Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[S:11]1[CH2:15][CH:14]([C:16]([OH:18])=[O:17])[NH:13][CH2:12]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:2]([N:13]1[CH:14]([C:16]([OH:18])=[O:17])[CH2:15][S:11][CH2:12]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O=C(O)C1CSCN1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(O)C1CSCN1C(=O)c1cccnc1
Temperature: 64 °C
Reaction time: 16 h
Yield: 56.4 %

Procedure:
Nicotinoyl chloride hydrochloride (534 g) is added over 1 hour at a temperature of between 30° and 52° C. to a solution of thiazolidine-4-carboxylic acid (400 g) and triethylamine (613 g) in chloroform (4,500 cc). The solution obtained is heated at a temperature of about 64° C. for 4 hours. After stirring at a temperature of about 20° C. for 16 hours, the crystals which have appeared are separated off by filtration, washed 3 times with chloroform (1,500 cc in total), then 3 times with diethyl ether (1,500 cc in total) and are dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. N-nicotinoylthiazolidine-4-carboxylic acid (403 g) is thus obtained in the form of white crystals melting at 190° C.
Reaction SMILES: Br[CH2:2][C@@H:3]([NH:5][C:6]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9])[CH3:4].[Na+].[C:29]1([S:35]([O-])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CS(C)=O.C(OCC)(=O)C>[C:26]([C:23]1[CH:24]=[CH:25][C:6]([NH:5][C@@H:3]([CH3:4])[CH2:2][S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9])#[N:27]
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CBr)cc1OC
Reactant: O=S(=O)([O-])c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CS(=O)(=O)c2ccccc2)cc1OC
Temperature: 90 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of (S)-2-(2-bromo-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (147 mg) in dimethylsulfoxide (2 mL) was added benzenesulfonic acid sodium salt (81.6 mg), and the mixture was stirred for 3 hours at 90° C. The resulting mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate (9:1) to give (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(2-phenylsulfonyl-1-methylethylamino)benzamide (94 mg) as a solid substance.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7](C(O)=O)[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:14][CH:15]=1
Reactant: O=C(O)C(Cc1ccc(Br)cc1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)CCc1ccc(Br)cc1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A solution of 2-(4-bromobenzyl)malonic acid (18 g, 66.18 mmol, 1.00 equiv) in dimethylsulfoxide (50 mL) was stirred at 160° C. for 2 h. The reaction mixture was cooled to room temperature and the product was precipitated by the addition of 200 mL ice and water. The solid was collected by filtration, washed with 1×50 mL of water and dried in a vacuum oven to give 14.8 g (98%) of 3-(4-bromophenyl)propanoic acid as a white solid. LC-MS: (ES, m/z): 229 [M+H]+. 1HNMR (400 MHz, DMSO-d6, ppm): δ 7.45 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 2.82-2.77 (m, 2H), 2.55-2.51 (m, 2H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([N:13]([CH3:15])[CH3:14])[CH:8]=1.[CH2:16]([N:23]([CH3:31])[CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[CH2:16]([N:23]([CH3:31])[CH:24]1[CH2:29][CH2:28][C:27]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]([CH3:15])[CH3:14])[CH:8]=2)([OH:30])[CH2:26][CH2:25]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)c1cc(Br)ccn1
Reactant: CN(Cc1ccccc1)C1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN(C)c1cc(C2(O)CCC(N(C)Cc3ccccc3)CC2)ccn1
Reaction time: 0.75 h
Yield: 71 %

Procedure:
n-BuLi (3 ml, 5.98 mmol, 1.2 eq., 2 M solution in hexane) was added at −78° C. to a solution of 4-bromo-N,N-dimethylpyridin-2-amine (978 mg, 5.23 mmol, 1.05 eq.) in diethyl ether (15 ml) and the mixture was stirred for 45 minutes. A solution of 4-(benzyl(methyl)amino)cyclo-hexanone (stage 3, AMN-50) (1.08 g, 4.9, 8 mmol 1.0 eq.) in diethyl ether (10 ml) was added dropwise thereto at the same temperature. The reaction mixture was stirred for 16 hours at RT and was then hydrolyzed with sat. ammonium chloride solution (30 ml) and extracted with ethyl acetate (3×60 ml). The combined org. phases were washed with sat. NaCl solution (100 ml), dried over sodium sulfate, concentrated and purified by column chromatography (silica gel, 2,5% MeOH in DCM). Yield: 71% (1.20 g, 3.54 mmol)
Reaction SMILES: C(O)CCC.[ClH:6].[OH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[OH:17])[CH2:11][CH2:12][NH2:13].C(O[CH:21](OCC)[CH2:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)C>Cl.O>[ClH:6].[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([S:23][CH2:22][CH:21]2[C:14]3[C:10](=[CH:9][C:8]([OH:7])=[C:16]([OH:17])[CH:15]=3)[CH2:11][CH2:12][NH:13]2)=[CH:25][CH:26]=1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CCOC(CSc1ccc(C)cc1)OCC
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: Cc1ccc(SCC2NCCc3cc(O)c(O)cc32)cc1
Yield: 106.9 %

Procedure:
To a mixture of n-butanol (10 ml), water (2.5 ml) and concentrated hydrochloric acid (1 drop) were added 3,4-dihydroxyphenethylamine hydrochloride (0.63 g) and (4-methylthiophenoxy)acetaldehyde diethyl acetal (1.0 g), and the mixture was refluxed for 5 hours. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The residue was crystallized by adding acetone, and the crystals were recrystallized by adding acetone, and the crystals were recryatallized from a mixture solvent of methanol and ether to give 1-(4-methylthiophenoxy)methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.2 g), mp 270°C (dec.).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[CH:12][C:11]=2[C:15](OCC)=[O:16])=[CH:6][CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[F:21][C:2]([F:1])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[CH:12][C:11]=2[CH2:15][OH:16])=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cnoc1-c1ccc(OC(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnoc1-c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
To a solution of ethyl 5-(4-trifluoromethoxyphenyl)isoxazole-4-carboxylate (6.60 g) in tetrahydrofuran (80 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 55 ml) at 0° C. The mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 5-(4-trifluoromethoxyphenyl)-4-isoxazolylmethanol (5.70 g, yield 99%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 45–46° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH3:17])=[CH:12][CH:11]=2)[N:3]=[CH:2]1.Cl.[NH2:20][NH:21][C:22]([NH2:24])=[O:23]>>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[N:20][NH:21][C:22]([NH2:24])=[O:23])[CH3:17])=[CH:12][CH:11]=2)[N:3]=[CH:2]1
Reactant: NNC(N)=O
Reactant: CC(=O)c1ccc(OCCCc2c[nH]cn2)cc1
Agent: Cl
Product: CC(=NNC(N)=O)c1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
1.2 mmol of (4-(3-(1H-imidazol-4-yl)propyloxy)phenyl)ethanone (Example 58) and 2.4 mmol of semicarbazide hydrochloride are treated as described in Example 138.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:26])[C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][C:12]=2[O:24]C)=[CH:4][CH:3]=1.B(Br)(Br)Br.O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:26])[C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:13][C:12]=2[OH:24])=[CH:4][CH:3]=1
Reactant: COc1cc(N2CCOCC2)cc(C)c1C(=O)NCc1ccc(F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1cc(N2CCOCC2)cc(O)c1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of N-[(4-fluorophenyl)-methyl]-2-methoxy-6-methyl-4-morpholin-4-yl-benzamide (2.50 g, 6.98 mmol) in dichloromethane (70 ml) is added neat boron tribromide (0.99 ml, 10.3 mmol) at −78° C. The temperature is slowly raised to RT over a period of 30 min and stirred for 1 h at RT. The reaction mixture is poured onto cold water and extracted with dichloromethane (3×50 ml). The combined organic layers are washed with brine (30 ml), dried over sodium sulfate and evaporated to dryness. The crude material is purified by column chromatography (silica gel, 25% ethyl acetate/hexane) affording N-[(4-fluorophenyl)-methyl]-2-hydroxy-6-methyl-4-morpholin-4-yl-benzamide (0.90 g, 2.58 mmol, 37%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]2[CH3:22])[C:9]2[C:4](=[C:5]([O:23][CH3:24])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([NH:30][CH3:31])=[CH:28][CH:27]=1>CN(C)C=O>[ClH:1].[CH3:24][O:23][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([N:30]([C:29]1[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=1)[CH3:31])[N:11]=[C:10]2[N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]1[CH3:22]
Reactant: COc1cccc2c(N3CCc4ccccc4C3C)nc(Cl)nc12
Reactant: CNc1ccc(F)cc1
Solvent: CN(C)C=O
Product: COc1cccc2c(N3CCc4ccccc4C3C)nc(N(C)c3ccc(F)cc3)nc12
Product: Cl
Yield: 48.2 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 1.00 g of the compound (2.94 mM) prepared in Example 5 and 15 ml of dimethyl-formamide, 0.77 g of 4-fluoro-N-methyl aniline(6.18 mM) was added, 0.66 g of the title compound was prepared.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH2:9]=[C:10]1[O:14][C:12](=[O:13])[CH2:11]1>C(O)(=O)C>[O:14]=[C:10]1[CH:11]([CH3:12])[C:4]2[C:3](=[CH:2][C:1]([NH:8][C:12](=[O:13])[CH2:11][C:10]([CH3:9])=[O:14])=[CH:6][CH:5]=2)[NH:7][CH2:9]1
Reactant: C=C1CC(=O)O1
Reactant: Nc1cccc(N)c1
Solvent: CC(=O)O
Product: CC(=O)CC(=O)Nc1ccc2c(c1)NCC(=O)C2C
Temperature: 15 °C
Yield: 83 %

Procedure:
129.6 gm of at least 98 percent pure 1,3-phenylene diamine (melting point: 60° to 62° C) and 750 ml of 10 percent acetic acid were placed in a sulfurizing flask, equipped with an anchor bolt, reflux cooler, drip funnel, thermometer and water bath. 211.2 gm of diketene were allowed to drip into the reaction mixture over the course of 1.5 hours at room temperature. The reaction was stirred during the addition. The temperature, with the aid of the reaction heat, was allowed to rise to 60° to 65° C. After completion of the addition of diketene, the mixture was allowed to continue for another hour at 60° to 65° C. and was then cooled to about 15° C. The precipitated product was then separated out and dried under vacuum at 60° to 70° C. until the precipate reached a constant weight. 257 gm. of raw, almost colorless, 1,2-dihydro-3oxo-4-methyl-7-acetoacetamido-quinoline was obtained having a melting point of about 238° C. This corresponded to a yield of about 83 percent, based on the m-phenylene diamine. After a single recrystallization from 67 percent acetic acid, the product had a melting point of 246.0° to 247.0° C. After one more recrystallization from the diluted acetic acid, the melting point was found not to have changed.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2>[Pd].C(O)(=O)C>[OH:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: O=C(O)c1cc2ccccc2cc1O
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)c1cc2c(cc1O)CCCC2
Reaction time: 7 h
Yield: 89.9 %

Procedure:
A mixture of 3-hydroxy-2-naphthalenecarboxylic acid (15.0 g, 0.08 moles), 10% Pd/C (4.46 g) and acetic acid (190 mL) was hydrogenated at 60° C. and 50 psi for 7 h. The cooled reaction mixture was filtered through diatomaceous earth and washed with ethanol (4×25 mL). The yellow filtrate was concentrated in vacuo to afford 13.82 g (91%) of a purple solid. 1H NMR (CDCl3) δ 7.61 (s, 1H), 6.71 (s, 1H), 2.74 (d, 4H), 1,78 (s, 4H). MS m/z 191 (M−H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.[C:11]([Li])([CH3:14])([CH3:13])C.[N:16]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:21][CH2:20][CH:19]([C:22]([O:24]CC)=O)[CH2:18][CH2:17]1>C1COCC1>[O:6]1[C:5]2[CH:9]=[CH:10][C:2]([C:22]([C:13]3[CH:11]=[CH:14][C:4]4[O:8][CH2:7][O:6][C:5]=4[CH:9]=3)([OH:24])[CH:19]3[CH2:18][CH2:17][N:16]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:21][CH2:20]3)=[CH:3][C:4]=2[O:8][CH2:7]1
Reactant: [Li]C(C)(C)C
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Brc1ccc2c(c1)OCO2
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)(c2ccc3c(c2)OCO3)c2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
To a stirring solution of 5-bromobenzo-1,3-dioxole (1.77 g, 8.8 mmol) in dry THF (10 mL) at −78° C. under N2 was added tert-butyllithium (10.5 mL, 17.9 mmol, 1.7M in pentane). After 2 h, 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (1.13 g, 4.4 mmol) was added dropwise to the reaction mixture at −78° C. and stirred for 1 h. The reaction mixture was subsequently warmed to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl (30 mL) and the aqueous layer extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The mixture was purified by flash chromatography (10-30% EtOAc/hexanes) to give tert-butyl 4-(bis(benzo[d][1,3]dioxol-5-yl)(hydroxy)methyl)piperidine-1-carboxylate as a white solid (1.3 g, 73%): 1H NMR 500 MHz (CDCl3) δ 6.93-6.89 (m, 4H), 6.73 (d, J=8.0 Hz, 2H), 5.91 (s, 4H), 4.14 (bs, 2H), 2.74-2.63 (m, 2H), 2.41-2.34 (m, 1H), 2.04 (s, 1H), 1.55-1.47 (m, 2H), 1.43 (s, 9H), 1.32-1.23 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.N1CCCC1.O.[C:22]([NH2:26])(=[O:25])[C:23]#[CH:24]>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[C:7]2[NH:26][C:22](=[O:25])[CH:23]=[CH:24][C:6]=2[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1
Reactant: C#CC(N)=O
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCNC1
Product: CC1CN(C(=O)OC(C)(C)C)Cc2ccc(=O)[nH]c21
Temperature: 25 °C
Yield: 55 %

Procedure:
tert-Butyl 3-methyl-4-oxopiperidine-1-carboxylate (commercially available from Ryan Scientific, Mt. Pleasant, S.C.)(1.7 g, 7.97 mmol) and pyrrolidine (1.3 mL, 15.94 mmol) were dissolved in toluene (9 mL), and the solution was heated under reflux, with the removal of water under Dean-Stark conditions, for 5 hours. The solution was then cooled to room temperature and propiolamide (prepared as described in EP 1813606)(1.1 g, 15.94 mmol) was added. The reaction mixture thus obtained was heated overnight under reflux. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel eluting with 0% to 10% MeOH in DCM to give the title compound (2.1 g, 55% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.36 (3H, d, J=7.04 Hz), 1.52 (9H, s), 3.37-3.44 (1H, m), 3.77-3.84 (1H, m), 4.12-4.17 (1H, m), 6.48 (1H, d, J=9.39 Hz), 7.21 (1H, d, J=9.39 Hz) ppm; LC/MS m/z: 265 (M+1).
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13].[C:16](Cl)(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>N1C=CC=CC=1>[C:16]([O:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13])(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCC(=O)Cl
Reactant: On1c(C(F)(F)F)nc2ncc(Cl)cc21
Solvent: c1ccncc1
Product: CCCCCCCC(=O)On1c(C(F)(F)F)nc2ncc(Cl)cc21

Procedure:
To 1-hydroxy-6-chloro-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine (2.37 grams) in 5 milliliters of pyridine was added octanoyl chloride (1.63 grams). The addition was carried out portionwise with stirring and resulted in the precipitation of a white solid. The reaction mixture was set on a steam bath for twenty minutes, then poured over ice cold aqueous HCl. An oil separated and subsequently crystallized on vigorous stirring. This precipitate was removed by filtration, dissolved in ether, dried over magnesium sulfate, filtered, and ether removed by evaporation under vacuum. The substance was purified by distillation, m.p., 33.5°-35.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:5].C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.C(O)C>C(Cl)(Cl)Cl>[CH3:29][O:28][C:20]1[C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:2]2[C:3]([C:4](=[O:5])[N:6]([CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=3)[C:38](=[O:40])[NH:1]2)=[CH:18][CH:19]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCCOc1c(OC)ccc(C(=O)NCCc2ccc([N+](=O)[O-])cc2)c1N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCCCCOc1c(OC)ccc2c(=O)n(CCc3ccc([N+](=O)[O-])cc3)c(=O)[nH]c12
Temperature: 50 °C
Reaction time: 11.5 h
Yield: 183.6 %

Procedure:
2-Amino-4-methoxy-N-[2-(4-nitrophenyl)ethyl]-3-pentyloxybenzamide (15.0 g, 37.4 mmol) obtained in Example 2-46, triethylamine (5.30 ml, 38.0 mmol) and chloroform (200 ml) were mixed, and a solution (10 ml) of triphosgene (4.75 g, 16.0 mmol) in chloroform was added dropwise to this solution. After stirring at 50° C. for 11.5 hours, ethanol (20 ml) was added to stop the reaction. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution (100 ml, 50 ml) and water (100 ml, 50 ml). This solution was dried over anhydrous magnesium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure. A hexane-chloroform solution (10:1, 110 ml) was added to the precipitated crystals, and the crystals were washed by stirring to give 7-methoxy-3-[2-(4-nitrophenyl)ethyl]-8-pentyloxy-1H-quinazoline-2,4-dione (12.56 g, 79%) as pale-yellow crystals.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12](=[NH:14])[NH2:13])[CH:11]=1)=[O:6])[CH3:3].Cl[C:16]1[C:25](Cl)=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CN(C=O)C.O>[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[NH:13][C:16]3=[N:17][C:18]4[C:23]([N:24]=[C:25]3[N:14]=2)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:11]=1)=[O:6])[CH3:3]
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: CCOC(=O)c1cnn(C(=N)N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(-c2nc3nc4ccccc4nc3[nH]2)c1
Yield: 42.2 %

Procedure:
A solution of 1-carbamimidoyl-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (0.220 g, 1.00 mmol), 2,3-dichloro-quinoxaline (200 mg, 1.00 mmol), and Cs2CO3 (1.63 g, 5.00 mmol) in DMF (2 mL) was stirred for 4 h. H2O (3 mL) was added and the mixture was acidified to pH 2 with aqueous 1M HCl to form a white precipitate. The precipitate was filtered, triturated with anhydrous EtOH (2 mL), and filtered to yield the titled compound (0.130 g, 43%). MS (CI): mass calcd. for C15H12N6O2, 308.1; m/z found, 309.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 9.08 (s, 1H), 8.23 (s, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.75 (t, J=7.1 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([N:18]3[CH2:34][CH2:33][C:21]4([CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH2:20][CH2:19]3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[CH2:25]1[C:21]2([CH2:20][CH2:19][N:18]([C:14]3[N:15]=[CH:16][N:17]=[C:12]([NH:11][C:7]4[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=4)[C:3]([NH:2][CH3:1])=[O:4])[N:13]=3)[CH2:34][CH2:33]2)[CH2:22][CH2:23][NH:24]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]
Reactant: CNC(=O)c1cccc(Nc2ncnc(N3CCC4(CCN(C(=O)OC(C)(C)C)C4)CC3)n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cccc(Nc2ncnc(N3CCC4(CCNC4)CC3)n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flask charged with tert-butyl 8-(4-(3-(methylcarbamoyl)phenylamino)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (300 mg, 0.642 mmol) was added DCM (5 mL), and TFA (494 mL, 6.42 mmol) respectively. The resulting mixture was stirred overnight at RT. The reaction mixture was concentrated, and the resulting solid was triturated with ethyl acetate to obtain 3-(4-(2,8-diazaspiro[4.5]decan-8-yl)-1,3,5-triazin-2-ylamino)-N-methylbenzamide as a bis-TFA salt (233 mg, 99% yield) as white solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH:6]([CH3:8])[CH3:7])=[O:4].[NH:9]1[CH2:12][CH:11]([C:13]2[CH:35]=[CH:34][C:16]3[C:17]4[N:18]=[C:19]([C:25]5[N:26]([CH:31]([CH3:33])[CH3:32])[N:27]=[C:28]([CH3:30])[N:29]=5)[S:20][C:21]=4[CH2:22][CH2:23][O:24][C:15]=3[CH:14]=2)[CH2:10]1.C(N(CC)CC)C.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH:6]([NH:5][C:3](=[O:4])[CH2:2][N:9]1[CH2:12][CH:11]([C:13]2[CH:35]=[CH:34][C:16]3[C:17]4[N:18]=[C:19]([C:25]5[N:26]([CH:31]([CH3:33])[CH3:32])[N:27]=[C:28]([CH3:30])[N:29]=5)[S:20][C:21]=4[CH2:22][CH2:23][O:24][C:15]=3[CH:14]=2)[CH2:10]1)([CH3:8])[CH3:7]
Reactant: CC(C)NC(=O)CCl
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CNC4)ccc2-3)n(C(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CN(CC(=O)NC(C)C)C4)ccc2-3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 11.6 %

Procedure:
2-Chloro-N-isopropylacetamide (0.124 g, 0.917 mmol) and tetra-n-butylammonium iodide (0.678 g, 0.00183 mol) were premixed in methylene chloride (3 mL). This solution was added dropwise to a solution of 8-azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 519 (0.350 g, 0.917 mmol) and triethylamine (0.256 mL, 0.00183 mol) in methylene chloride (7 mL). The reaction was stirred at room temperature for 24 hours. Water was added and the mixture was extracted 3 times with methylene chloride. The organic layers were combined, dried with MgSO4 and concentrated. The crude was purified by reverse-phase HPLC to obtain 527 as a white solid (51 mg). MS(ESI+) 481.2. 1H NMR (400 MHz, DMSO) δ 8.29 (d, J=8.2 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.20 (dd, J=8.3, 1.6 Hz, 1H), 7.03 (d, J=1.5 Hz, 1H), 5.87-5.65 (m, 1H), 4.36 (t, J=5.0 Hz, 2H), 3.87 (dq, J=13.2, 6.6 Hz, 1H), 3.76-3.59 (m, 3H), 3.42 (t, J=5.0 Hz, 2H), 3.22 (t, J=6.0 Hz, 2H), 3.04 (s, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6 Hz, 6H), 1.07 (d, J=6.6 Hz, 6H)