Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]([OH:42])[CH2:39][CH:40]=[O:41])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].CO.[BH4-].[Na+]>O1CCOCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]([OH:42])[CH2:39][CH2:40][OH:41])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCCCCC(O)CC=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCCCCC(O)CCO)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
In a 100 mL round-bottomed flask was 12-(Cholest-5-en-3β-oxy)-3-hydroxydodecanal (1.90 g, 3.25 mmol) dissolved in 1,4-Dioxane (10 ml) to give a colorless solution. MeOH (5 ml) was added slowly and only enough was added to keep the aldehyde in solution. SODIUM BOROHYDRIDE (0.184 g, 4.87 mmol) was added to the stirring solution which was then allowed to stir for 2 hours at room temperature. The reaction mixture was quenched by addition of 1N HCl (2 mL). The mixture was diluted to 100 mL with water and extracted with ethyl acetate (3×50 mL). The organic phase was combined, washed with brine (1×50 mL), dried over Na2SO4, filtered and concentrated to give 12-(Cholest-5-en-3β-oxy)dodecan-1,3-diol (1.85 g, 3.15 mmol, 97% yield) as a colorless wax. 1H NMR (300 MHz, CDCl3) δ0.69 (3H, s); 0.83-2.07 (58H, m); 2.13-2.28 (1H, m); 2.32-2.43 (1H, m); 3.14 (1H, tt, J=11.2, 4.4 Hz); 3.46 (2H, t, J=6.8 Hz); 3.60-4.19 (3H, m); 5.36 (1H, d, J=5.2 Hz).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([N:12]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([O:41]C)=[C:37]([Br:43])[CH:36]=2)=[CH:31][CH:30]=1)[C:13]([C:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][C:16]=1[CH2:24][CH2:25][CH2:26][CH3:27])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)=O.CC(C)=O.O>C(Cl)Cl>[CH2:5]([N:12]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([Br:43])[CH:36]=2)=[CH:33][CH:34]=1)[C:13]([C:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][C:16]=1[CH2:24][CH2:25][CH2:26][CH3:27])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCCc1oc2ccccc2c1C(=O)N(Cc1ccccc1)Cc1ccc(-c2ccc(OC)c(Br)c2)cc1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCCCc1oc2ccccc2c1C(=O)N(Cc1ccccc1)Cc1ccc(-c2ccc(O)c(Br)c2)cc1
Reaction time: 3 h
Yield: 75.5 %

Procedure:
Boron tribromide (22.0 mL of a 1 M solution in methylene chloride; 22.0 mmol) was added under nitrogen dropwise over 30 minutes to a solution N-benzyl-N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]-2-butyl-1-benzofuran-3-carboxamide (4.2 g, 7.22 mmol), of prepared in the previous step, in 150 mL of methylene chloride at dry ice-acetone temperature. After the addition the dry ice-acetone bath was replaced with an ice bath and the stirring continued for 3 h. At ice bath temperature water (100 mL) was added dropwise. The aqueous layer was separated and extracted two times with methylene chloride. The extracts were combined, extracted with saturated NaCl, dried (MgSO4) and the solvent removed under reduced pressure to give N-benzyl-N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-2-butyl-1-benzofuran-3-carboxamide (3.1 g, 72%) as an off-white solid, MS (ESI) m/z 568 [M+H]+. Elemental Analysis for C33H30BrNO3: Calc'd: C, 69.72; H, 5.32; N, 2.46; Found: C, 68.69; H, 5.42; N, 2.28.
Reaction SMILES: C[Si](C)(C)[O-].[K+].[C:7]([N:11]1[CH2:15][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[C@H:13]([C:24]([N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[CH:39]([CH3:44])[C:40]([O:42]C)=[O:41])[CH2:28][CH2:27]2)=[O:25])[CH2:12]1)([CH3:10])([CH3:9])[CH3:8]>O1CCCC1>[C:7]([N:11]1[CH2:15][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[C@H:13]([C:24]([N:26]2[CH2:27][CH:28]=[C:29]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[CH:39]([CH3:44])[C:40]([OH:42])=[O:41])[CH2:30][CH2:31]2)=[O:25])[CH2:12]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: COC(=O)C(C)c1cc(Cl)ccc1C1CCN(C(=O)[C@@H]2CN(C(C)(C)C)C[C@H]2c2ccc(F)cc2F)CC1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C(=O)O)c1cc(Cl)ccc1C1=CCN(C(=O)[C@@H]2CN(C(C)(C)C)C[C@H]2c2ccc(F)cc2F)CC1
Reaction time: 15 h

Procedure:
Potassium trimethylsilanolate (0.645 g, 5.03 mmol) was added to a stirred solution of methyl 2-[2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}piperidin-4-yl)-5-chlorophenyl]propanoate (2-5) (1.10 g, 2.01 mmol) in tetrahydrofuran (10 mL) at room temperature. After approximately 15 h, the volatiles were evaporated in vacuo and the crude residue was treated with a saturated solution of hydrogen chloride in ethyl acetate. After approximately 5 min, the reaction mixture was concentrated under reduced pressure and the crude residue triturated twice with dry diethyl ether to give 2-6 as an amorphous white solidm/z 533 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:15][CH3:16].Cl>CCO.O.[Fe]>[NH2:12][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([O:15][CH3:16])[C:2]=1[Cl:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(OC)c(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(N)c(Cl)c(OC)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 103.9 %

Procedure:
A suspension of methyl 4-chloro-3-methoxy-5-nitrobenzoate (3) (900 mg, 3.66 mmol) and iron powder (614 mg, 11.0 mmol) in a mixture of EtOH (15 mL) and water (15 mL) was heated to 70° C. and degassed with nitrogen for 20 min. Conc. HCl (44.5 μL, 1.47 mmol) was added and the reaction mixture was stirred at 70° C. for 3 h. Celite (1 g) was added and the suspension stirred for 10 min then filtered through a celite pad. The solvent was removed in vacuo and the residue was partitioned between EtOAc (15 mL) and water (15 mL). The phases were separated and the organic solution was washed with brine (2×15 mL). The solvent was removed in vacuo to afford methyl 3-amino-4-chloro-5-methoxybenzoate (0.82 g, 100% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ: 7.10 (1H, d), 6.78 (1H, d), 5.68 (2H, s), 3.81 (6H, m).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([I:11])=[C:7]([CH:10]=1)[CH2:8]O.P(Br)(Br)[Br:15]>CCOCC>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([I:11])=[C:7]([CH:10]=1)[CH2:8][Br:15]
Reactant: OCc1cc(C(F)(F)F)ccc1I
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: FC(F)(F)c1ccc(I)c(CBr)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Trifluoromethyl-2-iodobenzyl alcohol (45 g, 0.15 mol) is dissolved in anhydrous Et2O (400 mL) and treated with phosphorous tribromide (41 mL, 0.15 mol) by dropwise addition. The reaction mixture is stirred at room temperature overnight and quenched by slow addition of water (150 mL). The organic layer is separated, washed with saturated aqueous NaHCO3 (250 mL), brine (250 mL), dried (MgSO4) and concentrated by rotary evaporator to give 5-trifluoromethyl-2-iodobenzyl bromide as an oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([F:24])=[CH:19][N:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([F:24])=[CH:19][N:18]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: Cc1cc(Br)ncc1F
Reactant: O=C1NCCN1c1cnccc1C1CC1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Product: Cc1cc(N2CCN(c3cnccc3C3CC3)C2=O)ncc1F
Yield: 39 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 100 mg, 0.492 mmol) was reacted with 2-bromo-5-fluoro-4-methylpyridine (102 mg, 0.541 mmol) 1,4-dioxane (5 mL), copper iodide (9 mg, 0.0492 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (21 mg, 0.147 mmol) and potassium phosphate (313 mg, 1.47 mmol) to afford the crude product. Purification by column chromatography on silica gel (80% ethyl acetate in hexane) afforded 60 mg of the product (39.21% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]4[CH2:20][CH2:19][CH2:18][C:15]=4[CH:16]=3)[NH:11][C:10](=[O:21])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.O.[CH3:23][N:24]1C(=O)N(C)CCC1>>[O:21]=[C:10]1[CH2:9][CH:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:23]#[N:24])[C:17]2[C:12](=[CH:13][C:14]3[CH2:20][CH2:19][CH2:18][C:15]=3[CH:16]=2)[NH:11]1
Reactant: CN1CCCN(C)C1=O
Reactant: O=C1CC(c2cccc(Br)c2)c2cc3c(cc2N1)CCC3
Solvent: O
Product: N#Cc1cccc(C2CC(=O)Nc3cc4c(cc32)CCC4)c1
Temperature: 195 °C

Procedure:
A mixture of 4-(3-Bromo-phenyl)-1,3,4,6,7,8-hexahydro-cyclopenta[g]quinolin-2-one (160 mg, 0.47 mmol) and cuprous cyanide (50.3 mg, 0.56 mmol) in N,N′-dimethylpropyleneurea was heated at 195° C. for 14 hr under an atmosphere of argon. Water was added and the product extracted with ethyl acetate. The product (12 mg) was purified by flash chromatography on silica gel (eluent, hexane:ethyl acetate, 8:2, 7:3, 6:4) followed by reverse phase HPLC (water-acetonitrile gradient, 0.05% trifluoroacetic acid, 70:30 to 10:90, 20 min, linear gradient; flow, 15 ml/min; column, Phenomenex Luna 5μ C18, 100×21.2 mm; UV 254 and 218 nm).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[C:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=[O:27])[CH3:26]>>[C:25]([N:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:4]([F:24])[CH:3]=2)[C:29]1=[O:33])(=[O:27])[CH3:26]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(F)c2)C1=O
Yield: 53.9 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (235 mg) described in Preparation Example 114 and 1-acetylimidazolidin-2-one (115 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (142 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>C(Cl)Cl>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:31]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:32])=[CH:7][CH:8]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1
Yield: 78 %

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.36 mmol, example 9 (step 3) and DIEA (62.8 μL, 0.36 mmol) in DCM (2 mL) was added phenyl chloroformate (45.2 μL, 0.36 mmol). The resulting mixture was reacted under the same conditions as described for example 10 to give 112 mg (78% yield) of the title compound as an off-white oil. MS (ESI, positive ion) m/z: 398 (M+H).
Reaction SMILES: [H-].[Na+].[OH:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].Cl[CH2:16][CH2:17][CH2:18][N:19]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23]>CN(C)C=O>[CH2:24]([N:19]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][CH2:17][CH2:16][O:3][N:4]1[C:5](=[O:14])[C:6]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:7]2[C:8]1=[O:9])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCN(CCCC)CCCCl
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN(CCCC)CCCON1C(=O)c2ccccc2C1=O
Yield: 96.6 %

Procedure:
To a suspension of 1.75 g of sodium hydride in ml of N,N-dimethylformamide was added a mixture of 11.9 g of N-hydroxyphthalimide and 60 ml of N,N-dimethylformamide, and then the mixture was stirred for minutes. To the reaction solution was added a mixture of 15 g of 3-chloropropyldibutylamine and 10 ml of N,N-dimethylformamide, and then the mixture was heated at reflux for 5 hours. After evaporation of the solvent, ethyl acetate was added to the residue, and the mixture was washed with water. Evaporation of the solvent gave 23.4 g of N-(3-dibutylaminopropoxy)-phthalimide, which was then dissolved in 200 ml of methylene chloride. To the solution was added 20 ml of hydrazine monohydrate, and the mixture was stirred at room temperature for 3 hours. After removal of the insolubles by filtration, the filtrate was concentrated under reduced pressure and distilled under reduced pressure to give 10.3 g of O-(3-dibutylaminopropyl)hydroxylamine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].Cl.Cl.[CH3:28][N:29]1[CH2:32][C:31]2([CH2:35][NH:34][CH2:33]2)[CH2:30]1>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:34]4[CH2:35][C:31]5([CH2:32][N:29]([CH3:28])[CH2:30]5)[CH2:33]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CN1CC2(CNC2)C1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Agent: Cl
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CC5(CN(C)C5)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 2-methyl-2,6-diazaspiro[3.3]heptane dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.33 (d, J=2.27 Hz, 3 H) 2.80 (d, J=4.55 Hz, 3 H) 3.94-4.67 (m, 8 H) 7.61 (d, J=8.08 Hz, 1 H) 7.69-7.78 (m, 1 H) 8.16-8.29 (m, 2 H) 8.42 (d, J=8.59 Hz, 1 H) 8.69 (br. s., 1 H). ESI-MS m/z [M+H]+ 433.3.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]([P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])C1C=CC=CC=1.C1CCCCC=1>CCO.[Pd]>[NH2:8][CH:9]([P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])[P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CCOP(=O)(OCC)C(N(Cc1ccccc1)Cc1ccccc1)P(=O)(OCC)OCC
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCOP(=O)(OCC)C(N)P(=O)(OCC)OCC

Procedure:
Compound 143 (2.00 g, 4.14 mmol) was dissolved in EtOH (40 mL). To this solution was added palladium on carbon (10%, 1.5 g) and cyclohexene (2.5 mL, 24.7 mmol). The reaction mixture was refluxed under argon for 15 hours, filtered through celite and evaporated to give 144 as a slightly impure pale yellow oil (1.50 g, 119%), which was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 1.35 (t, J=7.0, 12H), 3.58 (t, J=20.3, 1H), 3.65-3.90 (br s, 2H), 4.20-4.28 (m, 8H).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[OH-].[Na+]>C(O)C>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]=1[CH2:11][NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(NCc2c(-c3ccccc3)noc2C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)O)cn1
Temperature: 80 °C
Yield: 91.1 %

Procedure:
To a suspension of 6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid methyl ester (1.86 g, 5.50 mmol) in ethanol (100 mL) was added aqueous sodium hydroxide (1 N, 17 mL, 17 mmol) and the resulting suspension was heated to 80° C. for 0.5 h. After the solution was cooled to ambient temperature the solvent was distilled off and the residue was diluted with water (50 mL) and washed with tert-butylmethylether (50 mL). The organic layers were extracted with aqueous sodium hydroxide (1 N, 20 mL) and the combined aqueous layers were acidified with aqueous hydrochloric acid (25%) to pH=3 and were extracted with a mixture of ethyl acetate and methanol (4:1, 30 mL). Drying over sodium sulfate and concentration afforded the title compound (1.55 g, 91%) which was obtained as a white solid. MS: m/e=310.3 [M+H]+.
Reaction SMILES: C1(N2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[CH3:49][O:50][C:51]1[CH:52]=[C:53]([CH:55]=[C:56]([O:58][CH3:59])[CH:57]=1)[NH2:54]>C(O)(=O)C>[CH3:59][O:58][C:56]1[CH:55]=[C:53]([N:54]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:52]=[C:51]([O:50][CH3:49])[CH:57]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COc1cc(N)cc(OC)c1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: COc1cc(OC)cc(-n2cnc3c(-c4ccccc4)csc3c2=O)c1
Yield: 68 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (72.3 mg, 0.31 mmol), triethyl orthoformate (0.62 ml), 3,5-dimethoxyaniline (88.8 mg, 0.58 mmol), and acetic acid (0.07 ml) were used to give 75.7 mg (0.21 mmol, 68% yield) of the title compound.
Reaction SMILES: C([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C:7](=[O:16])[NH:6][N:5]=1)(O)=O.C(=O)=O>>[CH3:15][O:14][C:10]1[CH:9]=[C:8]2[C:13]([CH:4]=[N:5][NH:6][C:7]2=[O:16])=[CH:12][CH:11]=1
Reactant: COc1ccc2c(C(=O)O)n[nH]c(=O)c2c1
Agent: O=C=O
Product: COc1ccc2cn[nH]c(=O)c2c1
Yield: 25 %

Procedure:
A hot solution of potassium permanganate (570 g, 3.6 mole) in water (1520 ml) was added in portions to a vigorously stirred mixture of 2-methyl-4-methoxyacetophenone (152 g, 0.93 mole) and potassium carbonate (76 g, 0.55 mole) in water (5700 ml) at 100°. The colour was allowed to discharge between additions, and the mixture was heated for a further 30 minutes after completion of the addition. The cold filtered solution was re-heated to 90° and the pH adjusted to 8.0. Hydrazine hydrate (51 g, 1.04 mole) was added and the volume of the solution was reduced to 3000 ml by evaporation. The filtered solution was made strongly acidic with hydrochloric acid and the resultant precipitate collected and washed with water. The solid was digested several times with methanol to leave a residue of 4-carboxy-7-methoxy-1(2H)-phthalazinone (51 g, 25%, m.p. 239°-240° (decomposition). The carboxylic acid was heated in an oil bath at 260° until evolution of carbon dioxide ceased (about 5 minutes), then immediately cooled. Soxhlet extraction of the product with water gave 7-methoxy-1(2H)-phthalazinone (41.3 g, 25%) m.p. 228°-229°).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH3:32].C(OCC)(=O)C>CN(C=O)C>[CH2:29]([N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCBr
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 95 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.350 g, 1.24 mmol), K2CO3 (0.427 g, 3.09 mmol), and 1-bromobutane (0.178 g, 1.30 mmol) in DMF (6.2 mL). Heat at 95° C. for 5.5 hours, then at 50° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL) and brine (1×30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 20% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+340.2 (M+H)+, HRMS calcd for C20H26N3O2 340.2025 (M+H)+, found 340.2019, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=9.6 min, 98.3% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:14])=[N:9]2)=[CH:4][CH:3]=1.F[C:16](F)(F)[C:17](OC(=O)C(F)(F)F)=[O:18]>>[CH3:14][C:10]1[CH2:11][C:12](=[O:13])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:17](=[O:18])[CH3:16])=[CH:7][CH:6]=2)[N:9]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC1=NN(c2ccc(N)cc2)C(=O)C1
Product: CC(=O)Nc1ccc(N2N=C(C)CC2=O)cc1
Yield: 65 %

Procedure:
Yield: 1.5 g of N-(4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)phenyl)acetamide (65% of theory), oil obtained analogously from 2-(4-aminophenyl)-5-methyl-2,4-dihydro-3-pyrazolone and trifluoroacetic anhydride is N-(4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-phenyl)trifluoroacetamide from 2-(3-aminophenyl)-5-methyl-2,4-dihydro-3-pyrazolone and trifluoroacetic anhydride is N-(3-(4,5-dihydro-3-methy-5-oxo-1H-pyrazol-1-yl)-phenyl)trifluoroacetamide from 2-(3-aminophenyl)-5-methyl-2,4-dihydro-3-pyrazolone and acetic anhydride is N-(3-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-phenyl)acetamide from 5-methyl-2-(4-aminophenyl)-2,4-dihydro-3-pyrazolone (prepared in analogy to Example 10) and acetic anhydride is N-(4-(4,5-dihydro-3-methyl-5-oxo-5H-pyrazol-1-yl)-phenyl)acetamide and by reaction with 2-ethylaniline N-(4-(4-(2-ethylanilinomethylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)phenyl)acetamide, m.p.: 230° C.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][N:5]1[C:9]2=[N:10][C:11]3[C:16]([CH:17]=[C:8]2[C:7]([C:20]([O:22]C)=[O:21])=[N:6]1)=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[CH:12]=3.C(=O)([O-])[O-].[K+].[K+]>>[CH3:24][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[C:9]2=[N:10][C:11]3[C:16]([CH:17]=[C:8]2[C:7]([C:20]([OH:22])=[O:21])=[N:6]1)=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[CH:12]=3
Reactant: COC(=O)c1nn(CCN(C)C)c2nc3cc(OC)ccc3cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc2cc3c(C(=O)O)nn(CCN(C)C)c3nc2c1

Procedure:
Methyl 1-[2-(dimethylamino)ethyl]-7-methoxy-1H-pyrazolo[3,4-b]quinoline-3-carboxylate can be hydrolyzed by heating it with aqueous potassium carbonate to produce the corresponding acid, 1-[2-(dimethylamino)ethyl]-7-methoxy-1H-pyrazolo[3,4-b]quinoline-3-carboxylic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH3:25][N:26]1[CH:30](P(OCC)(=O)OCC)[C:29](=[O:39])[NH:28][C:27]1=[O:40]>>[CH3:25][N:26]1[C:30](=[CH:6][C:5]2[CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:17])=[O:18])[CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])[C:29](=[O:39])[NH:28][C:27]1=[O:40]
Reactant: O=Cc1cc(OCCCS(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Reactant: CCOP(=O)(OCC)C1C(=O)NC(=O)N1C
Product: CN1C(=O)NC(=O)C1=Cc1cc(OCCCS(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]

Procedure:
Prepared from 2-nitro-5-[3-(phenylsulfonyl)propoxy]benzaldehyde and diethyl 1-methyl-2,4-dioxoimidazolidine-5-phosphonate analogous to the procedure of Example (2-8), m.p. 147°-158° C.