Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH:5]=[N:6][OH:7].N1C=CC=CC=1.ClN1C(=O)CCC1=O.[CH2:26]=[C:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:26][C:27]3([CH2:31][CH2:30][CH2:29][CH2:28]3)[O:7][N:6]=2)[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: C=C1CCCC1
Reactant: Cc1ccc(C=NO)cc1Br
Agent: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C2=NOC3(CCCC3)C2)cc1Br
Yield: 58.6 %

Procedure:
To a solution of 3-bromo-4-methylbenzaldehyde oxime (0.85 g, 4 mmol, 1.0 eq) in THF (50 mL) was added pyridine (0.2 mL, 2.4 mmol, 0.6 eq) followed by N-chlorosuccinimide (530 mg, 4 mmol, 1.0 eq) and the resulting mixture was refluxed for 1 h. The reaction was cooled to room temperature before the addition of a solution of methylenecyclopentane (0.42 mL, 4 mmol, 1.0 eq) in THF (5 mL) followed by triethyl amine (0.94 mL, 7 mmol, 1.7 eq). The resulting solution was refluxed for 1 h. The solvent was evaporated under vacuum and usual work up afforded 690 mg of the title product as a white solid. 1HNMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 3.22 (s, 2H), 2.41 (s, 3H), 2.14-2.11 (m, 2H), 1.88-1.84 (m, 2H), 1.77-1.72 (m, 4H); ESI-MS (m/z) 294, 296 [(MH)+, Br79,81].
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[CH:14][C:15]([C:16]([O:18]CC)=[O:17])=[C:9]3[CH:8]=2)[C@@H:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[CH2:3]1.[Li+].[OH-].[OH-].[Na+]>C1COCC1.CO.O>[F:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[C:9]3[CH:8]=2)[C@@H:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[CH2:3]1
Reactant: CCOC(=O)c1cnn2ccc(N3C[C@@H](F)C[C@@H]3c3cccc(F)c3)cc12
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cnn2ccc(N3C[C@@H](F)C[C@@H]3c3cccc(F)c3)cc12
Temperature: 50 °C

Procedure:
To a suspension of ethyl 5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (X-1) (51 mg, 0.14 mmol) in THF:MeOH:H2O 3:2:1 (3 mL) was added LiOH (29 mg, 0.7 mmol). The reaction was heated to 50° C. for 48 hours then cooled to room temperature and neutralized to pH 6 with 1M NaOH. The mixture was reduced to dryness and purified by column chromatography on silica gel with DCM/MeOH gradient as eluant to yield 5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (X-3). 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1 H), 8.15 (d, J=7.6 Hz, 1 H), 7.36-7.29 (m, 1 H), 7.09-7.04 (m, 2 H), 7.00-6.92 (m, 2 H), 6.24 (dd, J=2.4, 7.6 Hz, 1 H), 5.41 (d, J=52.8 Hz, 1 H), 5.06 (t, J=8.4 Hz, 1 H), 4.29-3.92 (m, 2 H), 2.94-2.82 (m, 1 H), 2.24-2.05 (m, 1 H). MS m/z 344.1 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:8]([CH3:15])=[C:9]2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:20][O:19][C:17](=[O:18])[CH2:16][C:7]1[C:8]([CH3:15])=[C:9]([C:12]([N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[O:14])[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C(=O)O)c1C
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc2ccc(F)cc2c(C(=O)N2CCN(c3ccc(F)cc3)CC2)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.6 %

Procedure:
To a solution of 7-fluoro-3-methoxycarbonylmethyl-2-methyl-naphthalene-1-carboxylic acid (27.6 mg, 0.10 mmol) and 1-(4-fluoro-phenyl)-piperazine (19.8 mg, 0.11 mmol) in N,N-dimethylformamide (2 mL) was added bromo-tris-pyrrolidino phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and N,N-diisopropylethylamine (34.7 μL, 0.20 mmol). After being stirred at room temperature for 24 hours, the resulting mixture was diluted with ethyl acetate (10 mL), and washed with 1N hydrochloric acid (10 mL), a saturated aqueous solution of sodium carbonate (10 mL), and brine (10 mL). The resulting organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (gradient elution with 20-40% ethyl acetate in petroleum ether) to afford {6-fluoro-4-[4-(4-fluoro-phenyl)-piperazine-1-carbonyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (36.2 mg, 83%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B.O1CCCC1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[C:9]([Cl:11])[N:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: OCc1ccc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
Dissolve 2,6-dichloronicotinic acid (1000 mg, 5.21 mmol) in anhydrous tetrahydrofuran (5 mL). Cool to 0° C. Add borane-tetrahydrofuran complex (7.82 mL, 7.82 mmol, 1.0 M in tetrahydrofuran) slowly. Stir the mixture at room temperature overnight. Add water (1 mL) and potassium carbonate, stir for 2 hours, filter and concentrate to give a residue. Chromatograph the residue on silica gel eluting with 10:90 to 20:80 ethyl acetate:hexanes to give (2,6-dichloropyridin-3-yl)-methanol (876 mg, 94%). 1H NMR (400 MHz, MeOH-d4) δ 7.96 (d, 1H, J=8.0 Hz), 7.45 (d, 1H, J=8.0 Hz), 4.64 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:3]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH:19]([F:21])[F:20])=O)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[SH:22][CH2:23][C:24]([O:26][CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+].C(#N)C>Cl>[F:20][CH:19]([F:21])[O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[C:3]2[N:4]=[C:5]([S:8][CH3:9])[N:6]=[CH:7][C:2]=2[S:22][C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)CS
Reactant: CSc1ncc(Cl)c(C(=O)c2ccccc2OC(F)F)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1sc2cnc(SC)nc2c1-c1ccccc1OC(F)F
Temperature: 60 °C
Yield: 97.9 %

Procedure:
A mixture of 303 mg of [5-chloro-2-(methylsulfanyl)pyrimidin-4-yl][2-(difluoromethoxy)phenyl]methanone 7, 107 mg of methyl sulfanylacetate, 253 mg of potassium carbonate and 5 ml of acetonitrile is microwave-heated in a sealed tube at 60° C. for 4 h. The mixture is diluted with a 0.5 N aqueous hydrochloric acid solution and extracted twice with ethyl acetate and once with dichloromethane. The organic phases are dried over magnesium sulfate, filtered, and then concentrated under vacuum so as to obtain 343 mg of methyl 7-[2-(difluoromethoxy)phenyl]-2-(methylsulfanyl)thieno[3,2-d]pyrimidine-6-carboxylate 8 in the form of a pale yellow solid.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]3[CH:19]=[N:20][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][CH:23]=3)=[C:13]2[N:12]=[C:11]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:10]=1[C:36]#[N:37].CCN(C(C)C)C(C)C.[OH:47][C@H:48]([CH2:52][OH:53])[C:49](O)=[O:50].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[NH2:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]3[CH:19]=[N:20][C:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][CH:23]=3)=[C:13]2[N:12]=[C:11]([CH:30]2[CH2:31][CH2:32][N:33]([C:49](=[O:50])[C@H:48]([OH:47])[CH2:52][OH:53])[CH2:34][CH2:35]2)[C:10]=1[C:36]#[N:37]
Reactant: N#Cc1c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Reactant: O=C(O)[C@H](O)CO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(C2CCN(C(=O)[C@H](O)CO)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile TFA salt (0.1 mmol), DIEA (87 μL, 0.5 mmol) in DMF (2 mL) was added a solution of (R)-2,3-dihydroxypropanoic acid (11 mg, 0.1 mmol), HOBt (14 mg, 0.1 mmol), EDCI (29 mg, 0.15 mmol) in DMF (1 mL). The reaction was stirred at rt for 2.5 hour and the mixture was directly purified by HPLC to furnish the title compound. LC/MS RT=2.86 min. Mass calculated for M+H 484.2, observed 484.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([NH:9][C:10]2[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[O:13])=[O:8])=[CH:3][CH:2]=1.[CH2:26]([Br:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Br-:33].[CH2:26]([N+:1]1[CH:6]=[CH:5][C:4]([C:7]([NH:9][C:10]2[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[O:13])=[O:8])=[CH:3][CH:2]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cc1)c1ccncc1
Product: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cc1)c1cc[n+](Cc2ccccc2)cc1
Product: [Br-]
Yield: 72.5 %

Procedure:
Using the procedure described in Example 26, Part B, 2-(4-pyridinecarbonyl)amino-N-(4-chlorophenyl)benzamide (500 mg, 1.42 mmol) and benzyl bromide (0.25 mL, 2.13 mmol) yielded 538 mg (73%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][CH2:34]Cl)=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(B(O)O)=CC=1)(C)(C)C.O.[C:50]([O:53][CH2:54][CH3:55])(=O)[CH3:51].C[N:57](C)C=O>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][CH2:34][N:57]5[CH2:55][CH2:54][O:53][CH2:50][CH2:51]5)=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)ccnc2cc1OCCCCl
Reactant: CCOC(C)=O
Reactant: CN(C)C=O
Agent: CC(C)(C)c1ccc(B(O)O)cc1
Solvent: O
Product: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)ccnc2cc1OCCCN1CCOCC1
Temperature: 70 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
(4-Tert-butylphenyl)-{4-[7-(3-chloropropoxy)-6-methoxy-4-quinolyloxy]phenyl}amine (40 mg) (starting compound A) was dissolved in N,N-dimethylformamide (1 ml) to prepare a solution. Morpholine (30 μl) (starting compound B) was then added to the solution, and the mixture was stirred at 70° C. for 2 days. Water and ethyl acetate were added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and was dried over sodium sulfate. The solvent was removed by evaporation under the reduced pressure, and the residue was purified by thin-layer chromatography on silica gel using chloroform/methanol for development to give the title compound (12 mg, yield 27%).
Reaction SMILES: [S:1]1[C:5]([C@H:6]([O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)/[CH:7]=[CH:8]/[C@H:9]2[C:13](=[CH2:14])[CH2:12][C@H:11]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:4][C:3]2[CH:50]=[CH:51][CH:52]=[CH:53][C:2]1=2>CO.[Li+].[OH-].C(OCC)(=O)C>[S:1]1[C:5]([C@H:6]([O:32][Si:33]([C:46]([CH3:48])([CH3:49])[CH3:47])([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)/[CH:7]=[CH:8]/[C@H:9]2[C:13](=[CH2:14])[CH2:12][C@H:11]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:4][C:3]2[CH:50]=[CH:51][CH:52]=[CH:53][C:2]1=2
Reactant: C=C1C[C@H](OC2CCCCO2)[C@H](C/C=C\CCCC(=O)OC)[C@H]1/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc2ccccc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C=C1C[C@H](OC2CCCCO2)[C@H](C/C=C\CCCC(=O)O)[C@H]1/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc2ccccc2s1
Temperature: 4 °C

Procedure:
(Z)-Methyl 7-((1R,2R,5S)-2-((R,E)-3-(benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)prop-1-enyl)-3-methylene-5-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoate (17a, limiting reagent) is dissolved in a 3:1 methanol and 1 N LiOH solution (0.01 M) and stirred at 4° C. Upon completion of the reaction, as judged by TLC, the reaction mixture is diluted with ethyl acetate, washed with 5% aqueous KHSO4 and brine. The organic phase is dried over sodium sulfate, filtered, and the solvent is evaporated. The crude product is purified by flash chromatography on regular silica gel eluted with hexanes-ethyl acetate to afford the title intermediate 19a.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1.Br[CH2:27][CH2:28][CH2:29][C:30]([CH2:44][CH3:45])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>>[CH2:44]([C:30]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([CH2:29][CH2:28][CH2:27][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1)[CH2:31][C:32]([O:34][CH:35]([CH3:36])[CH3:37])=[O:33])[CH3:45]
Reactant: O=C(NC1CCNCC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCC(CCCBr)(CC(=O)OC(C)C)c1ccccc1
Product: CCC(CCCN1CCC(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1)(CC(=O)OC(C)C)c1ccccc1

Procedure:
Prepared from 4′-trifluoromethyl-biphenyl-2-carboxylic acid-piperidin-4-ylamide and isopropyl 5-bromo-2-ethyl-2-phenyl-pentanecarboxylate.
Reaction SMILES: [NH:1]([C:3]1[S:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=1)[NH2:2].Cl.[N:15]([O-])=O.[Na+]>C(OCC)C.O>[N:1]([C:3]1[S:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=1)=[N+:2]=[N-:15]
Reactant: CCOC(=O)c1sc(NN)nc1C
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1sc(N=[N+]=[N-])nc1C
Reaction time: 0.17 h
Yield: 47.1 %

Procedure:
To a cooled (0° C.) suspension of ethyl 2-hydrazinyl-4-methylthiazole-5-carboxylate (3.00 g, 14.92 mmol) in a mixture of diethyl ether (15 mL) and water (15 mL) was added hydrochloric acid (2.72 mL) dropwise. The reaction mixture was stirred for 10 minutes, and a solution of sodium nitrite (1.21 g, 17.46 mmol) in water (2 mL) was added. The mixture was stirred for 2 hours at 0° C. and extracted with diethyl ether. The organic layer was separated, washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:hexanes, 1:4) to afford the title compound as a yellowish solid (1.49 g, 47%): 1H NMR (300 MHz, CDCl3) δ 4.29 (q, J=6.0 Hz, 2H), 2.62 (s, 3H), 1.33 (t, J=6.0 Hz, 3H); MS (ES+) m/z 213.2 (M+1).
Reaction SMILES: [CH:1]1([C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.Cl[C:16]1[N:25]=[C:24]([NH2:26])[C:23]2[C:18](=[CH:19][C:20]([O:29][CH3:30])=[C:21]([O:27][CH3:28])[CH:22]=2)[N:17]=1>>[NH2:26][C:24]1[C:23]2[C:18](=[CH:19][C:20]([O:29][CH3:30])=[C:21]([O:27][CH3:28])[CH:22]=2)[N:17]=[C:16]([N:12]2[CH2:11][CH2:10][N:9]([C:7]([CH:1]3[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]3)=[O:8])[CH2:14][CH2:13]2)[N:25]=1
Reactant: O=C(C1CC=CCC1)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Product: COc1cc2nc(N3CCN(C(=O)C4CC=CCC4)CC3)nc(N)c2cc1OC

Procedure:
N-(3-cyclohexenylcarbonyl)piperazine (7.65 g., 0.04 mole) and 2-chloro-4-amino-6,7-dimethoxyquinazoline (9.6 g., 0.04 mole) are reacted according to the procedure of Example 1(a). The crude product crystallized from methanol affords analytically pure 4-amino-2-[4-(3-cyclohexenylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline, m.p. 211°-213° C. resolidifying and melting at 234.0° -236.0°C. (corr.).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C)C=O>[CH2:41]([NH:48][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])=[O:9])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: Cc1ccsc1C(=O)O
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccsc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.5 %

Procedure:
To a stirred mixture of 3-methyl-2-thiophenecarboxylic acid (5.00 g, 35.17 mmol), 1-hydroxybenzotriazole (7.13 g, 52.73 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.11 g, 52.74 mmol) in anhydrous N,N-dimethylformamide (50 mL) was added N,N-diisopropylethylamine (18.4 mL, 105.6 mmol), followed by benzylamine (3.84 mL, 35.19 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 h, and partitioned between ethyl acetate (200 mL) and 10% aqueous hydrochloric acid (100 mL). The organic layer was washed with 10% aqueous hydrochloric acid (100 mL), saturated aqueous sodium bicarbonate (2×100 mL) and water (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with 5% ethyl acetate in hexanes to afford the title compound as a colorless solid (6.63 g, 81%): 1H NMR (300 MHz, CDCl3) δ 7.40-7.25 (m, 6H), 6.90 (d, J=4.9 Hz, 1H), 6.08 (br s, 1H), 4.62 (d, J=5.6 Hz, 2H), 2.53 (s, 3H); MS (ES+) m/z 232.3 (M+1).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](=[O:14])[CH3:13])[CH:6]=[CH:5]2.[CH2:15]([NH:17][CH2:18][CH2:19][OH:20])[CH3:16].O>C(OCC)(=O)C>[CH2:15]([N:17]([CH2:18][CH2:19][OH:20])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](=[O:14])[CH3:13])[CH:6]=[CH:5]2)[CH3:16]
Reactant: CC(=O)c1ccc2cc(O)ccc2c1
Reactant: CCNCCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(CCO)c1ccc2cc(C(C)=O)ccc2c1
Yield: 12 %

Procedure:
A mixture of 1-(6-hydroxy-2-naphthyl)ethanone (744 mg, 3.92 mmol), sodium hydrogen sulfate(IV) (1.66 g, 16 mmol), 2-ethylaminoethanol (2 mL) and water (5 mL) was heated in a steel bomb at 130-140° C. for 3 days. After cooling, the mixture was distributed between water and ethyl acetate, and the organic layer was washed with brine, dried and evaporated. The residue was dissolved in acetone and loaded onto a 4 mm dry silica plate for radial chromatography. The plate was eluted with a 1:1 mixture of petroleum ether and ethyl acetate. Appropriate fractions were collected and evaporated to give 125 mg(12%)of 1-{6-[ethyl-(2-hydroxylethyl)-amino]-2-naphthyl}ethanone.
Reaction SMILES: C(O[C:9]1[CH:10]=[C:11]([CH2:23][CH:24]=O)[CH:12]=[CH:13][C:14]=1OCC1C=CC=CC=1)C1C=CC=CC=1.C([Mg:34][Br:35])CCCCCCC>CCOCC>[Mg:34].[CH2:10]([Br:35])[CH2:9][CH2:14][CH2:13][CH2:12][CH2:11][CH2:23][CH3:24]
Reactant: O=CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: CCCCCCCC[Mg]Br
Solvent: CCOCC
Product: CCCCCCCCBr
Product: [Mg]

Procedure:
After gradually adding 0.5 g of 3,4-dibenzyloxyphenylacetaldehyde to 10 mg of an ether solution of n-octylmagnesium bromide obtained from 0.12 g of magnesium and 0.97 g of n-octyl bromide, the mixture was stirred for 30 minutes at room temperature. To the reaction mixture thus obtained was added 10 ml of an aqueous 5% hydrochloric acid solution and after stirring the mixture, the ether layer was collected. The ether solution was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide 0.5 g of 1-(3,4-dibenzyloxyphenyl)-2-decanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[C:19]([C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[S:30])[CH:25]=[CH:26][CH:27]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[CH:23]=[C:24]([NH:28][C:29](=[S:30])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:25]=[CH:26][CH:27]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1cccc(N=C=S)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cccc(C(C)=O)c1
Yield: 67.6 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.971 g, 4.00 mmol) and 3-acetylphenyl isothiocyanate (0.709 g, 4.00 mmol) to afford the product (1.135 g); m.p. 176-177° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29]([OH:31])=O)[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl.[CH3:36][O:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[CH3:36][O:37][CH:38]1[CH2:43][CH2:42][N:41]([C:29](=[O:31])[CH:28]([N:26]2[CH:27]=[C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:33])([F:34])[F:1])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)[CH:24]=[N:25]2)[CH3:32])[CH2:40][CH2:39]1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Reactant: COC1CCNCC1
Agent: Cl
Product: COC1CCN(C(=O)C(C)n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and 4-methoxypiperidine hydrochloride (Matrix and Cat. No. 015567). LCMS (M+H)+: m/z=571.3.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH3:2].[NH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([Cl:28])=[CH:20][CH:19]=1.[BH4-].[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.CO>[Cl:28][C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([NH:17][CH2:11][C:10]2[CH:13]=[CH:14][C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:15][CH3:16])[CH2:1][CH3:2])=[CH:8][CH:9]=2)=[CH:19][CH:20]=1
Reactant: CCN(CC)CCOc1ccc(C=O)cc1
Reactant: Nc1ccc(Cl)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCN(CC)CCOc1ccc(CNc2ccc(Cl)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 2089.2 %

Procedure:
A stirred solution of 0.2 gram (0.0001 mole) of 4-(2-(diethylamino)ethoxy)benzaldehyde (prepared in the manner of Step A, Example 3), 0.22 gram (0.0001 mole) of 1-amino-4-chloronaphthalene (available from Aldrich Chemical Company), and one drop of p-toluenesulfonic acid monohydrate (available from Aldrich Chemical Company) in 5 mL of toluene was heated at reflux for ten hours. At the conclusion of this period, the reaction mixture was concentrated under reduced pressure, yielding a residue. The residue was taken up in 5 mL of methanol and about 0.2 grams (0.004 mole) of sodium borohydride was added. The resulting mixture was stirred at ambient temperature for about 18 hours. After this time, the mixture was quenched with water and extracted with several portions of diethyl ether. The extracts were combined, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 0.8 gram of Compound 84. The NMR spectrum was consistent with the proposed structure.