Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=C(C(O)(C)C)C=1)C=O.C(O)(=O)CC(O)=O.C([O-])(=O)C.[NH4+:25].[Cl:26][C:27]1[CH:28]=[C:29]([CH:37]=[CH:38][C:39]([OH:41])=[O:40])[CH:30]=[C:31]([C:33]([OH:36])([CH3:35])[CH3:34])[CH:32]=1>C(O)(C)C>[NH2:25][CH:37]([C:29]1[CH:30]=[C:31]([C:33]([OH:36])([CH3:35])[CH3:34])[CH:32]=[C:27]([Cl:26])[CH:28]=1)[CH2:38][C:39]([OH:41])=[O:40]
Reactant: [NH4+]
Reactant: CC(C)(O)c1cc(Cl)cc(C=CC(=O)O)c1
Agent: CC(=O)[O-]
Agent: CC(C)(O)c1cc(Cl)cc(C=O)c1
Agent: O=C(O)CC(=O)O
Solvent: CC(C)O
Product: CC(C)(O)c1cc(Cl)cc(C(N)CC(=O)O)c1

Procedure:
A suspension of 3-chloro-5-(2-hydroxypropan-2-yl)benzaldehyde (2.35 g, 11.83 mmol), malonic acid (1.50 g, 14.41 mmol) and ammonium acetate (1.85 g, 24.00 mmol) in isopropanol (30.0 mL) was heated at reflux under nitrogen atmosphere for 4 h to afford a colorless suspension in a yellow-orange solution. The hot reaction mixture was filtered and the solid was washed with hot isopropanol (2×25 mL) and discarded. The filtrate was evaporated in vacuo to afford a mixture of the desired acid (40%) and the byproduct: 3-(3-chloro-5-(2-hydroxypropan-2-yl)phenyl)acrylic acid (60%) as a cream yellow foamy solid. The solid was recrystallized several times (×5) from ethyl acetate to afford the pure desired product, free from the byproduct impurity, as a colorless solid (632.8 mg). LC-MS analysis of the solid shows the desired product's mass: m/z 258 (35ClM+H), m/z 260 (37ClM+H), m/z 240 (35ClM+H−H2O) and m/z 242 (37ClM+H−H2O); Calcd for C12H16ClNO3: 257.71. 1H NMR (400 MHz, DMSO-d6): δ 1.42 (s, 6H, (CH3)2C—), 2.30 (dd, J=8.0 and 6.0 Hz, 2H, —CH2—COOH), 4.21 (appt, J=7.0 Hz, 1H, —NH—CH—CH2—COOH), 6.33 (s, 1H, (CH3)2—C—OH), 7.31 (appt, J=1.60 Hz, 1H), 7.38 (appt, J=1.70 Hz, 1H), 7.42 ((d, J=9.0 Hz, 1H). 1H NMR spectrum of the sample was consistent with the suggested structure of the product.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:16][C:17]#[N:18]>>[C:17](/[C:16](/[C:15]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([O:12][CH3:11])[CH:14]=1)=[CH:7]\[C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)#[N:18]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccc(C#N)cc2)cc1OC
Yield: 112.9 %

Procedure:
4-Cyanobenzaldehyde (1.97 g) and 3,4-dimethoxybenzyl cyanide (1.80 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (3.33 g, yield: 77%).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].O.O.[F-].[K+].[O:15]1[C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH2:18][CH2:17][CH2:16]1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>[O:15]1[C:16]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:17][CH2:18][CH2:19][CH2:20]1
Reactant: CC1(C)OB(C2=CCCCO2)OC1(C)C
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1C1=CCCCO1
Temperature: 85 °C
Yield: 82.2 %

Procedure:
A mixture of 5-chloro-1-methyl-4-nitro-1H-pyrazole (200 mg, 1.25 mmol), potassium fluoride dihydrate (235 mg, 2.5 mmol) and 3,4-dihydro-2H-pyran-6-boronic acid pinacol ester (394 mg, 1.88 mmol) in THF (3 mL) was degassed by bubbling nitrogen through it for 15 min. Tris(dibenzylideneacetone)dipalladium/tri-tert-butyl phosphonium tetrafluoroborate mixture (mole ratio: 1/1.2, 151 mg, 0.13 mmol) was added and the mixture degassed for a further 10 min before being heated in the microwave at 85° C. for 2 hr. Water (10 mL) was added and the mixture extracted with EtOAc (3×5 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel chromatography (0-5% EtOAc/isohexane) gave 5-(3,4-dihydro-2H-pyran-6-yl)-1-methyl-4-nitro-1H-pyrazole as a yellow solid (215 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 5.22 (t, J=3.9 Hz, 1H), 4.20 (t, J=5.1 Hz, 2H), 3.88 (s, 3H), 2.31-2.24 (m, 2H), 2.05-1.96 (m, 2H).
Reaction SMILES: [O-2].[Mg+2].[OH:3][CH2:4][CH2:5][N:6]([C:30](=[O:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:7][CH2:8][N:9]([C:13](=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:10][CH2:11][OH:12].[C:47](Cl)(=O)[CH2:48]CCCCCCCCCCCCCC.C(Cl)(=O)CCCCCCC/C=C\CCCCCCCC>O1CCOCC1.O>[OH:3][CH2:4][CH2:5][N:6]([C:30](=[O:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:7][CH2:8][N:9]([CH2:10][CH2:11][OH:12])[C:13](=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:47][CH3:48]
Reactant: CCCCCCCCCCCCCCCC(=O)N(CCO)CCN(CCO)C(=O)CCCCCCCCCCCCCCC
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCO)CCN(CCO)C(=O)CCCCCCCCCCCCCCC
Reaction time: 1 h
Yield: 348.5 %

Procedure:
Into a 500 ml rounded-flask, were introduced 4.0 g of magnesium oxide and 80 g of distilled water. The mixture was stirred. Thereto was added 7.3 g of N,N'-bis(2-hydroxyethyl)-1,2-diaminoethane prepared in Example 27, and then was added 250 ml of 1,4-dioxane. 13.4 g of palmitoyl chloride was gradually added dropwise to the resulting mixture for 1 hour under violent stirring at 10° C. After stirring for 2 hours at 10° C., 14.7 g of oleoyl chloride was gradually added dropwise thereto for 1 hour. After stirring for 2 hours, the mixture was filtered, and then the filtrate was mixed with 200 ml of chloroform, and washed twice with 200 ml of distilled water. The organic phase was cooled to produce solid material, which was recovered by filtration. The solid material was dried and recrystallized from acetone, to give 26.5 g of the title compound as white powder, which was identified by IR and NMR. The results are shown in Table 3.
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1C)C.C([Li])(C)(C)C.CCCCC.[N:27]1(C#N)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C1COCC1>[CH3:12][O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([OH:14])=[N:3][C:15]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[CH:16]2
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Reactant: N#CN1CCOCC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc2c(O)nc(N3CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.5 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (500 mg, 2.259 mmol) in THF (5 ml) at −78° C. was added dropwise tert-butyllithium 1.7 M in pentane (2658 μl, 4.52 mmol) and the solution was stirred for 0.5 h before addition of morpholine-4-carbonitrile (253 mg, 2.259 mmol) in THF (5 ml). The resulting solution was warmed to rt and stirred for 16 h. The reaction mixture was quenched with water, neutralized with 1 N HCl. The precipitated solid was collected and washed with water to give 6-methoxy-3-morpholinoisoquinolin-1-ol (350 mg, 60% yield) as a solid after drying.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8]([O:15][C:16](ON1C(=O)CCC1=O)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[CH2:8]([O:15][C:16]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCCC(=O)O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: O=C(O)CCCNC(=O)OCc1ccccc1

Procedure:
Gamma-aminobutyric acid (1.03 g:0.010 mol) and N-benzyloxycarbonyloxysuccinimide (2.49 g:0.01 mol) in N,N'-dimethylformamide (10 ml) was stirred for 18 hours at 22° C. The resulting clear solution was concentrated and the residue was treated with water. The resulting oil yielded white crystals which were then dried to yield a residue which was purified on a silica gel column employing dichloromethane:methanol mixture (95:5) as an eluent to yield gamma-(benzyloxycarbonylamino)butyric acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:19][CH:18]=1.O>C(O)(=O)C>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([N+:13]([O-:15])=[O:14])=[C:2]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:21][CH:22]=1
Reactant: CC(C)(C#N)c1ccc(N)cc1
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)cc2c1Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C#N)c1ccc(Nc2c([N+](=O)[O-])cnc3ccc(Cl)cc23)cc1

Procedure:
A solution of 4,6-dichloro-3-nitroquinoline (Compound of Preparation E, 4.0 g, 16.46 mmol) and 2-(4-aminophenyl)-2-methylpropanenitrile (2.63 g, 16.46 mmol) in acetic acid (350 ml) was stirred for 2 hours. Water was added and the yellow precipitate was filtered off, washed with water and saturated aqueous NaHCO3. The yellow solid was dried to obtain the title compound. Yield: 5 g (83%); 1H NMR (DMSO-d6, 300 MHz): δ 10.074 (s, 1H), 9.062 (s, 1H,), 8.552-8.558 (d, 1H, J=1.8 Hz), 7.995-8.025 (d, 1H, J=9 Hz), 7.875-7.912 (t, 1H), 7.437-7.466 (d, 2H, J=8.4 Hz), 7.100-7.128 (d, 2H, J=8.4 Hz), 1.664 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].O.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:15][S:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(N)cc1C1OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(NS(C)(=O)=O)cc1C1OCCO1
Reaction time: 20 h
Yield: 88.1 %

Procedure:
To a solution of 2-(5-amino-2-methoxyphenyl)-1,3-dioxolane (867 mg, 4.4 mmol) in pyridine (2 ml) was added methanesulfonyl chloride (375 μl, 4.84 mmol) and stirred for 20 hr. To the resulted reaction mixture was added water and aqueous NaHCO3, and then extracted with ether/CH2Cl2. The extract was evaporated in vacuo to give crude 2-(5-methylsulfonylamino-2-methoxyphenyl)-1,3-dioxolane (1.06 g, 88.1%) as a slight brown oil.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.COB(OC)OC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:40]1[CH:41]=[CH:42][C:43]([F:48])=[C:44]([CH:47]=1)[CH:45]=[O:46].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:48][C:43]1[CH:42]=[CH:41][C:40]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH3:3])=[CH:8][CH:9]=2)=[CH:47][C:44]=1[CH:45]=[O:46]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: BrCCCOc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COB(OC)OC
Solvent: C1CCOC1
Product: CCCOc1ccc(-c2ccc(F)c(C=O)c2)cc1
Temperature: -11 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, magnesium (4311 mg, 177.34 mmol) was suspended in 270 ml of tetrahydrofuran, which was then refluxed. Under reflux, 90 ml of a tetrahydrofuran solution of p-bromopropoxybenzene (37.08 g, 172.41 mmol) was dropped and refluxed for 1.5 hours. After cooling to −11° C., a solution of trimethoxyborane (17.92 ml, 172.41 mmol) in 90 ml of tetrahydrofuran was dropped at −11 to −8° C. Stirring was conducted at −10° C. for 1 hour. At room temperature, palladium (II) acetate (11 mg, 0.04926 mmol) and subsequently triphenylphosphine (52 mg, 0.1970 mmol) were added and stirred at room temperature for 30 minutes. 5-Bromo-2-fluorobenzaldehyde (20 g, 98.52 mmol) and subsequently 85 ml of an aqueous solution of potassium carbonate (71.49 g, 517.23 mmol) were added at room temperature and heated under reflux for 4 hours. After cooling to room temperature, 450 ml of a 2N hydrochloric acid was dropped at 20 to 30° C. After phase separation had occurred, the water layer was extracted with 450 ml of toluene. The organic layers were combined and washed with 300 ml of a 2N hydrochloric acid, two 300-ml portions of a 2N sodium hydroxide, 300 ml of a 20% brine, 300 ml of a 2N hydrochloric acid and two 300-ml portions of a 20% brine. To the organic layer, 1.0 g of activated carbon (Shirasagi A) was added and stirred at room temperature for 20 minutes. After filtration, the residue was washed with 50 ml of toluene and then the filtrate was concentrated under vacuum, resulting in 30.5 g of crude 2-fluoro-5-(4-propoxyphenyl)benzaldehyde as a brown oily matter, which was used in the next step without being purified. A part of the product was purified by column chromatography to yield 2-fluoro-5-(4-propoxyphenyl)benzaldehyde as white crystals.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([O:21][CH3:22])[CH:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:14]([O:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:5]([CH2:4][CH2:3][OH:2])=[CH:6][C:7]=1[O:21][CH3:22])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)Cc1cc(OC)c(OCc2ccccc2)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CCO)cc(OC)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
(4-Benzyloxy-3,5-dimethoxy-phenyl)-acetic acid methyl ester (3.57 g, 11.3 mmol) was dissolved in THF (113 mL). A solution of LAH (1M in THF, 11.3 mL) was added dropwise to the stirring reaction mixture. After completion of addition the reaction continued to stir at room temperature overnight. The next day, the reaction was quenched with water. The aqueous layer was extracted with ethyl acetate. All of the combined organic layers were dried over sodium sulfate, filtered, and concentrated to yield a crude material (2.89 g, 89%), which was used in the next step without any additional purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5](OC(=O)C)[C:6]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[C:8]([Cl:14])[CH:7]=1)[CH3:2].[I-].[Sm+3].[I-].[I-].O1CCCC1>CN(C)P(N(C)C)(N(C)C)=O.CO.O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[C:8]([Cl:14])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(OC(C)=O)c1ccc(SC)c(Cl)c1
Agent: [I-]
Agent: [Sm+3]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(SC)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 59.6 %

Procedure:
A solution of acetoxy-(3-chloro-4-methylsulfanyl-phenyl)-acetic acid ethyl ester (1.47 g, 4.87 mmol) in hexamethylphosphoramide (7.2 mL) and methanol (20 μL) was treated with a 0.1M solution of samarium iodide in tetrahydrofuran (146 mL, 14.6 mmol). The reaction mixture was stirred at 25° C. under nitrogen for 6 min. During this time period, the reaction mixture changed from purple to white. The reaction mixture was diluted with water (150 mL) and then extracted with methylene chloride (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded (3-chloro-4-methylsulfanyl-phenyl)-acetic acid ethyl ester (0.71 g, 60%) as a light yellow oil: EI-HRMS m/e calcd for C11H13ClO2S (M+) 244.0324, found 244.0332.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[C:15](O)=O>C[Si](OP(=O)=O)(C)C>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:15]([C:14]3[CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[C:12]([O:11][CH3:10])[CH:13]=3)=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: COc1cc(C(=O)O)ccc1-c1ccccn1
Agent: C[Si](C)(C)OP(=O)=O
Product: COc1cc(-c2nc3cc(Br)ccc3o2)ccc1-c1ccccn1
Temperature: 200 °C

Procedure:
To 20 mL trimethylsilyl polyphosphate was added 2-amino-4-bromophenol (752 mg, 4.00 mmol) and 3-methoxy-4-pyridin-2-ylbenzoic acid (916 mg, 4.00 mmol). The mixture was heated at 200° C. for 2 h, quenched over ice, and made basic (pH 14) with 1N NaOH. The aqueous phase was extracted with MTBE (3×300 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated in vacuo, and purified by column chromatography (20–50% EtOAc/hexanes) to give 5-bromo-2-(3-methoxy-4-pyridin-2-ylphenyl)-1,3-benzoxazole as a pink solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.71 (d, 1H), 8.10 (d, 1H), 8.00 (t, 1H), 7.97–7.86 (m, 4H), 7.84 (d, 1H), 7.63 (dd, 1H), 7.39 (dt, (s, 3H); MS (ESI) 382 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[Cl:5][C:6]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14](Cl)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.C(N(CC)CC)C>ClCCl>[Cl:5][C:6]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([NH:4][CH2:1][C:2]#[CH:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: C#CCN
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Propargylamine (25 mL, 0.36 mol) was added dropwise over a period of five minutes to a 4.5° C. solution of 2,4-dichloro-3-nitroquinoline (84.4 g, 0.347 mol) and triethylamine (73 mL, 0.52 mol) in dichloromethane (1.2 L). After one hour, the solution was allowed to warm to room temperature. After several days, the solvent was evaporated under reduced pressure and the resulting solid was triturated with water and isolated by filtration. The solid was rinsed with water and toluene (500 mL), then was dissolved in dichloromethane and toluene and concentrated under reduced pressure to remove residual water. The solid was dissolved in methanol and ether and concentrated under reduced pressure to afford 2-chloro-3-nitro-N-prop-2-ynylquinolin-4-amine as yellow-brown solid (79.5 g) that contained some impurities and was used without further manipulation.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[O:19])[C:13]2[C:8](=[CH:9][C:10]([CH3:33])=[CH:11][CH:12]=2)[N:7]=1)=[O:5])C.[OH-].[Na+]>C1COCC1>[C:29]([O:28][C:26]([N:23]1[CH2:22][CH2:21][N:20]([C:18](=[O:19])[CH2:17][O:16][C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH3:33])=[CH:11][CH:12]=3)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:15]=2)[CH2:25][CH2:24]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)c1cc(OCC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(C)cc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc2c(OCC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc(C(=O)O)nc2c1
Reaction time: 2 h

Procedure:
To a solution of 988 mg 4-[2-(4-tert-Butoxycarbonyl-piperazin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid ethyl ester in 10 ml THF were added 2.2 ml aqueous NaOH (1 M) at 0° C. After 2 h the mixture was brought to pH 4 by using Amberlite IR-120 ion exchange resin. The reaction mixture was filtered and concentrated and the crude product obtained used in the next step without further purification. Yield: 925 mg.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:13]1[NH:14][C:15]([CH2:22][CH2:23][C:24](O)=O)=[C:16]2[C:21]=1[CH2:20][CH2:19][CH2:18]C2.ClC1C=CC(C2CCNCC2)=CC=1>>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:24][CH2:23][CH2:22][C:15]3[NH:14][N:13]=[C:21]4[CH2:20][CH2:19][CH2:18][C:16]=34)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Clc1ccc(C2CCNCC2)cc1
Product: c1ccc(N2CCN(CCCc3[nH]nc4c3CCC4)CC2)cc1

Procedure:
In the same manner as in Example 102 except that 3-(2,4,5,6-tetrahydrocyclopentapyrazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 4 and 1-phenylpiperazine are used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 2,4,5,6-tetrahydro-3-(3-(4-phenylpiperazin-1-yl)propyl)cyclopentapyrazole is obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH2:21][NH:20][CH2:19][CH2:18][C:11]=3[N:12]=[C:13]([NH:15][CH2:16][CH3:17])[N:14]=2)=[CH:5][CH:4]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:20]1[CH2:19][CH2:18][C:11]2[N:12]=[C:13]([NH:15][CH2:16][CH3:17])[N:14]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=3)[C:10]=2[CH2:21]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CCNc1nc2c(c(-c3ccc(Cl)cc3)n1)CNCC2
Agent: Cl
Product: CCNc1nc2c(c(-c3ccc(Cl)cc3)n1)CN(Cc1ccccc1)CC2
Yield: 27.2 %

Procedure:
The title compound was prepared as described in Example 5 starting with 4-(4-chlorophenyl)-2-ethylamino- 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine hydrochloride (1.1 g, 3.4 mmol) and benzyl bromide (0.4 mL, 3.4 mmol) to produce 0.35 g (27%) of 6-benzyl-4-(4- chlorophenyl)-2-ethylamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. m.p. 138°-141° C. MS: 379 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([NH:20][C:21]#[N:22])=[N:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[N:15]3)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.N1C=CC=CC=1>C(OCC)(=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:9][C:10]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:11]=3[CH:12]=[CH:13][CH:14]=[N:15]4)=[N:20][C:21]#[N:22])=[CH:23][CH:24]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: N#CNC(=Nc1cccc2ncccc12)NCc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: N#CN=C(NCc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cc1)Nc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
N-(4-Amino-benzyl)-N′-cyano-N″-quinolin-5-yl-guanidine (50 mg, 0.16 mmol) and 4-chloro-benzenesulfonyl chloride (41 mg, 0.19 mmol) were added to pyridine (1 mL). An exothermic reaction occurred and the suspension became homogeneous. This solution was shaken at room temperature for 12 hours. The reaction mixture was then diluted with ethyl acetate (8 mL) and washed with water (5 mL×3). The organic phase was dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was triturated with diethyl ether to give a solid product in 76% yield. 1H NMR (DMSO-d6, ppm): 10.37 (s, 1H), 9.39 (s, 1H), 8.96 (m, 1H), 8.12 (m, 1H), 8.02 (d, 1H), 7.69 (m, 3H), 7.63 (d, 2H), 7.49 (m, 2H), 7.39 (m, 1H), 7.08 (m, 4H), 4.21 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:28])[N:13]([CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1.[CH:29](N(CC)C(C)C)(C)[CH3:30].ICC>O1CCOCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:28])[N:13]([CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:29][CH3:30])[CH2:24][CH2:23]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Nc1cccc2c1C(=O)N(CCC1CCNCC1)C2=O)c1ccc(Cl)s1
Solvent: C1COCCO1
Solvent: CCI
Product: CCN1CCC(CCN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50.1 mg (0.12 mmol) of 5-chloro-N-{1,3-dioxo-2-[2-(4-piperidinyl)ethyl]-2,3-dihydro-1H-isoindol-4-yl}-2-thiophenecarboxamide are dissolved in 1 ml of 1,4-dioxane, and 25 μl (0.144 mmol) of N,N-diisopropylethylamine and 10 μl (0.12 mmol) of iodoethane are added. The mixture is stirred at room temperature overnight and, after concentration, chromatographed on silica gel (dichloromethane/methanol 97:3).