consistent with the assigned structure. Additional product was obtained by basic hydrolysis of the neutral fraction, followed by silica gel/toluene chromatography.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[OH:10][CH2:11][CH2:12][C@H:13]1[CH2:15][C@H:14]1[CH:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1>>[CH3:8][C:6]1[C:5]([CH3:9])=[CH:4][N:3]=[C:2]([N:19]2[CH2:20][CH2:21][CH:16]([CH:14]3[CH2:15][CH:13]3[CH2:12][CH2:11][OH:10])[CH2:17][CH2:18]2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC([C@@H]2C[C@@H]2CCO)CC1
Reactant: Cc1cnc(Cl)nc1C
Product: Cc1cnc(N2CCC(C3CC3CCO)CC2)nc1C
Temperature: 90 °C

Procedure:
The titled compound was prepared from 2-chloro-4,5-dimethylpyrimidine and rac cis-tert-Butyl 4-[2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate by a procedure analogous to that described in Example 6, step 2, with the exception of reaction temperature and time. The reaction was heated at 90° C. for 2 h.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:18][N:17]([CH3:19])[CH2:16][C:15]3[N:14]=[C:13]([OH:20])[CH:12]=[CH:11][C:10]2=3)=[CH:5][CH:4]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OC([N+](C(OC(C)(C)C)=O)=[N-])=O)(C)(C)C.[N:56]1([CH2:62][CH2:63][CH2:64]O)[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:18][N:17]([CH3:19])[CH2:16][C:15]3[N:14]=[C:13]([O:20][CH2:64][CH2:63][CH2:62][N:56]4[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]4)[CH:12]=[CH:11][C:10]2=3)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2CN(C)Cc3nc(O)ccc32)cc1
Reactant: OCCCN1CCCCC1
Agent: CC(C)(C)OC(=O)[N+](=[N-])C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C2CN(C)Cc3nc(OCCCN4CCCCC4)ccc32)cc1
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
To a mixture of 5-(4-methoxy-phenyl)-7-methyl-5,6,7,8-tetrahydro-[1,7]naphthyridin-2-ol (0.10 g, 0.37 mmol) and PPh3 (0.097 g, 0.37 mmol) in THF (5 mL) was added a solution of di-tert-butyldiazodicarboxylate (0.085 g, 0.37 mmol) in THF (5 mL). After 30 min, a solution of 3-piperidin-1-yl-propan-1-ol (0.053 g, 0.37 mmol) in THF (5 mL) was added slowly. After 18 h, the mixture was concentrated, and the resulting solid was purified (SiO2; 0-8% 2 M NH3 in MeOH/DCM) to give the title compound (30 mg, 20%). MS (ESI): mass calcd. for C24H33N3O2, 395.26; m/z found, 396.6 [M+H]+. 1H NMR (CDCl3): 7.10-7.04 (m, 3H), 6.83 (d, J=8.6, 2H), 6.45 (d, J=8.4, 1H), 4.33-4.25 (m, 2H), 4.15-4.10 (m, 1H), 3.79 (s, 3H), 3.76-3.70 (m, 1H), 3.57-3.50 (m, 1H), 3.02-2.97 (m, 1H), 2.53-2.45 (m, 3H), 2.44 (s, 3H), 2.42-2.38 (m, 3H), 2.00-1.92 (m, 2H), 1.66-1.54 (m, 7H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[F:11][C:12]1[C:19]([O:20][CH2:21][CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:18][CH:17]=[C:16]([F:30])[C:13]=1[CH:14]=[O:15].[OH-].[K+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:14]([C:13]3[C:16]([F:30])=[CH:17][CH:18]=[C:19]([O:20][CH2:21][CH2:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:12]=3[F:11])[OH:15])=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=Cc1c(F)ccc(OCCOC2CCCCO2)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC(c1c(F)ccc(OCCOC2CCCCO2)c1F)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-bromo-7-azaindole (67, 118 mg, 0.000597 mol) in methanol (9.0 mL) were added 2,6-difluoro-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzaldehyde (541, 180.0 mg, 0.63 mmol) and potassium hydroxide (601.9 mg, 10.7 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give crude compound that was used directly in the next step.
Reaction SMILES: C(N1CCC(=O)C(C2C=CC=CC=2)C1)CCC.[CH2:18]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH:22]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34]CCCC)[CH:28]=2)[CH2:21]1)C.C(N1CC[C@H](O)[C@H](C2C=CC=C(OCCCCC)C=2)C1)C.C(N1CC[C@@H](O)[C@H](C2C=CC=C(OCCCCC)C=2)C1)C>>[CH3:18][N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH:22]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[CH2:21]1
Reactant: CCCCCOc1cccc(C2CN(CC)CCC2=O)c1
Agent: CCCCCOc1cccc([C@@H]2CN(CC)CC[C@@H]2O)c1
Agent: CCCCCOc1cccc([C@@H]2CN(CC)CC[C@H]2O)c1
Agent: CCCCN1CCC(=O)C(c2ccccc2)C1
Product: COc1cccc(C2CN(C)CCC2O)c1

Procedure:
In a similar manner but replacing 1-methyl-3-(3-methoxylphenyl)-4-piperidone with 1-butyl-3-phenyl-4-piperidone or 1-ethyl-3-(3-pentyloxyphenyl)-4-piperidinone, cis-1-butyl-3-phenyl-4-piperidone, trans-1-butyl-3-phenyl-4-piperidone, cis-1-ethyl-3-(3-pentyloxyphenyl)-4-piperidinol and trans-1-ethyl-3-(3-pentyloxyphenyl)-4-piperidinol are obtained.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[NH:17][CH2:18][C@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])C.[NH:39]1[CH2:44][CH2:43][CH2:42][N:41]=[C:40]1[NH2:45]>CN(C)C=O>[C:23]([O:22][C:20](=[O:21])[C@@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:18][NH:17][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[C:14]=1[N:15]=[CH:16][N:8]2[CH2:7][CH2:6][CH2:5][C:4](=[O:3])[NH:45][C:40]1[NH:41][CH2:42][CH2:43][CH2:44][N:39]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: NC1=NCCCN1
Reactant: CCOC(=O)CCCn1cnc2c(NC[C@H](NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)ncnc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNc1ncnc2c1ncn2CCCC(=O)NC1=NCCCN1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
200 mg (0.38 mmol) of 4-[6-((2S)-2-benzyloxycarbonylamino-2-tert-butoxycarbonyl-ethylamino)-purin-9-yl]-butyric acid ethyl ester was dissolved in 2 ml of dimethylformamide and 188 mg (1.9 mmol) of 1,4,5,6-tetrahydro-pyrimidin-2-ylamine was added. The solution was stirred at room temperature for 16 hours. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed twice with 10% aqueous citric acid solution and twice with water. Product in the combined aqueous phase was extracted five times with dichloromethane. The combined organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/methanol (10/1), followed by DCM/AcOH/water (85:15:1.5:1.5). Yield: 70.6 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.N1C=C[CH:23]=[CH:22][CH:21]=1.C(OCC)(OCC)(OCC)CC>C1(C)C=CC=CC=1.ClC(Cl)C>[CH2:22]([C:23]1[N:12]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:21]
Reactant: Nc1cnc2ccccc2c1NCCOCCO
Reactant: c1ccncc1
Agent: CCOC(CC)(OCC)OCC
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1nc2cnc3ccccc3c2n1CCOCCO
Temperature: 25 °C
Yield: 904.4 %

Procedure:
A mixture of 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethanol (43.0 g, 155 mmol) and pyridine hydrochloride (1.79 g, 15.5 mmol) in toluene (200 mL) and dichloroethane (100 mL) was heated at reflux until a solution formed. The solution was allowed to cool to room temperature, then was cooled to 0° C. Triethyl orthopropionate (30.1 g, 171 mmol) was added and the mixture was heated at reflux for 3 hours. The solution was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was diluted with chloroform, and 4 M NaOH was added to adjust the pH to 9. A solid formed. The mixture was filtered, and the isolated solid dissolved when it was washed with water and chloroform. The filtrate was transferred to a separatory funnel and washed twice with brine. The combined aqueous layers were back-extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to provide 40.0 g of 2-[2-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethanol as a tan solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[CH:3]=1.[CH2:17]([C@H:19]1[O:21][CH2:20]1)[Cl:18]>>[Cl:18][CH2:17][C@H:19]([OH:21])[CH2:20][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[CH:3]=1
Reactant: ClC[C@@H]1CO1
Reactant: CCCC(CCC)COc1cccc(Br)c1
Product: CCCC(CCC)COc1cccc(C[C@@H](O)CCl)c1

Procedure:
Metallation of 1-bromo-3-(2-propylpentyloxy)benzene followed by addition of (S)-(+)-epichlorohydrin gave (R)-1-chloro-3-(3-(2-propylpentyloxy)phenyl)propan-2-ol. Yield (1.55 g, 59%): 1H NMR (400 MHz, DMSO-d6) δ 7.14 (t, J=7.8 Hz, 1H), 6.77-6.72 (m, 3H), 5.13 (d, J=4.8 Hz, 1H), 3.88-3.82 (m, 1H), 3.78 (d, J=5.6 Hz, 2H), 3.52 (dd, J=10.8, 4.4 Hz, 1H), 3.43 (dd, J=10.8, 5.6 Hz, 1H), 2.74 (dd, J=13.6, 5.2 Hz, 1H), 2.61 (dd, J=13.2, 7.4 Hz, 1H), 1.74-1.69 (m, 1H), 1.39-1.25 (m, 8H), 0.85 (t, J=7.0 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=S.C1(C)C=CC=CC=1.C(Br)C1C=CC=CC=1.[N:41]#[C:42][NH2:43]>C(#N)C.O.FC(F)(F)C(O)=O.CN1CCCC1=O>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][NH:6][C:4]2[C:3]3[CH:22]=[CH:23][CH:24]=[N:25][C:2]=3[N:1]=[C:42]([NH2:43])[N:41]=2)=[CH:9][CH:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#CN
Reactant: Nc1ncccc1C(=S)NCc1ccc(OCc2ccccc2)cc1
Agent: BrCc1ccccc1
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(NCc2ccc(OCc3ccccc3)cc2)c2cccnc2n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 4.2 %

Procedure:
To a mixture of 2-amino-N-(4-benzyloxy-benzyl)-thionicotinamide described in Example A-22 (30 mg, 0.083 mmol) and toluene (1 mL) was added benzyl bromide (0.044 mL, 0.37 mmol), and the solution was refluxed for 3 hours. After cooling, the solvent was evaporated in vacuo, and the residue was washed with diethyl ether twice. A mixture of a portion (13 mg) of the resulting crude product (33 mg), cyanamide (20 mg, 0.48 mmol) and N-methylpyrrolidinone (1 mL) was stirred for 2 hours at 120° C. After cooling, the reaction solution was directly purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and ditrifluoroacetic acid salt of the title compound (0.75 mg, 0.0013 mmol, 4.2%) was obtained.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[N+:8]([C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9].Cl[C:19]1[CH:20]=[CH:21][N:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:23]2=[O:34]>O.C(OCC)(=O)C>[N+:8]([C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[O:17][C:19]1[CH:20]=[CH:21][N:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:23]2=[O:34])([O-:10])=[O:9]
Reactant: CCOC(=O)c1ccc2cc(Cl)ccn2c1=O
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(Oc3cccc([N+](=O)[O-])c3)ccn2c1=O
Reaction time: 2 h
Yield: 67 %

Procedure:
An oven-dried 50 ml three-necked round-bottom flask was purged with argon and charged with sodium hydride (200 mg, 60% suspension in oil, 5 mmol and washed with hexane) and 10 ml dry DMF. To this suspension, m-nitrophenol (626 mg, 4.5 mmol) was added in one portion. After gas evolution had ceased, ethyl 8-chloro-4-oxo-4H-quinolizine-3-carboxylate (2) (1.00 g, 4 mmol) was added in one portion and stirring was continued at room temperature for 2 h. When the reaction was complete as indicated by thin layer chromatography (ethyl acetate), the reaction mixture was poured into 250 ml of water. The aqueous layer was extracted three times with 200 ml dichloromethane, and the combined organic layers were washed three times with 200 ml water. The organic solvent was evaporated and the crude product was stirred overnight with 30 ml ether. Filtration gave a bright yellow solid (950 mg, 67%). M.p. 161-163° C. 1H NMR (δ, CDCl3): 1.42 (t, J=7 Hz, 3H), 4.41 (q, J=7 Hz, 2H), 6.39 (d, J=8 Hz, 1H), 6.70 (d, J=2 Hz, 1H), 6.99 (dd, J=0.5 Hz, J=7 Hz, 1H), 7.55 (d, J=7 Hz, 1H), 7.72 (dd, J=8 Hz, J=8 Hz, 1H), 8.07 (s, 1H), 8.24 (d, J=8 Hz, 1H), 8.32 (d, J=8 Hz, 1H), 9.43 (d, J=7 Hz, 1H). MS: m/z 354.0850; required for C18H14N2O6: 354.0852.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:16])=[C:4]([C:11]([O:13]CC)=O)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].[NH2:17][C:18]1[N:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=1.BrC1C=CC=CC=1.C(Cl)(Cl)Cl>CO>[Cl:24][C:21]1[N:20]=[N:19][C:18]([NH:17][C:11]([C:4]2[C:5](=[O:10])[N:6]([CH3:9])[C:7]([CH3:8])=[C:2]([F:1])[C:3]=2[OH:16])=[O:13])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1c(O)c(F)c(C)n(C)c1=O
Reactant: Nc1ccc(Cl)nn1
Solvent: CO
Solvent: Brc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1c(F)c(O)c(C(=O)Nc2ccc(Cl)nn2)c(=O)n1C
Temperature: 160 °C
Reaction time: 4 h
Yield: 66.4 %

Procedure:
600 mg of ethyl 5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 194 mg of 3-amino-6-chloropyridazine were added to 5 ml of bromobenzene, and the mixture was stirred at 160° C. for 4 hours. The reaction mixture was cooled to room temperature, and subjected to silica gel chromatography (chloroform:methanol=20:1). The resulting crude product was washed with a mixture of t-butyl methyl ether and n-hexane, and dried to obtain 311 mg of N-(6-chloro-3-pyridazinyl)-5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 19) represented by the formula:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.C1C(=O)N([I:19])C(=O)C1>>[F:11][C:2]([F:1])([F:10])[C:3]1[C:8]([I:19])=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(C(F)(F)F)ccn1
Product: Nc1cc(C(F)(F)F)c(I)cn1

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 20.0 g (123 mmol) 4-trifluoromethyl-pyridin-2-ylamine and 27.8 g (123 mmol) NIS. Yield after precipitation from the reaction mixture and isolation of additional product from the mother liquid by chromatography in slilca gel: 20.3 g (57%).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([CH3:33])[C:21](OC4C=CC([N+]([O-])=O)=CC=4)=[O:22])[C:14]=3[Cl:34])[C:5]2=[N:4][C:3]=1[CH3:35].[CH3:36][NH2:37]>CO>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([CH3:33])[C:21]([NH:37][CH3:36])=[O:22])[C:14]=3[Cl:34])[C:5]2=[N:4][C:3]=1[CH3:35]
Reactant: CN
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)Oc4ccc([N+](=O)[O-])cc4)c3Cl)cccn2c1Br
Solvent: CO
Product: CNC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl

Procedure:
A mixture of 3-bromo-8-[2,6-dichloro-3-[N-methyl-N-(4-nitrophenyloxycarbonyl)amino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (63 mg) and 30% solution of methylamine in methanol (2 ml) was heated under reflux for 3 hours. After addition of 30% solution of methylamine in methanol (1 ml), the mixture was heated under reflux for additional 1 hour. The mixture was evaporated in vacuo and the residue was extracted with ethyl acetate. The extract was evaporated in vacuo and the residue was purified by preparative thin-layer chromatography (5% solution of methanol in dichloromethane) followed by crystallization from diethyl ether to give 3-bromo-8-[2,6-dichloro-3-(N-methyl-N'-methylureido)benzyloxy]-2-methylimidazo[1,2-a]pyridine (28 mg) as crystals.