Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[C:27]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:32]=[CH:31][C:30]([CH2:33][O:34][C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[CH2:41][CH:40]([CH2:45][CH2:46]O)[CH2:39][CH2:38]3)=[CH:29][CH:28]=1>C1COCC1.O>[C:27]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:32]=[CH:31][C:30]([CH2:33][O:34][C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[CH2:41][CH:40]([CH2:45][CH2:46][I:25])[CH2:39][CH2:38]3)=[CH:29][CH:28]=1
Reactant: OCCC1CCc2cc(OCc3ccc(-c4ccccc4)cc3)ccc2C1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: ICCC1CCc2cc(OCc3ccc(-c4ccccc4)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.8 %

Procedure:
To a solution of triphenylphosphine (12.5 g) in THF (200 ml) were successively added imidazole (3.25 g) and iodine (12.1 g). A solution of 6-(4-biphenylyl) methoxy-2-(2-hydroxyethyl)tetralin (13.15 g) in THF (100 ml) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 5 min, diluted with water, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by silica gel column chromatography (eluent; toluene) to obtain the titled compound (13.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C([O:16][N:17]=O)CCC>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6](=[N:17][OH:16])[CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: CCCCON=O
Product: O=C1C(=NO)Cc2cc(Br)ccc21

Procedure:
Similar procedure as described in example 9B was used, starting from 5-Bromo-indan-1-one and n-butylnitrite to give 5-Bromo-indan-1,2-dione 2-oxime. LC-MS: m/e 240 (MH+).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[C:8]([Cl:13])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:14]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[Cl:26])[C:17]=1[CH:27]=[CH2:28])=[O:15])=[CH2:2].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>ClCCl>[N:29]1([CH2:28][CH2:27][C:17]2[C:18]3[C:23](=[C:22]([Cl:26])[CH:21]=[CH:20][CH:19]=3)[CH:24]=[CH:25][C:16]=2[C:14]([C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][C:8]=3[Cl:13])[C:3]=2[CH2:1][CH2:2][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:15])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: C1CCNCC1
Reactant: C=Cc1c(C(=O)c2ccc3c(Cl)cccc3c2C=C)ccc2c(Cl)cccc12
Solvent: ClCCl
Product: O=C(c1ccc2c(Cl)cccc2c1CCN1CCCCC1)c1ccc2c(Cl)cccc2c1CCN1CCCCC1

Procedure:
Vinyl-5-chloro-2-naphthylketone (21.4 mg) and piperidine (8.4 mg) were reacted in dichloromethane (0.3 mL).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(O)C.[I-].[Na+]>[CH2:19]([O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)c2ccc(OCCCCCCCCCCCCCCCCCC)cc2)cc1
Yield: 84.9 %

Procedure:
Sodium metal (0.46 g, 20 mmol) was dissolved in ethanol (50 mL) and 4,4'-dihydroxybenzophenone (1.0 g, 4.67 mmol) was added followed by 1-bromooctadecane (7.8 g, 23.4 mmol) and a catalytic amount of sodium iodide (approximately 30 mg) and the reaction mixture was refluxed for 48 hours. The resulting suspension was cooled and filtered. The solid was washed with dichloromethane followed by hexane and the white solid was dried to afford compound 22 (2.85 g, 84.8% yield). 1H NMR (300 MHz, pyridine-d5) δ7.95 (d, J=8.7 Hz, 4H, aryl), 7.09 (d, J=8.7 Hz, 4H, aryl), 4.05 (t, J=6.6 Hz, 4H, 2×OCH2), 1.80 (tt, J=6.6 and 7.5 Hz, 4H), 1.48 (m, 4H), 1.33 (brS, 60H), 0.87 (t, J=6.6 Hz, 6H, 2×CH3).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]=[O:8])[C:4]([CH:9]=O)=[CH:3][CH:2]=1.[CH2:11]([O:13][C:14](=[O:38])[C:15](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:16][CH2:17][CH3:18])[CH3:12]>>[CH2:11]([O:13][C:14](=[O:38])/[C:15](/[CH2:16][CH2:17][CH3:18])=[CH:9]/[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[CH:7]=[O:8])[CH3:12]
Reactant: O=Cc1ccccc1C=O
Reactant: CCCC(C(=O)OCC)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCC/C(=C\c1ccccc1C=O)C(=O)OCC

Procedure:
From o-phthalaldehyde and 2-(triphenylphosphoranylidene)-pentanoic acid ethyl ester.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:31][CH2:32]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f28) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:24]=O.O>C(O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[O:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(N2CCN(C(=O)OCC3CCNCC3)CC2)cc1
Reactant: C=O
Solvent: O
Solvent: O=CO
Product: Cc1ccc(N2CCN(C(=O)OCC3CCN(C)CC3)CC2)cc1
Temperature: 95 °C
Reaction time: 0.33 h
Yield: 43 %

Procedure:
(1-piperidin-4-yl)methyl 4-(4-methylphenyl)piperazine-1-carboxylate (Example 3; 9.75 g, 30.7 mmol) was dissolved in formic acid (3 mL), 35% aqueous formaldehyde solution (3 mL) and water (20 mL). The reaction mixture was heated at 95° C. for 45 minutes, and then cooled to room temperature. The reaction mixture was quenched by slowly pouring it onto 1M aq Na2CO3 solution (400 mL) and extracted with EtOAc (4×150 mL). The combined organic layers were washed with brine (75 mL), dried (MgSO4) and concentrated in vacuo. The residue was recrystallised from heptane and then purified by reverse phase column chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (70 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo. The residue was recrystallised from heptane to give (1-methylpiperidin-4-yl)methyl 4-(4-methylphenyl)-piperazine-1-carboxylate (4.38 g, 43.0%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]([CH:13]=[CH:14][CH:15]([OH:27])[CH2:16][CH:17]([OH:26])[CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[C:11]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].O.[OH-].[Na+:37]>C1COCC1>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:27])[CH2:16][CH:17]([OH:26])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:37]
Reactant: CC(C)n1c(C=CC(O)CC(O)CC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Reaction time: 9.5 h
Yield: 77.5 %

Procedure:
A 1 liter reactor was loaded with Fluvastatin tert-butyl ester (70 g, 0.15 mole), water (576 ml), THF (280 ml) and NaOH (6 g). After 2 h THF (35 ml) was added and the mixture was stirred for another 9.5 h. The solution was extracted with ethyl acetate (2×200 ml). The aqueous phase was distilled and acetonitrile (1050 ml) was added and the mixture was stirred at room temperature over night. The product was isolated by filtration under nitrogen flow, washed with acetonitrile and dried at 40° C. in a vacuum oven for 24 h to obtain 50.4 g (77.6%) of fluvastatin sodium crystal Form LXXIII (water content: 5.9% wt. % by KF, LOD by TGA 6.0 wt. %).
Reaction SMILES: ClCl.[CH3:3][O:4][C:5](=[O:20])[C:6]1[CH:15]=[C:14](S)[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=1[N+:17]([O-:19])=[O:18].C(O)(=O)C.[S:25]([Cl:29])(Cl)(=[O:27])=[O:26]>O>[CH3:12][O:11][C:9](=[O:10])[C:8]1[CH:13]=[C:14]([S:25]([Cl:29])(=[O:27])=[O:26])[CH:15]=[C:6]([C:5]([O:4][CH3:3])=[O:20])[C:7]=1[N+:17]([O-:19])=[O:18]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1cc(S)cc(C(=O)OC)c1[N+](=O)[O-]
Agent: ClCl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(S(=O)(=O)Cl)cc(C(=O)OC)c1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
Chlorine gas is passed into a stirred slurry of 6.4 g. of dimethyl-2-nitro-5-mercaptoisophthalate in a mixture of 50 ml. of acetic acid and 15 ml. of water. The temperature of the reaction rises to 70° C. as all the solid goes into solution. Introduction of chlorine is continued as a heavy precipitate forms. Stirring is continued for 15 min.; then the mixture is diluted with 300 ml. of water. The solid is collected, washed with water and dried, giving 7.5 g. of the sulfonyl chloride, m.p. 124°-125° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:5]=[C:6]([F:8])[CH:7]=1.CN(C)CCN(C)C.C([Li])CCC.[S:30]1[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]1>C1COCC1>[CH2:12]([O:11][C:10](=[O:16])[NH:9][C:4]1[CH:3]=[C:2]([F:1])[C:7]([C:33]2([OH:36])[CH2:34][CH2:35][S:30][CH2:31][CH2:32]2)=[C:6]([F:8])[CH:5]=1)[CH:13]([CH3:14])[CH3:15]
Reactant: O=C1CCSCC1
Reactant: CC(C)COC(=O)Nc1cc(F)cc(F)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)COC(=O)Nc1cc(F)c(C2(O)CCSCC2)c(F)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A stirred solution of isobutyl 3,5-difluorophenylcarbamate (Step A, 10.0 g, 43.6 mmol) and N,N,N′,N′-tetramethylethylenediamine (13.7 mL, 87.3 mmol) in anhydrous THF (87 mL) at −78° C. under N2 is treated n-butyllithium (1.6M in hexanes, 35.8 mL, 89.4 mmol) dropwise over 35 mins. The mixture is stirred at −78° C. for 20 mins and is then treated with a solution of tetrahydro-2H-thiopyran-4-one (5.32 g, 45.8 mmol) in anhydrous THF (15 mL) dropwise over 10 mins. After 45 mins at −78° C., the cooling bath is removed and the mixture is allowed to warm to ambient temperature and is then quenched by the slow addition of saturated aqueous ammonium chloride (50 mL). Water (50 mL) and EtOAc (100 mL) are added, the layers are separated, and the organic phase is washed with water (100 mL) and saline (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product is triturated and filtered from EtOAc (approx. 25 mL) to remove an insoluble impurity, and the filtrate is chromatographed on two Flash 40M 90 g silica gel cartridges, eluting with EtOAc/heptane (20/80). Pooling and concentration of those fractions with an Rf=0.26 by TLC (EtOAc/hexanes, 25/75) gives the title compound, mp 103–104° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C@@H:25]([OH:26])[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.CCN(CC)CC.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:36]([O:26][C@@H:25]1[C:10]2[C:11](=[N:12][C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:9]=2)[O:22][C:23]([CH3:28])([CH3:27])[CH2:24]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)C[C@H](O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C[C@H](OC(=O)c2ccccc2)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Reaction time: 2 h

Procedure:
To a solution of the product of Step A (21.6 mg, 0.05 mmol), NEt3 (21 μL, 0.15 mmol), and catalytic amount of DMAP in 10 mL of CH2Cl2 at rt was added benzoyl chloride (11.5 μL, 0.10 mmol). After stirring for 2 h, the reaction was quenched by adding saturated aq NaHCO3 (5 mL) and the resulting mixture was stirred at rt for 30 min. The reaction mixture was partitioned between CH2Cl2 (50 mL) and saturated aq NaHCO3 (50 mL). The aq layer was separated and extracted with CH2Cl2 (3×10 mL). The organic layers were combined, dried over MgSO4, and concentrated. Chromatography on Biotage 40+S cartridges using 3:17 v/v EtOAc/hexanes as the eluant afforded the title compound: 1H NMR δ 1.57 (s, 3H), 1.65 (s, 3H), 2.24 (dd, J=6.7, 14.2, 1H), 2.46 (dd, J=5.9, 14.3, 1H), 6.40 (t, J=6.2, 1H), 7.00 (d, J=8.4, 2H), 7.16-7.28 (m, 5H), 7.45-7.60 (m, 3H), 7.77 (s, 1H), 8.07 (d, J=7.5, 2H).
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[N:4]1.Br[CH2:12][CH2:13]Br.O>CN(C)C=O>[O:3]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:13][CH2:12]2)=[N:4]1
Reactant: N#CCc1ccon1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(c2ccon2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a suspension of sodium hydride (136 mg, 5.39 mmol) in N,N-dimethylformamide (5 mL) was added a solution of 2-(isoxazol-3-yl)acetonitrile (233 mg, 2.16 mmol) in N,N-dimethylformamide (2.5 mL) at 0° C. After the addition, the mixture was warmed to room temperature and stirred for 1 h. The mixture was cooled to 0° C. and 1,2-dibromoethane (0.3 mL, 3.48 mmol) was added. The reaction mixture was stirred at 0° C. for 4 h. Water was added to the mixture. The mixture was extracted with ethyl acetate (3×). The combined organics were washed with water, washed with aqueous hydrochloric acid (1N), washed with aqueous sodium bicarbonate and brine. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved with dichloromethane and washed with aqueous lithium chloride solution (10%). The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure and dried under a stream of nitrogen to afford 1-(isoxazol-3-yl)cyclopropanecarbonitrile (243 mg). 1H NMR (500 MHz, CDCl3) δ 1.71-1.76 (m, 2H), 1.79-1.83 (m, 2H), 6.51 (s, 1H), 8.40 (s, 1H). The material was used without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:7]3[CH:6]=[N:5][C:4]4[C:8]3=[N:9][CH:10]=[N:11][C:3]=4[NH:2][C:36]([NH:35][CH2:33][CH3:34])=[O:37])=[CH:17][CH:16]=2)=[CH:23][C:24]=1[C:29]([F:31])([F:32])[F:30]
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CCN=C=O
Agent: Cl
Product: CCNC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and ethyl isocyanate by using the same techniques as in Example 119.
Reaction SMILES: B(F)(F)F.CSC.C[O:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38](=[O:40])[CH3:39])[CH:32]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1>ClCCl>[OH:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38](=[O:40])[CH3:39])[CH:32]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: COc1cc(C)cc(-c2c(-c3ccnc(-c4cccc(NC(C)=O)c4)c3)cnn2CC#N)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Product: CC(=O)Nc1cccc(-c2cc(-c3cnn(CC#N)c3-c3cc(C)cc(O)c3)ccn2)c1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.13 mL, 1.2 mmol) was dropwise added to a solution of the methoxy compound (52.5 mg, 0.12 mmol) prepared in Example 39 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL) and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (28 mg, 55%).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[C:21]=1[C:22](Cl)=[O:23]>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[C:21]=1[C:22]([NH:1][C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3)=[O:23]
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: COc1ccc2c(c1)CCn1c-2cc(N)nc1=O
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)CCn1c-2cc(NC(=O)c2c(Cl)cc(Cl)cc2Cl)nc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.7 %

Procedure:
To a suspension of 2-amino-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (7) (40 mg, 0.16 mmol) in CHCl3 (3 mL), DMAP (30.1 mg, 0.24 mmol) and 2,4,6-trichlorobenzoyl chloride (37.5 uL, 0.24 mmol) was added and stirred at 25° C. overnight. After cooling, the mixture was purified on BondElut® SCX (Varian Incorporated) then column chromatography on silica gel (CHCl3/MeOH=50/1 as eluant) to give the title compound (17.1 mg, 24%). 1H-NMR (400 MHz, CDCl3) δ 7.90 (d, 1H), 7.42 (s, 2H), 6.95 (dd, 1H), 6.82 (d, 1H), 4.27 (t, 2H), 3.90 (s, 3.17) and 3.03 (t, 2H); MS (ESI) (M+H)+ 449.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)([O-:13])=[O:12]>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=3[CH:17]([C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=3)[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc([N+](=O)[O-])c1

Procedure:
Reaction of 18.4 g of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 10 g of 3-nitrobenzaldehyde in an analogous manner to that described in Example 1 gave 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-(3-nitrophenyl)-1,8-(2H,5H)-acridinedione. Crystallization from dimethylformamide/water gave 22.6 g of pure material as pale yellow crystals of melting point >280° C.,
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]([F:24])([F:23])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15]>C1COCC1>[F:24][C:13]([F:12])([F:23])[C:14]1([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH2:8][O:15]1
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Fc1ccc(C2(C(F)(F)F)CO2)cc1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. The reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([CH3:17])=[C:15]([C:18]([F:21])([F:20])[F:19])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([CH3:17])=[C:15]([C:18]([F:19])([F:21])[F:20])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1c(-c2cc(C(=O)O)c(Cl)cc2F)nn(C)c1C(F)(F)F
Agent: B
Solvent: C1CCOC1
Product: Cc1c(-c2cc(CO)c(Cl)cc2F)nn(C)c1C(F)(F)F
Temperature: 0 °C
Yield: 90.4 %

Procedure:
A solution of 1.5 g of 2-chloro-5-[1,4-dimethyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzoic acid (Ex. 2) in 30 mL of anhydrous THF was treated with 10 mL of 1.0M borane-THF solution and heated to reflux for 24 hr. The mixture was allowed to cool and added to ice water. A precipitate formed which was collected by filtration, washed with cold water and dried to give 1.3 g of 2-chloro-5-[1,4-dimethyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzenemethanol as a white solid: mp 58° C.; 1HNMR (CDCl3) δ 2.09 (q, 3H), 4.00 (s, 3H), 4.75 (s, 2H), 7.20 (d, 1H), 7.57 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:22](Cl)(=[O:25])[CH2:23][CH3:24].CO>C1COCC1>[CH3:20][C:12]1([N:5]2[C:4](=[O:21])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:22](=[O:25])[CH2:23][CH3:24])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]
Reactant: CC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCC(=O)Nc1cccc2c1C(=O)N(C1(C)CCC(=O)NC1=O)C2=O
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a suspension of 4-amino-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione (0.10 g, 0.35 mmol) in THF (15 ml) was added propionyl chloride (0.07 g, 0.70 mmol). The mixture was heated to reflux for 18 h. The reaction mixture was allowed to cool and to the solution was added methanol (2 ml). The reaction mixture was stirred for an additional 15 minutes followed by solvent evaporation in vacuo. The resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.07 g (63%) of product as an off-white solid: mp 222-224° C.; 1H NMR (DMSO-d6) 11.03 (s, 1H), 9.63 (s, 1H), 8.51 (d, J=8.3 Hz, 1H), 7.79 (t, J=7.6 Hz, 1H), 7.51 (d, J=7.3 Hz, 1H), 2.76-2.45 (m, 5H), 2.10-2.03 (m, 1H), 1.90 (s, 3H), 1.12 (t, J=7.5 Hz, 3H); 13C NMR (DMSO-d6) 172.70, 172.14, 172.03, 168.80, 167.37, 136.48, 135.94, 131.20, 125.59, 117.67, 116.21, 58.81, 29.71, 29.07, 28.53, 20.97, 14.74, 9.18; Anal. Calcd. For C17H17N3O5: C, 59.47; H, 4.99; N, 12.24 Found: C, 59.24; H, 5.06; N, 11.97.