Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15]Br>CO>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: BrCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(OCCCCBr)cc1
Temperature: 70 °C
Yield: 17.9 %

Procedure:
To a solution of hydroquinone (2.0 g, 18.2 mmol) in MeOH (20 mL), KOH (1.0 g, 18.2 mmol) was added. Then, 1,4-dibromobutane (2.7 mL, 22.7 mmol) was added dropwise over 10 min. After the addition was complete, the mixture was refluxed for 12 hours at 70° C. The reaction mixture was concentrated and quenched with water (100 mL), and then the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was washed with water, then brine, and dried over Na2SO4. The solvent was evaporated to give a colorless oil, which was purified by column chromatography to isolate the intermediate 12a (0.8 g, 3.26 mmol, 18% yield). 1H NMR (CDCl3, 400 MHz) δ 6.78 (s, 4H), 4.53 (s, 1H), 3.95 (t, J=6 Hz, 2H), 3.52 (t, J=6.8 Hz, 2H), 1.86-2.15 (m, 4H).
Reaction SMILES: [F:1][B-](F)(F)F.[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[N:15]=2)[N:10]=[CH:9][C:8]=1[N+]#N>C1C2C(CCCC2)CCC1.C(Cl)(Cl)Cl>[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[N:15]=2)[N:10]=[CH:9][C:8]=1[F:1]
Reactant: COc1ccc2ncc([N+]#N)c(Br)c2n1
Reactant: F[B-](F)(F)F
Solvent: C1CCC2CCCCC2C1
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(F)c(Br)c2n1
Temperature: 180 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
A suspension of 4-bromo-6-methoxy-[1,5]naphthyridine-3-diazonium tetrafluoroborate (31.42 g, 89.0 mmol) in decalin (mixed isomers, 500 mL) in a 2 L flask* was heated to 180° C. and held at this temperature for 5 min. The mixture was cooled and diluted with CHCl3 (500 mL, to keep the product in solution), and the resulting mixture was stirred vigorously for 30 min to break up a black solid byproduct. The mixture was then poured onto a column of silica gel and the column was eluted with CHCl3 to remove decalin and then with 3% EtOAc/CHCl3 to afford the title compound (9.16 g, 40%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N+:11]([O-])=O)#[N:2].O.O.[Sn](Cl)Cl.C(=O)(O)[O-:20].[Na+].O>C(O)C>[NH2:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[C:1]([NH2:2])=[O:20]
Reactant: O=C([O-])O
Reactant: COc1ccc(C#N)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(N)=O)c(N)c1
Temperature: 25 °C

Procedure:
To a solution of 37.4 g (0.210 mol) of 4-cyano-3-nitroanisole in 500 mL of ethanol was added 221.6 g (0.982 mol) of tin(II) chloride dihydrate. The reaction mixture was stirred and heated under reflux for 1 hour. After cooling to room temperature, the reaction mixture was poured onto ice. Aqueous sodium bicarbonate was added slowly to the ice mixture until the solution reached pH 7-8. Additional water was added to the mixture, which was then extracted with methylene chloride (2×400 mL) and ethyl acetate (1×300 mL). The separated aqueous layers were filtered between each of the extractions. The off white residue collected on the filters was rinsed with methylene chloride and ethyl acetate several times. The combined organic phases were then dried over magnesium sulfate, filtered and evaporated in the rotary evaporator to obtain 28.5 g crude product (mp 154-155° C.).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[C:11]([CH3:29])=[CH:12][CH:13]=[C:14]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[NH2:38][N:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1>O1CCCC1>[CH3:45][N:42]1[CH2:43][CH2:44][N:39]([NH:38][CH2:2][C:3]2[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]3[CH:15]=[C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:20]=[CH:19][N:18]=4)[CH:13]=[CH:12][C:11]=3[CH3:29])=[O:8])=[CH:5][CH:4]=2)[CH2:40][CH2:41]1
Reactant: CN1CCN(N)CC1
Reactant: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1NC(=O)c1ccc(CCl)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1NC(=O)c1ccc(CNN2CCN(C)CC2)cc1
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
N-(5-(4-chloromethylbenzoylamino)-4-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (1.5 g, 3.49 mmol) was dissolved in tetrahydrofuran (30 ml), pyridine (560 μl, 6.98 mmol) was added, and the mixture was stirred for 30 minutes. 1-Amino-4-methylpiperazine (580 μl, 5.23 mmol) was added thereto, and the resulting mixture was refluxed for 12 hours and then filtered. The filtrate was concentrated and crystallized from dimethylether to give 4-(4-methylpiperazin-1-ylaminomethyl)-N-[2-methyl-5-(4-(pyridin-3-yl)pyrimidin-2-yl)aminophenyl]benzamide (1.7 g).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CC(=O)CC>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: C1COCCN1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Solvent: O
Solvent: CCC(C)=O
Product: COc1ccccc1OCCCc1oc(N2CCOCC2)nc1-c1ccc(Cl)cc1
Yield: 82.4 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (378 mg), morpholine (435 mg) and 2-butanone (10 ml) was stirred with heating under reflux for 2 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml×2). The organic layer was washed with a 10% aqueous solution of citric acid (100 ml) and dried over anhydrous magnesium sulfate. After the organic layer was concentrated, the residue was recrystallized from ethyl acetate-hexane to give 4-(4-chlorophenyl)-2-(4-morpholinyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole as pale yellow prisms (353 mg, 82%). Melting point 81-82° C.
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH2:5][N:6]1[CH:15]=[C:9]2[N:10]=[CH:11][C:12]([Br:14])=[CH:13][C:8]2=[N:7]1)[C:3]#[N:4].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[S:24])=[CH:21][CH:20]=1>>[Br:14][C:12]1[CH:11]=[N:10][C:9]2=[CH:15][N:6]([CH2:5][C:2]([NH:1][C:23](=[S:24])[C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=3)([C:3]#[N:4])[CH3:16])[N:7]=[C:8]2[CH:13]=1
Reactant: CC(N)(C#N)Cn1cc2ncc(Br)cc2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1cc2ncc(Br)cc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (223 mg described in Example 182) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (145 mg, 38%). MS (ES): M/Z [M+H]=484. 1H NMR: (400 MHz, CHLOROFORM-d): 1.95 (s, 3H), 4.86 (d, J=14.0 Hz, 1H), 5.01 (d, J=14.1 Hz, 1H), 7.78 (d, J=8.3 Hz, 2H), 7.84-7.90 (m, 2H), 8.11 (s, 1H), 8.22 (dd, J=2.0, 1.0 Hz, 1H), 8.42 (d, J=0.8 Hz, 1H) and 8.64 (d, J=2.0 Hz, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.2 (s, 3F).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:28])[O:10][C:11]3[C:16]([C:17]=2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=[C:13]([O:26][CH3:27])[CH:12]=3)=[CH:4][CH:3]=1.[Br:29][CH:30](Br)[CH3:31].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:28])[O:10][C:11]3[C:16]([C:17]=2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:31][CH2:30][Br:29])=[CH:21][CH:20]=2)=[CH:15][CH:14]=[C:13]([O:26][CH3:27])[CH:12]=3)=[CH:6][CH:7]=1
Reactant: COc1ccc2c(Cc3ccc(O)cc3)c(-c3ccc(Cl)cc3)c(=O)oc2c1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc2c(Cc3ccc(OCCBr)cc3)c(-c3ccc(Cl)cc3)c(=O)oc2c1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A solution of 3-(4-chlorophenyl)-4-(4-hydroxybenzyl)-7-methoxychromen-2-one (21.2 g, 54 mmol), dibromoethane (50.7 g, 270 mmol), and K2CO3 (8.3 g, 60 mmol) in 200 mL of acetone was heated at reflux for 12 h. The reaction mixture was cooled to room temperature and volatiles were removed under reduced pressure. Hexanes (500 mL) was added with stirring and the resulting solid that formed was collected by filtration. The material was rinsed with hexanes (2×100 mL), collected and dried under vacuum to provide the desired product (22.5 g, 83%). 1H NMR (300 MHz, DMSO) δ 7.50 (d, 1H, J=9.1 Hz), 7.48 (d, 2H, J=8.2 Hz), 7.35 (d, 2H, J=8.2 Hz), 7.07 (d, 2H, J=8.5 Hz), 7.04 (d, 1H, J=2.6 Hz), 6.86 (dd, 1H, J=9.1, 2.6Hz), 6.82 (d, 2H, J=8.5 Hz), 4.24 (t, 2H, J=5.8 Hz), 3.98 (s, 2H), 3.84 (s, 3H), 3.76 (t, 2H, J=5.8 Hz). MS (ESI) m/z 500 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH:26][CH:27]([C:31]1[CH:32]=[C:33]([NH:37][C:38](=[O:40])[CH3:39])[CH:34]=[CH:35][CH:36]=1)[CH2:28][NH:29][CH3:30].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:38]([NH:37][C:33]1[CH:32]=[C:31]([CH:27]([OH:26])[CH2:28][N:29]([CH2:20][C:18]2[S:19][C:12]3[C:11](=[O:23])[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:9])=[CH:15][N:14]([CH3:16])[C:13]=3[C:17]=2[CH3:22])[CH3:30])[CH:36]=[CH:35][CH:34]=1)(=[O:40])[CH3:39]
Reactant: CNCC(O)c1cccc(NC(C)=O)c1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(C(O)CN(C)Cc2sc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn(C)c3c2C)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 43.7 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), N-{3-[1-hydroxy-2-(methylamino)ethyl]phenyl}acetamide (Preparation 45) (79 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 6 hours at that temperature. After cooling to room temperature, the solution was concentrated under high vacuum. The oil residue was purified with a silica gel chromatotron plate to give the title compound (62 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:26]1([CH2:32][CH2:33][OH:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Na+].O>C1(C)C=CC=CC=1>[CH2:33]([O:34][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)[CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OCCc1ccccc1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(Cl)nn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(OCCc3ccccc3)nn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
A mixture of [4-(6-chloropyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (0.075 g, 0.202 mmol), 2-phenylethanol (0.025 g, 0.202 mmol) and sodium hydride (0.010 g) in 5 mL of toluene was stirred at room temperature for 1 hour, and then refluxed overnight. The reaction mixture was cooled to room temperature, added 20 mL of water, and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate, concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a white solid (58 mg, 62.9%). 1H NMR (400 MHz, CDCl3) δ 7.73, 7.61-7.64, 7.53-7.56, 7.36, 7.22-7.30, 7.20-7.24, 7.02, 6.86, 4.64, 3.91-3.98, 3.57, 3.48-3.52, 3.32, 3.11.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[N:20]=[N:21][N:22]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:23]=2)=[CH:9][CH:8]=1)(=O)=O.[CH2:43]([C:47]1[NH:48][C:49]([CH:53]=[O:54])=[C:50]([Cl:52])[N:51]=1)[CH2:44][CH2:45][CH3:46].[BH4-].[Na+]>O>[CH2:43]([C:47]1[N:48]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[N:20]=[N:21][N:22]([C:24]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:23]=3)=[CH:11][CH:12]=2)[C:49]([CH2:53][OH:54])=[C:50]([Cl:52])[N:51]=1)[CH2:44][CH2:45][CH3:46]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: CS(=O)(=O)OCc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the reaction mixture of Example 10 was added 2-n-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (0.01 m=1.86 g). The reaction was stirred overnight at room temperature. Water (0.87 mL) was added dropwise followed by sodium borohydride pellets (0.37 g). After stirring for 5 hours, the reaction mixture was added slowly to 100 mL water containing 3 mL acetone. The temperature was maintained at about 25° C. during the addition. The resultant slurry was stirred for an additional 45 minutes, then filtered. The solid was rinsed with two 50 mL portions of water. The wet cake was recrystallized first from 50 mL of n-butyl chloride, then from 30 mL of ethyl acetate to give 1.95 g title compound in 28% overall yield; mp 168°-169° C.
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH2:8]([O:10][C:11](=[O:19])[CH2:12][C:13](=[O:18])[CH2:14][C:15](=[O:17])[CH3:16])[CH3:9].[CH:20]1([C:23]2[C:32]([CH:33]=O)=[C:31]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH2:22][CH2:21]1>C(O)(=O)C>[CH2:8]([O:10][C:11](=[O:19])[CH2:12][C:13](=[O:18])[CH2:14][C:15](=[O:17])/[CH:16]=[CH:33]/[C:32]1[C:23]([CH:20]2[CH2:21][CH2:22]2)=[N:24][C:25]2[C:30]([C:31]=1[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:9]
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(=O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reaction time: 1 h
Yield: 82 %

Procedure:
In a mixture solution of 1.37 g of an oily 60% sodium hydride and 10 ml of tetrahydrofuran, a mixture solution of 2.36 g of 3,5-dioxohexanoic acid ethyl ester and 10 ml of tetrahydrofuran was dropped in 5 minutes while keeping an inner temperature of 20° C. After stirring the mixture for 1 hour at that temperature, a mixture of 2.01 g of 2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-carbaldehyde and 20 ml of tetrahydrofuran was dropped for 20 minutes. After stirring the mixture for 4 hours, a reaction solution was added in 3.09 g of acetic acid and 20 ml of water to terminate the reaction. An organic phase was extracted with 40 ml of ethyl acetate and was then washed with 20 ml of saturated brine, followed by being dried with 2 g of anhydrous sodium sulfate. As a result of analysis on the resulting organic phase, 2.52 g of (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dioxohept-6-enic acid ethyl ester (DOXE) (yield 82%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:38][C:39]([F:44])([F:43])[CH:40]1[CH2:42][O:41]1.O>CN(C=O)C>[F:38][C:39]([F:44])([F:43])[CH:40]([OH:41])[CH2:42][N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][N:23]2[CH:24]=[C:20]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([S:11]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)(=[O:12])=[O:13])[CH:7]=3)[CH:21]=[N:22]2)[CH2:27][CH2:28]1
Reactant: FC(F)(F)C1CO1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCNCC3)c2)c2ccc(F)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCN(CC(O)C(F)(F)F)CC3)c2)c2ccc(F)cc21
Reaction time: 8 h
Yield: 47.2 %

Procedure:
A mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole (Intermediate 21; 111 mg; 0.25 mmol), K2CO3 (35 mg; 0.25 mmol) and 2-(trifluoromethyl)oxirane (142 mg; 1.27 mmol) in DMF (10 mL) was stirred overnight under nitrogen. The reaction mixture was added water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by reverse phase flash chromatograph to afford 65 mg (47%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[C:25](Cl)(=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([NH:9][C:10]([C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:25](=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNC(=O)[C@H]1CCCCN1
Reactant: CCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCNC(=O)[C@H]1CCCCN1C(=O)CCCCCCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(R)-(+)-2-piperidinecarboxylic acid n-octyl amide (23) (100 mg; 0.416 mmol) is dissolved in methylene chloride (3 mL) at ambient temperature. Triethylamine (63 mg; 0.624 mmol) is added and the solution cooled in an ice-bath. Octanoyl chloride (74 mg; 0.458 mmol) is added dropwise via syringe. The solution is stirred for 15 minutes and then allowed to warm to ambient temperature. After stirring for an additional 4.5 hours, the solution is poured onto saturated sodium bicarbonate solution and extracted with methylene chloride (20 mL). The methylene chloride extract is washed with water, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography using a gradient elution (0%→40% ethyl acetate in hexanes) affording the desired product (28) as an oil. ISMS: MH+367.4
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=O)[CH2:10][CH:11]([CH3:13])[CH3:12].[N:15]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>O.Cl>[OH:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][N:15]=[C:9]2[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CC(=O)c1cc(O)ccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CC(C)Cc1n[nH]c2ccc(O)cc12
Yield: 41.1 %

Procedure:
In an analogous manner to the procedure of Example XIV, 783 mg (4.05 mmol) of 1-(2-amino-5-hydroxyphenyl)-3-methyl-1-butanone in 30 ml of half-conc. hydrochloric acid are reacted with 294 mg (4.25 mmol) of sodium nitrite in 15 ml of water and 914 mg (4.05 mmol) of tin(II) chloride dihydrate in 15 ml of conc. hydrochloric acid to give 317 mg (41%) of 5-hydroxy-3-isobutyl-1H-indazole.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:12]1([CH2:18][CH2:19][CH:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[NH:22][C:21]2=[O:28])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH2:18][CH2:19][C:20]2([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=[CH:4][N:3]=3)[C:25](=[O:26])[NH:24][C:23](=[O:27])[NH:22][C:21]2=[O:28])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ncnc2ccccc12
Reactant: O=C1NC(=O)C(CCc2ccccc2)C(=O)N1
Product: O=C1NC(=O)C(CCc2ccccc2)(c2ncnc3ccccc23)C(=O)N1
Temperature: 170 °C

Procedure:
A mixture of 3.3 g of 4-chloroquinazoline and 4.65 g of 5-(2-phenylethyl) barbituric acid was heated to 170° C. for two and one-half hours, then cooled to form the 5-(2-phenylethyl)-5-(4-quinazolyl) barbituric acid. This compound was hydrolyzed, without isolation, by adding 40 ml of water and 4.5 g of NaOH to the mixture, heating to reflux for four hours. The mixture was cooled, acidified with HCl, refluxed two additional hours, then cooled, and neutralized. Product was extracted into CH2Cl2, which was then separated, dried, and evaporated. The residue was absorbed onto silica gel and eluted with 10% EtOAc/CH2Cl2 →20% EtOAc/CH2Cl2. Fractions containing product were combined. TLC showed impurities present. The product was rechromatographed using 15% EtOAc/CH2Cl2, however, impurities remained. Solvent was evaporated and the residue was redissolved in pentane. The product dissolved in pentane leaving impurities as a gummy residue. The pentane solution was decanted, filtered, and evaporated to give 0.75 g of the title product as a light oil.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C1CCN2C(=NCCC2)CC1.[CH2:22]([N:26]1[C:31]2=[N:32][N:33]([CH2:41][C:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH:45]=[CH:44][CH:43]=3)[C:34]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)=[C:30]2[C:29](=[O:52])[NH:28][C:27]1=[O:53])[CH:23]([CH3:25])[CH3:24]>CN(C)C=O>[CH2:22]([N:26]1[C:31]2=[N:32][N:33]([CH2:41][C:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH:45]=[CH:44][CH:43]=3)[C:34]([C:35]3[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=3)=[C:30]2[C:29](=[O:52])[N:28]([CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:27]1=[O:53])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc21
Reactant: ClCCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)Cn1c(=O)n(CCN2CCOCC2)c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc21
Temperature: 80 °C
Yield: 91.1 %

Procedure:
4-(2-chloroethyl)morpholine hydrochloride (0.0435 g) followed by DBU (0.094 g) were added to a solution of 7-isobutyl-2-(1-naphthylmethyl)-3-pyridin-4-yl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (0.0668 g) in dimethylformamide (1 ml). The mixture was heated at 80° C. for 18 hours then cooled to room temperature. The crude reaction was purified on preparative HPLC to give the title compound (0.077 g). Mass: 538.90 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[CH:9][C:8]([O:26][CH3:27])=[CH:7][CH:6]=2.Br[CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[F:39].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:39][C:33]1[C:34]([F:38])=[CH:35][CH:36]=[CH:37][C:32]=1[O:31][CH2:30][CH2:29][N:18]1[CH2:19][CH2:20][C:15]([CH2:14][CH2:13][CH2:12][C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:26][CH3:27])[CH:9]=3)[N:4]=[CH:3][C:2]=2[F:1])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][CH2:17]1
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCNCC1
Reactant: Fc1cccc(OCCBr)c1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCOc2cccc(F)c2F)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 75.9 %

Procedure:
A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.3 g of 1-(2-bromoethoxy)-2,3-difluorobenzene, 0.181 g of potassium iodide and 0.74 g of potassium carbonate in 15 cm3 of acetonitrile was stirred for 18 hours at a temperature in the region of 70° C. After cooling to about 20° C., the reaction mixture was concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40° C. The evaporation residue was purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200μ; mass 12 g), eluting with a mixture of ethyl acetate/40-60° C. petroleum ether (8/2 by volume). The fractions containing the product were combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.43 g of ethyl 1-[2-(2,3-difluorophenoxy)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate was obtained.