Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)(=O)=O)=CC=1.[F:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([OH:25])=[CH:20][C:19]=1[N:26]1[C:30](=[O:31])[C:29]2[CH2:32][CH2:33][CH2:34][CH2:35][C:28]=2[C:27]1=[O:36].C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C>[F:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([O:25][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:20][C:19]=1[N:26]1[C:30](=[O:31])[C:29]2[CH2:32][CH2:33][CH2:34][CH2:35][C:28]=2[C:27]1=[O:36]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
Cyclopentyl p-toluenesulfonate (1.90 g, 8.11 mmol) was added to a solution of N-(2-fluoro-4-chloro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (2.0 g, 6.76 mmol) and potassium carbonate (0.60 g, 4.34 mmol) in acetonitrile (50 ml), followed by stirring for 2 hours at 80° C. After completion of the reaction, 1N hydrochloric acid (20 ml) was added to the resulting reaction mixture, and the mixture was extracted with ethyl acetate (20 ml×3 times). The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol (5 ml) was added to the resulting pale yellow oily substance, and the precipitated N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide as a white solid (0.77 g, 2.12 mmol, 31.4% yield) was isolated by filtration. The spectral data and the like are as described in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:13][N:12]=1>CC(O)CC>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:13][N:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cn1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Solvent: CCC(C)O
Product: COc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cn1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A RBF was charged with 6-methoxypyridin-3-amine (155 mg, 1.25 mmol), 1-chloro-4-phenylphthalazine (300 mg, 1.25 mmol), and 2-butanol (4 mL). The vessel was sealed and the mixture was stirred overnight at 90° C. LC/MS shows completion of reaction. Reaction cooled to RT and purified by silica gel chromatography (1-5% MeOH/DCM) to afford N-(6-methoxypyridin-3-yl)-4-phenylphthalazin-1-amine as tan solid. MS [M+H]=329.1. Calc'd for C20H16N4O: 328.4.
Reaction SMILES: C1COCC1.[O:6]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH:19](=[O:28])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(O)C.CCCCCC>[O:28]=[C:19]1[O:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20]1
Reactant: O=CC=Cc1ccccc1
Reactant: CCOC(=O)C(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)O
Product: CCOC(=O)C1(c2ccccc2)OC(=O)CC1c1ccccc1
Temperature: 23 °C
Reaction time: 36 h

Procedure:
A flame dried 2 dram vial equipped with a stirbar is brought into the glovebox and charged with (+)-4 (0.016 mmol, 0.10 equiv), TBD (6.6 mg, 0.048 mmol, 0.30 equiv), and 4 Å molecular sieves (100 mg). The vial is then sealed with a screw cap equipped with a teflon septa. The vial is then taken out of the glovebox and THF (0.80 mL), ethyl 2-oxo-2-phenylacetate (57 mg, 0.32 mmol, 2.0 equiv) and cinnamaldehyde (21 mg, 0.16 mmol) are added. The reaction mixture is then stirred at 23° C. for 36 hours (monitored by GC/MS). The crude reaction mixture is filtered through celite and an aliquot is taken to determine dr. After filtration the crude mixture is concentrated and the crude residue is purified by column chromatography on silca gel (2% EtOAc/Hex) to provide the pure products. Analytical data matches that reported in the literature (Li, Y. et al., Adv. Synth. Catal. 2008, 350, 1885, incorporated herein by reference). Major diastereomer (Cis) 1H NMR (500 MHz, CDCl3): δ 7.72-7.67 (m, 2H), 7.45-7.27 (m, 8H), 4.08 (dd, J=8.4, 4.1 Hz, 1H), 3.87-3.80 (m, 2H), 2.88 (dd, J=17.6, 8.4 Hz, 1H), 2.79 (dd, J=17.7, 4.1 Hz, 1H), 0.89 (d, J=7.7 Hz, 3H). Enantiomeric ratio is determined by chiral phase HPLC (chiralcel AD-H; i-PrOH-hexane, 2:98, 1.0 mL/min, 210 nm); tr (major)=39.4 min, tr (major)=60.0 min. and tr (minor)=17.1 min, tr (minor)=18.7 min. Absolute stereochemistry is assigned by analogy.
Reaction SMILES: CC1O[CH:6]([CH3:8])[O:5][CH:4]([CH3:9])O1.[OH2:10].[C:11]1(C)C=C[C:14](S(O)(=O)=O)=[CH:13][CH:12]=1>O1CCOCC1>[O:5]1[C:4]2[CH:9]=[CH:11][CH:12]=[CH:13][C:14]=2[O:10][CH:8]=[CH:6]1
Reactant: CC1OC(C)OC(C)O1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: C1=COc2ccccc2O1
Yield: 745.5 %

Procedure:
Reaction of 3,5-(1,1-dimethylethyl)-2-hydroxybenzenemethanol (7.03 g, 0.03 mol), paraldehyde (13.2, 0.3 mol), p-dioxane (150 mL) and p-toluenesulfonic acid hydrate (0.57 g, 0.003 mol) as described in Example 4, provided after distillation 4.12 g (52% yield, GLC purity 99%), of 6,8-(1,1-dimethylethyl)-2-methyl-4H-1,3-benzodioxin. Crystallization from methanol provided 3.0 g of pure benzodioxin, mp 59°-61° C.; 1H-NMR (CDCl3)δ1.20 (9H, s), 1.30 (9H, s), 1.50 (3H, d, J=5 Hz), 4.83 (2H, dd, J=5 and 14 Hz), 5.10 (1H, q, J=6 Hz), 6.72 (1H, d, J=2 Hz), 7.10 (1H, d, J=2 Hz); IR (CDCl3)λmax 2955, 1490, 1455, 1410 cm-1 ; MS m/e 262, 218, 203, 177, 161; UVλmax (ethanol) 224 nm (ε=4650), 280 nm (ε=1190).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:14]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[S:12][N:11]=1)#[N:2].[CH3:21][NH2:22]>C(O)C>[C:1]([N:3]=[C:4]([NH:22][CH3:21])[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:14]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[S:12][N:11]=1)#[N:2]
Reactant: CN
Reactant: CSC(=NC#N)NCCSCc1nsc(NC(=N)N)n1
Solvent: CCO
Product: CNC(=NC#N)NCCSCc1nsc(NC(=N)N)n1

Procedure:
A suspension of 3-[2-(3-cyano-2-methylisothioureido)-ethylthiomethyl]-5-guanidino-1,2,4-thiadiazole (10 g.) in ethanol (200 ml.) was stirred and cooled to 10° with external ice cooling. Methylamine (166 g.) was passed into the suspension over 2 hours at such a rate that the temperature did not rise above 17° with external ice cooling. After 80 g. had been added, all was in solution. After 4 hours the ice bath was removed and excess methylamine was allowed to evaporate overnight. The final volume was about 120 ml. The product was filtered off, washed with a little ethanol, sucked dry and dried at 60°/0.3 m.m. Recrystallisation from aqueous ethanol (1:3 v/v) gave 3-[2-(2-cyano-3-methylguanidino)-ethylthiomethyl]-5-guanidino-1,2,4-thiadiazole, m.p. 198°-199°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[N:44]1([CH2:50][CH2:51][NH2:52])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:52][CH2:51][CH2:50][N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:42])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: NCCN1CCCCC1
Reactant: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1NC(=O)NCCN1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methoxyaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (139 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 2-piperidino-1-ethanamine (60 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (80 mg, yield 54%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[CH:34]=[C:35]([OH:41])[CH:36]=[C:37]([F:40])[C:38]=1[F:39].[CH2:42]([C@H:47]1[CH2:52][CH2:51][C@H:50]([CH2:53]O)[CH2:49][CH2:48]1)[CH2:43][CH2:44][CH2:45][CH3:46]>O1CCCC1>[CH2:42]([C@H:47]1[CH2:52][CH2:51][C@H:50]([CH2:53][O:41][C:35]2[CH:34]=[C:33]([F:32])[C:38]([F:39])=[C:37]([F:40])[CH:36]=2)[CH2:49][CH2:48]1)[CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCC[C@H]1CC[C@H](CO)CC1
Reactant: Oc1cc(F)c(F)c(F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](COc2cc(F)c(F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.31 g (7.5 mmol) of diethyl azodicarboxylate are added at 0° C. to 1.97 g (7.50 mmol) of triphenylphosphine in 30 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 0.5 hour. 1.11 g (7.50 mmol) of 3,4,5-trifluorophenol and 1.38 g (7.50 mmol) of trans-4-pentylcyclohexylmethanol are then added, and the mixture is stirred at room temperature for 18 hours. Evaporation of the solvent and chromatography on silica gel using hexane give 1.23 g of product. ##STR5## Phase sequence: X 14 (-26) I
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:14]=1[CH:15]=O.[NH4+].[Cl-].C1C[O:27]CC1>C(Cl)Cl>[OH:27][C:14]1([C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][CH:13]1[F:12])[CH2:15][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][N:6]=1
Reactant: c1cnccn1
Reactant: O=Cc1c(F)cccc1Cl
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClCCl
Product: OC1(Cc2cnccn2)C(Cl)=CC=CC1F
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
35 ml of a 2.5M solution of butyl lithium were added to 14 ml of TMP in 35 ml THF over a period of 10 minutes at a temperature of -70° C. After stirring at -70° C. for 10 minutes, the reaction mixture was allowed to warm up to 0° C. and kept at 0° C. for 10 minutes. The reaction mixture was then cooled to -70° C. again and a solution of 5.0 g of pyrazine in 25 ml THF was then added over a period of 15-20 minutes, while maintaining the temperature below -60° C. The reaction mixture was then stirred at -70° C. for one hour. 10.4 g of 2-fluoro-6-chlorobenzaldehyde were added, while keeping the temperature below -60° C. and the resulting reaction mixture was then stirred at -70° C. for about two hours. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. 45 ml of saturated NH4Cl were added to the reaction mixture. Then, 150 ml of methylene chloride were added and the layers were separated. The methylene chloride layer was washed with brine, dried (MgSO4), filtered and stripped to a dark brown residue. The residue was put on a silica gel column and eluted with a 4:1 mixture of hexane:diethyl ether, then 2:1 hexane:diethyl ether. The desired fraction yielded 2.0 g of 2-(1-hydroxy-2'-fluoro-6'-chlorobenzyl)pyrazine in a yellow, semi-solid form.
Reaction SMILES: [C:1]1([S:7][C@@H:8]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C@@H:25]([O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C@H:17]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:9]2[O:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:51])C=1.CSC>C(Cl)Cl>[C:11]([O:10][C@@H:9]1[C@@H:17]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:21])[CH3:22])[C@H:25]([O:26][C:27](=[O:32])[C:28]([CH3:29])([CH3:30])[CH3:31])[C@@H:33]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[O:34][C@H:8]1[S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:51])(=[O:16])[C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Solvent: ClCCl
Solvent: CSC
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](S(=O)c2ccccc2)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: -15 °C
Yield: 89.4 %

Procedure:
To a solution of 44 (1.24 g, 2.04 mmol) in 25 mL of CH2Cl2 at -78° C. is added a solution of 64% m-CPBA (550 mg, 2.04 mmol) in 10 mL of CH2Cl2. The reaction mixture is allowed to warm to -15° C., quenched with methyl sulfide (2.07 mL, 1.75 g, 6.8 mmol) and warmed to room temperature. The reaction mixture is then diluted with 25 mL CH2Cl2, washed with saturated NaHCO3 (50 mL), H2O (50 mL), saturated NaCl (50 mL), dried over Na2SO4, filtered, concentrated and purified by flash chromatography (30% EtOAc/hexane) to afford 1.14 g (89%) of the title compound 45 as a mixture of diastereomers: Rf 0.14 and 0.28 (10% EtOAc/hexane).
Reaction SMILES: COC1C=CC(N2CCN([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)CC2)=CC=1C.C1(CC[N:32]2[CH2:37][CH2:36][N:35]([C:38]3[CH:43]=[CH:42][C:41]([O:44]C)=[C:40]([F:46])[CH:39]=3)[CH2:34][CH2:33]2)CCCCC1>>[CH:17]1([CH2:16][CH2:15][CH:34]2[CH2:33][NH:32][CH2:37][CH2:36][N:35]2[C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([F:46])[CH:39]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1C
Reactant: COc1ccc(N2CCN(CCC3CCCCC3)CC2)cc1F
Product: Oc1ccc(N2CCNCC2CCC2CCCCC2)cc1F

Procedure:
Production Example 10 was repeated except that 1-(4-methoxy-3-methylphenyl)-4-phenethylpiperazine was replaced with 1-(2-cyclohexylethyl)-4-(3-fluoro-4-methoxyphenyl)piperazine (218 mg) and the resulting crude product was purified on TLC (developer, chloroform: methanol=18:1) to provide 4-[4-(2-cyclohexylethyl-piperazin-1-yl]-2-fluorophenol (77 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:21])[N:8]([CH2:9][CH2:10][CH2:11][Si:12]([O:17][CH3:18])([O:15][CH3:16])[O:13][CH3:14])[C:7](=[O:19])[NH:6][C:5]1=[O:20].[H-].[H][H].Cl[CH2:26][CH2:27][CH2:28][Si:29]([O:34][CH3:35])([O:32][CH3:33])[O:30][CH3:31]>CN(C)C=O>[CH3:14][O:13][Si:12]([CH2:11][CH2:10][CH2:9][N:8]1[C:4]([CH3:21])([CH3:3])[C:5](=[O:20])[N:6]([CH2:26][CH2:27][CH2:28][Si:29]([O:34][CH3:35])([O:32][CH3:33])[O:30][CH3:31])[C:7]1=[O:19])([O:17][CH3:18])[O:15][CH3:16]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: CO[Si](CCCN1C(=O)NC(=O)C1(C)C)(OC)OC
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[Si](CCCN1C(=O)N(CCC[Si](OC)(OC)OC)C(C)(C)C1=O)(OC)OC
Temperature: 85 °C

Procedure:
A 2.4 g portion of a dispersion containing 50% by weight of sodium hydride in a liquid paraffin was added in portions under an inert atmosphere to a solution containing 14.5 g (0.05 mole) 5,5-dimethyl-3-trimethoxysilylpropyl hydantoin and 150 cc of anhydrous N,N-dimethylformamide. The temperature of the reaction mixture was maintained at from 15° to 20° C. during the addition of the hydride. Following completion of the addition the mixture was stirred until hydrogen evolution ceased, at which time it was heated to 85° C., and 98.8 g of chloropropyltrimethoxysilane were added dropwise to the reaction mixture. A white precipitate formed as the addition progressed. Following completion of the addition the reaction mixture was heated at 95° C. for 16 hours, at which time the reaction mixture was cooled, filtered and the liquid phase distilled under reduced pressure to remove the N,N-dimethylformamide. The liquid paraffin was washed from the product using hexane. The identity of the residue as the expected silylhydantoin was confirmed using infra-red and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11][C@H:10]2[O:20][CH3:21])=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.Cl[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C.ClCCl.O>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:28]3[N:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:11][C@H:10]2[O:20][CH3:21])=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: Clc1ncccn1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCCN)C[C@H]1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCCNc2ncccn2)C[C@H]1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
A mixture of 4.6 parts of cis-4-amino-N-[1-(4-aminobutyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide, 1.4 parts of 2-chloropyrimidine and a few drops of N,N-dimethylacetamide was stirred overnight at 80° C. The reaction mixture was taken up in a mixture of dichloromethane, water and hydrochloric acid. The separated aqueous layer was treated with sodium carbonate and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (96:3:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.34 parts (24.1%) of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[4-(2-pyrimidinylamino)butyl]-4-piperidinyl]benzamide; mp. 114.8° C. (compound 29).
Reaction SMILES: [H-].[Na+].[CH:3]([CH:6]([C:12]([CH3:14])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:5])[CH3:4].[H][H].[CH2:17](Br)[C:18]#[CH:19]>C(O)C>[CH2:19]([C:6]([CH:3]([CH3:5])[CH3:4])([C:12]([CH3:14])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:18]#[CH:17]
Reactant: CCOC(=O)C(C(C)=O)C(C)C
Reactant: [H][H]
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: C#CCC(C(C)=O)(C(=O)OCC)C(C)C
Temperature: 75 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A 1 liter flask was equipped with a mechanical stirrer, addition funnel, reflux condenser and nitrogen inlet. The flask was dried with external heat and then charged with 12.00 grams (0.25 mol) of 50% sodium hydride dispersed in mineral oil. The mineral oil was removed by two 50 milliliter washings with toluene and then 200 milliliters of toluene was added to the flask. 43.06 grams (0.25 mol) of ethyl 2-isopropylacetoacetate was added dropwise to the flask along with three drops of dry ethanol. Hydrogen was virorously evolved and the reaction temperature rose to 65° C. When all the ethyl 2-isopropylacetoacetate had been added, the reaction mixture was heated to 75° C. for one hour and then cooled to 10° C. with an ice bath. The reaction mixture at this point was thick and light green in color. 37.18 grams (0.25 mol) of propargyl bromide was then added dropwise and the reaction mixture was allowed to stir overnight at room temperature. After one hour of stirring, the reaction mixture had thinned and turned a rust color. Following the overnight stirring period, the reaction mixture was heated to 85° C. for two hours and then cooled to room temperature. The reaction mixture was cautiously quenched with 10 milliliters of ice water followed by the addition of 250 milliliters of ice water and the resulting layers were separated. The toluene was washed three times with water, dried (MgSO4) and removed under vacuum to leave a red oil. The red oil was vacuum distilled through a vigreux still to give 33.5 grams (0.16 mol) of ethyl 2-propargyl-2-isopropylacetoacetate having a boiling point of 61°-68° C. at 0.20 millimeters pressure.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][CH2:11][N:12]3[CH2:15][CH2:16][CH3:17])[CH2:7][C:6]=2[N:18]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].N>C(Cl)(Cl)Cl.CO>[C:25]([NH:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][CH2:11][N:12]3[CH2:15][CH2:16][CH3:17])[CH2:7][C:6]=2[N:18]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CCCN1CCC[C@H]2Cc3nc(N)ncc3C[C@@H]21
Agent: N
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Product: CCCN1CCC[C@H]2Cc3nc(NC(C)=O)ncc3C[C@@H]21

Procedure:
A solution was prepared containing 0.75 g of trans-(±)-2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline in 20 ml. of pyridine and 0.34 g. of acetic anhydride was added thereto in dropwise fashion. The reaction mixture was heated to reflux temperature under a nitrogen blanket overnight. TLC at this point in time indicated that starting material was still present; therefore, about 1.5 ml. more acetic anhydride were added and the reaction mixture again heated to reflux temperature under a nitrogen blanket. TLC, using a 9:1 chloroform/methanol solvent system containing ammonia, indicated that the reaction had gone largely toward completion but that some starting material was still present. The reaction mixture was therefore concentrated in vacuo and the resulting residue triturated in hot ethyl acetate. On cooling, crystals formed which were isolated by filtration. Thirty-four hundredths grams of trans-(±)-2-acetylamino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline were obtained; molecular ion at 288; nmr and infrared spectra were in comformance with the proposed structure.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]5[CH2:34][O:33][CH2:32]5)[CH2:27][C@@H:26]4[CH2:35][CH3:36])=[CH:21][N:20]=3)[C:15](=[O:37])[N:14]([CH3:38])[CH:13]=2)=[CH:10][C:9]([F:39])=[CH:8][C:7]=1[N:40]1[CH2:51][CH2:50][N:49]2[C:42](=[CH:43][C:44]3[CH2:45][C:46]([CH3:53])([CH3:52])[CH2:47][C:48]=32)[C:41]1=[O:54])(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[CH2:35]([C@H:26]1[CH2:27][N:28]([CH:31]2[CH2:32][O:33][CH2:34]2)[CH2:29][CH2:30][N:25]1[C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[C:15](=[O:37])[N:14]([CH3:38])[CH:13]=[C:12]([C:11]3[C:6]([CH2:5][OH:4])=[C:7]([N:40]4[CH2:51][CH2:50][N:49]5[C:48]6[CH2:47][C:46]([CH3:53])([CH3:52])[CH2:45][C:44]=6[CH:43]=[C:42]5[C:41]4=[O:54])[CH:8]=[C:9]([F:39])[CH:10]=3)[CH:17]=2)=[N:20][CH:21]=1)[CH3:36]
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3COC(C)=O)cn(C)c2=O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3CO)cn(C)c2=O)nc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 40.4 %

Procedure:
A mixture of 114g (115 mg, 0.16 mmol) and lithium hydroxide (38 mg, 1.6 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure and the residue was extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 114 (45 mg, 40%) as a white solid. MS: [M+H]+ 696.4. 1H NMR (500 MHz, CDCl3) δ 8.55-8.54 (m, 1H), 7.91 (s, 1H), 7.80 (d, J=1.5 Hz, 1H), 7.47 (s, 1H), 7.26 (d, J=3.0 Hz, 1H), 7.17 (d, J=9.0 Hz, 1H), 6.95 (dd, J=2.5, 8.5 Hz, 1H), 6.83-6.81 (m, 2H), 4.71 (t, J=6.5 Hz, 2H), 4.67 (t, J=6.0 Hz, 1H), 4.62 (t, J=6.0 Hz, 1H), 4.57-4.55 (m, 1H), 4.41-4.38 (m, 1H), 4.32-4.30 (m, 1H), 4.24-4.14 (m, 3H), 3.92-3.87 (m, 1H), 3.71 (s, 3H), 3.56-3.50 (m, 1H), 3.33-3.29 (m, 1H), 3.13-3.11 (m, 2H), 2.58-2.56 (m, 3H), 2.52 (s, 2H), 2.44-2.43 (m, 2H), 2.38-2.32 (m, 1H), 1.66-1.64 (m, 1H), 1.42-1.37 (m, 1H), 1.28 (s, 6H), 0.82 (t, J=7.0 Hz, 3H).