Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]=[CH2:3].[Cl:13][C:14]([Cl:19])(Cl)[C:15](Cl)=[O:16].C(COC)OC.CCCCCC>C(OCC)C.[Zn]>[C:5]([O:4][CH2:1][CH:2]1[CH2:3][C:15](=[O:16])[C:14]1([Cl:19])[Cl:13])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=CCOC(=O)c1ccccc1
Agent: [Zn]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: COCCOC
Product: O=C(OCC1CC(=O)C1(Cl)Cl)c1ccccc1
Yield: 37.1 %

Procedure:
To a suspension of benzoic acid allyl ester (100 g, 0.617 mol) and zinc (activated Zn) (161 g, 2.47 mol) in diethyl ether (1.23 L) was added dropwise a solution of trichloroacetyl chloride (223 g, 1.23 mol) and dimethoxyethane (110 g, 1.23 mol) in diethyl ether (1.23 L, 2 L/mol) over 40 minutes under nitrogen with vigorously stirring, and then the mixture was stirred at room temperature (internal temperature: 30° C.) for 29 hours. During the stirring, additional zinc (activated Zn) (respectively, 150 g (2.29 mol) and 100 g (1.53 mol)) was added at 7 and 24 hours after the beginning of the stirring. To the reaction mixture was added hexane (1 L), and the mixture was stirred for 10 minutes, and then the solid was removed by decantation and the supernatant was washed with water (1 L), aqueous saturated sodium bicarbonate solution (3×1 L) and saturated saline (500 mL), and dried over magnesium sulfate. The mixture was evaporated and the precipitated white solid was collected by filtration and washed with hexane (500 mL) to give the titled compound (62.5 g, 37%).
Reaction SMILES: P(OCCOC(N1C2C(=CC=CC=2)/C(=C/C2NC(C)=CC=2C)/C1=O)=O)(O)(O)=O.CO[O:31][P:32]([O:37][CH2:38][CH2:39][CH2:40][O:41][C:42]([N:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)/[C:46](=[CH:53]/[C:54]2[NH:55][C:56]([CH3:60])=[CH:57][C:58]=2[CH3:59])/[C:45]1=[O:61])=[O:43])([O:34]OC)=[O:33]>>[P:32]([O:37][CH2:38][CH2:39][CH2:40][O:41][C:42]([N:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)/[C:46](=[CH:53]/[C:54]2[NH:55][C:56]([CH3:60])=[CH:57][C:58]=2[CH3:59])/[C:45]1=[O:61])=[O:43])([OH:34])([OH:33])=[O:31]
Reactant: COOP(=O)(OCCCOC(=O)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21)OOC
Agent: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCCOP(=O)(O)O)c3ccccc32)[nH]1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCCCOP(=O)(O)O)c3ccccc32)[nH]1

Procedure:
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 3-phosphonooxypropyl ester was prepared using the same procedure for preparing 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-phosphonooxyethyl ester but substituting 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-(dimethoxy-phosphonooxy)-ethyl ester with 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 3-(dimethoxy-phosphonooxy)propyl ester.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c2cc(I)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(Cl)c2cc(I)ccc2n1
Temperature: 0 °C

Procedure:
4-Hydroxy-6-iodo-2-methylquinoline (10 g; see step (i) above) in phosphorous oxychloride (70 mL) was heated at 80° C. for 1 hour. The reaction mixture was then cautiously added to ice/water and solid sodium carbonate until the solution reached pH 8.0. The mixture was extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The resulting solid was triturated with diethyl ether to give the sub-title compound (6.4 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].CN(C=O)C.Br[CH:17]([CH3:23])[C:18](OCC)=[O:19].C([O-])(O)=O.[Na+]>[Cl-].[Na+].O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:10][C:18](=[O:19])[CH:17]([CH3:23])[NH:9]2
Reactant: CCOC(=O)C(C)Br
Reactant: Nc1ccc(F)c(Br)c1N
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1Nc2ccc(F)c(Br)c2NC1=O
Temperature: 90 °C
Reaction time: 15 h
Yield: 95.5 %

Procedure:
A 500 mL round-bottomed flask charged with 3-bromo-4-fluorobenzene-1,2-diamine (600c) (18 g, 88 mmol), DMF (100 mL), ethyl 2-bromopropionate (Sigma Aldrich, 11.54 mL, 89 mmol) and NaHCO3 (7.60 g powder, 90 mmol) was heated to 90° C. with a reflux condenser for 30 min, then at 120° C. for 15 h. The reaction mixture was cooled to RT, treated with brine and extracted with EtOAc (2×200 mL), washed with brine (3×) and dried over Na2SO4, filtered and concentrated affording crude 8-bromo-7-fluoro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (21.75 g, 84 mmol, 96% yield) as an orange-brown viscous oil. The material was used in the subsequent step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.67 (s, 1H) 6.78-6.89 (m, 1H) 6.48-6.78 (m, 1H) 6.07-6.35 (m, 1H) 1.25 (d, J=6.46 Hz, 3H). 19F NMR (377 MHz, DMSO-d6) δ ppm −120.49 (1F, s). m/z (ESI, +ve ion) 259.0/261.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=S)[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6]C(C)(C)C)[CH3:2].O[O:20][S:21]([O-:23])=O.[K+].[K].[OH2:26]>CO>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:6][S:21]([C:5]([CH3:11])([CH3:6])[CH3:4])(=[O:23])=[O:20])[CH3:2]
Reactant: O=S([O-])OO
Reactant: O
Reactant: CCOC(=S)C(Cc1ccccc1)CC(C)(C)C
Agent: [K+]
Agent: [K]
Solvent: CO
Product: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.5 g of 2-benzyl-3-tert.-butylthio-propionic acid ethyl ester is dissolved in 8 ml of methanol and, while cooling with ice, 1.63 g of oxone® (potassium peroxomonosulphate, 50% KHSO5, Ventron GmbH, Karlsruhe) in 7 ml of water are added and the whole is stirred overnight at room temperature. The solution is diluted with water and extracted with methylene chloride, and the extracts are dried and concentrated by evaporation. 1H-NMR (DMSO-d6): 1.0 ppm (t, 3H), 1.3 (s, 9H); 2.8-3.5 (m, 5H), 3.95 (q, 2H); 7.15-7.3 (m, 5H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([NH:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][C:7]=1[F:14])=[O:4].[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([NH:28][C:29]([NH:1][C@@H:2]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]([NH:5][C:6]2[C:7]([F:14])=[CH:8][C:9]([F:13])=[CH:10][C:11]=2[F:12])=[O:4])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1c(F)cc(F)cc1F
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)Nc1c(F)cc(F)cc1F

Procedure:
Following the procedure of Example 58 only using the product of Example 50 and phenylisocyanate, the title compound was obtained, mp 225°-233° C.
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>C1COCC1.ClCCl>[C:15]([O:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)(=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: OCc1ccco1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C(=O)OCc1ccco1
Temperature: 5 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
Furfuryl alcohol (5 mL, 1 eq.) was dissolved in THF (20 mL) in a dry, round bottomed flask and stirred with triethylamine (10 mL, 1.25 eq.). The solution was cooled to 5° C. and isobutyryl chloride (60.1 mL, 1.0 eq.) was added dropwise. The mixture was stirred for 2 h at 20° C. The reaction was worked up by diluting with dichloromethane (30 mL) and filtered through a celite plug to remove the triethylammonium chloride, and the solvent was removed under vacuum. The residue was purified by silica column chromatography using tert-butylmethyl ether-hexane (1:5) (Rf 0.54) to give an oil (8.5 g 87.5% yield). IR (cm−1): 1737 (C═O st), 3145, 3124 (═C—H st), 816, 745 (C—H δ, furan ring). 1H NMR (CDCl3, 300 MHz): δ 2.57 (sept, 1H, C—H(CH3)2, J=6.9 Hz), 1.17 (d, 6H, CH(CH3)2, J=6.9 Hz), 5.06 (s, 2H, CH2O) ppm. Furan ring: 6.39 (bd, 1H, H-3′, J3′,4′=3.3 Hz), 6.35 (dd, 1H, H-4′, J4′,5′=1.8 Hz), 7.41 (m, 1H, H-5′) ppm. 13C NMR (CDCl3, 75 MHz): δ 176.7 (C═O), 33.9 [CH(CH3)2], 18.9 [CH(CH3)2] ppm. Furan ring: 149.8 (C-2′), 110.5, 110.3 (C-3′, C-4′), 143.1 (C-5′) ppm. CI-Mass Spectrometry. m/z: 168 (M+), 97 [(OCH2-fur)+], 81 (main peak) [(CH2-fur)+], 71 [(CH3)2CHCO)+]. HRMS: Theoretical molecular weight for C9H12O3 (M+) 168.078644, experimental molecular weight: 168.078182.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:18])[CH2:16][CH3:17].O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:15](=[O:18])[CH2:16][CH3:17])[CH:3]=1
Reactant: Nc1cc(Br)ccn1
Reactant: CCC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)Nc1cc(Br)ccn1
Reaction time: 0.33 h
Yield: 84.3 %

Procedure:
To a solution of 4-bromo-2-aminopyridine (580 mmol) in 1.5 L dichloromethane was added pyridine (1.16 mol). The mixture was stirred for 20 min. Propionyl chloride (669 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 5 h. Water was added and the reaction mixture was extracted with dichloromethane. The combined organic layer was washed with brine, dried and concentrated. The residue was recrystallized from hexane/ethyl acetate (6:1) to afford 112 g of N-(4-bromopyridin-2-yl)propanamide (85% yield).
Reaction SMILES: [C:1]([O:5][C:6]([C@:8]1([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][C@@H:12](Br)[C@@H:11]2[C@H:9]1[C@H:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:30]1[CH:34]=[N:33][C:32]([SH:35])=[N:31]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([C@:8]1([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][C@H:12]([S:35][C:32]2[N:33]=[CH:34][NH:30][N:31]=2)[C@@H:11]2[C@H:9]1[C@H:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@@H](Br)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Reactant: Sc1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@H](Sc2nc[nH]n2)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
Add to a solution of ditert-butyl(1R,2S,4R,5R,6R)-4-bromo-2-(tert-butoxycarbonylamino)bicyclo[3.1.0]hexane-2,6-dicarboxylate (2 g, 4.20 mmol) in dimethylformamide (10 mL), 1H-1,2,4-triazole-3-thiol (525 mg, 5.04 mmol) and potassium carbonate (1.16 g, 8.4 mmol). Stir the mixture at 80° C. overnight. Cool to room temperature and dilute with ethyl acetate, wash with 10% citric acid and brine, dry over anhydrous sodium sulfate, filter and concentrate to dryness. Purify by silica gel chromatography (80 g silica column) eluting with hexane:ethyl acetate (80:20 to 0:100) to obtain the title compound (1.64 g, 78%). MS (m/z): 497 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[S:16][C:17]=1[CH3:18])[CH:6]=[O:7].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[S:16][C:17]=1[CH3:18]
Reactant: COc1cc(C=O)ccc1OCc1nc(N2CCCCC2)sc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1OCc1nc(N2CCCCC2)sc1C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of 3-methoxy-4-[(5-methyl-2-piperidin-1-yl-1,3-thiazol-4-yl)methoxy]benzaldehyde (0.50 g) in tetrahydrofuran (5 mL)-ethanol (5 mL) was gradually added sodium borohydride (0.05 g) at room temperature. After stirring for 1 hr, water was added to the reaction mixture and the precipitated crystals were collected by filtration to give {3-methoxy-4-[(5-methyl-2-piperidin-1-yl-1,3-thiazol-4-yl)methoxy]phenyl}methanol as colorless crystals (0.44 g, yield 90%). melting point: 92-93° C.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([CH2:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[C:22]([C@H:24]3[CH2:28][CH2:27][CH2:26][N:25]3[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:23])[N:10]2[CH2:13][CH3:14])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[CH2:35]([O:42]C(Cl)=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:13]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([C:1](=[NH:2])[NH:3][C:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:42])[CH:12]=2)[CH:8]=[C:9]1[CH2:15][CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([C@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:23])[CH3:14]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CN1CCC[C@@H]1C(=O)N1CCC[C@H]1CCc1cc2ccc(C(=N)N)cc2n1CC
Product: CCOC(=O)CN1CCC[C@@H]1C(=O)N1CCC[C@H]1CCc1cc2ccc(C(=N)NC(=O)c3ccccc3)cc2n1CC

Procedure:
60 mg of ethyl 2-[(R)-2-[[(S)-2-[2-(6-amidino-1-ethylindol-2-yl)ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]acetate obtained in Example 60 was reacted with 24 μl of benzylchloroformate according to the same procedure as Example 154 to obtain 64 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([N:22]=[C:23]3[N:27]([CH2:28][O:29][CH3:30])[CH:26]=[CH:25][S:24]3)[N:21]=2)[C:17]#[N:18])[CH2:9][CH2:8]1)=[O:6].[Cl-].O[NH3+:37].C(=O)([O-])[O-].[K+].[K+].[CH2:44]([OH:46])[CH3:45]>>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[N:21]=[C:20]([N:22]=[C:23]3[N:27]([CH2:28][O:29][CH3:30])[CH:26]=[CH:25][S:24]3)[CH:19]=[C:16]([C:17]3[N:37]=[C:44]([CH3:45])[O:46][N:18]=3)[CH:15]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: [NH3+]O
Reactant: COCn1ccsc1=Nc1cc(C#N)cc(CN2CCN(C(=O)c3cccc(Cl)c3F)CC2)n1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Product: COCn1ccsc1=Nc1cc(-c2noc(C)n2)cc(CN2CCN(C(=O)c3cccc(Cl)c3F)CC2)n1
Temperature: 25 °C

Procedure:
A mixture of 31.1 mg of 2-((4-(3-chloro-2-fluorobenzoyl)piperazin-1-yl)methyl)-6-((3-(methoxymethyl)-thiazol-2(3H)-ylidene)amino)isonicotinonitrile obtained in Example 104-(3), 13.0 mg of hydroxylammonium chloride, 17.2 mg of potassium carbonate and 3ml of ethanol was heated under reflux for 18 hours. The reaction solution was cooled to room temperature, and then concentrated. To the residue was added 3.0 ml of acetic anhydride followed by heating under reflux for 4 hours. The reaction solution was cooled to room temperature, and then concentrated. The reaction solution was diluted with chloroform and then washed with saturated potassium carbonate. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by a thin-layer chromatography for fractionation (eluent: chloroform/methanol=10/1) to give the title compound.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[C:7]1[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=O)[CH2:9][CH2:8]1.O1CCOCC1.[CH2:32]([N:34](CC)CC)C.ClCC#N>Cl.C1COCC1>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[C:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:32]#[N:34])[CH2:11][CH2:12]1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2nnco2)CC1
Agent: Cl
Agent: N#CCCl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N#CCN1CCC(=C(c2ccccc2)c2nnco2)CC1
Reaction time: 1 h
Yield: 51.7 %

Procedure:
tert-Butyl 4-((1,3,4-oxadiazol-2-yl)(phenyl)methylene)piperidine-1-carboxylate (100 mg, 0.29 mmol) was diluted with 4 M HCl in 1,4-dioxane (1.2 mL, 4.8 mmol) and stirred 1 h. The reaction was concentrated and the residue diluted with THF (1.5 mL), triethylamine (0.5 mL, 3.8 mmol) and chloroacetonitrile (0.25 mL, 3.9 mmol). The reaction was stirred 3 d, concentrated, diluted with MeOH, filtered and purified by preparative HPLC to yield 45 (43 mg, 0.15 mmol, 53%) as a white solid. 1H NMR: (500 MHz, CDCl3) δ 8.27 (s, 1H), 7.41-7.31 (m, 3H), 7.20-7.16 (m, 2H), 3.55 (s, 2H), 3.02 (t, J=5.8 Hz, 2H), 2.75 (t, J=5.8 Hz, 2H), 2.61 (t, J=5.8 Hz, 2H), 2.39 (t, J=5.8 Hz, 2H); LC/MS: (ES+) m/z (M+H)=281; HPLC Rt=0.97 min., column G, conditions B.
Reaction SMILES: [NH:1]1[CH:5]=[C:4](B(O)O)[CH:3]=[N:2]1.N1C2C(=CC=CC=2)C=C(B(O)O)C=1.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2C.Br[C:46]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:47]=1[C:48]1([C:80]3[C:71](=[CH:72][C:73]4[O:78][CH2:77][CH2:76][O:75][C:74]=4[CH:79]=3)[O:70][CH2:69]1)[C:49](=[O:68])[N:50]2[CH:55](C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:55][N:50]1[C:51]2[C:47](=[C:46]([C:4]3[CH:3]=[N:2][NH:1][CH:5]=3)[CH:54]=[CH:53][CH:52]=2)[C:48]2([C:80]3[C:71](=[CH:72][C:73]4[O:78][CH2:77][CH2:76][O:75][C:74]=4[CH:79]=3)[O:70][CH2:69]2)[C:49]1=[O:68]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Reactant: OB(O)c1cn[nH]c1
Agent: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: OB(O)c1cnc2ccccc2c1
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(-c3cn[nH]c3)cccc21

Procedure:
Following the procedure as described in EXAMPLE 2.46 and making non-critical variations using 1H-pyrazole-4-boronic acid to replace quinolin-3-ylboronic acid, and 4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 1′-methyl-4′-(1H-pyrazol-4-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (54%) as a colorless solid: mp 250-251° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.35 (dd, J=7.9, 7.9 Hz, 1H), 7.10-7.00 (m, 3H), 6.86 (d, J=7.8 Hz, 1H), 6.40 (s, 1H), 6.31 (s, 1H), 4.66 (d, J=9.1 Hz, 1H), 4.47 (d, J=9.1 Hz, 1H), 4.23-4.08 (m, 4H), 3.26 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.0, 155.4, 144.8, 144.3, 138.0, 130.6, 129.2, 127.9, 125.4, 122.5, 111.4, 107.3, 99.6, 64.6, 63.9, 58.2, 26.8; MS (ES+) m/z 376.0 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[Cl:14][C:15]1[N:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:14][C:15]1[N:16]=[N:17][C:18]([N:21]2[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)[CH2:25][CH2:26]2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(N2CCNCC2)nn1
Reactant: COc1ccc(OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(OCCCN2CCN(c3ccc(Cl)nn3)CC2)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
A mixture of 5 parts of 1-(3-chloropropoxy)-4-methoxybenzene, 3.9 parts of 3-chloro-6-(1-piperazinyl)pyridazine 8.5 parts of sodium carbonate and 188 parts of N,N-dimethylformamide was stirred overnight at about 65° C. The reaction mixture was poured into ice water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 4.9 parts (67.5%) of 3-chloro-6-[4-[3-(4-methoxyphenoxy)propyl]-1-piperazinyl]pyridazine; mp. 122.9° C. (comp. 87).
Reaction SMILES: O1CCOCC1.CO.[CH3:9][O:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[S:20][C:19](/[CH:21]=[CH:22]/[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=3)=[N:18][C:17]=2[CH:32]=1)=[O:12].[Cl-].[Ca+2].[Cl-]>O.[Zn]>[NH2:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)/[CH:22]=[CH:21]/[C:19]1[S:20][C:16]2[CH:15]=[CH:14][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:32][C:17]=2[N:18]=1
Reactant: COC(=O)c1ccc2sc(/C=C/c3cccc([N+](=O)[O-])c3)nc2c1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2sc(/C=C/c3cccc(N)c3)nc2c1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To a solvent mixture of 50 ml of dioxane and 30 ml of methanol, 2.0 g of 5-methoxycarbonyl-2-(trans-3-nitrostyryl)benzothiazole was added and, under vigorous stirring, a solution of 0.37 g of calcium chloride in 55 ml of water and 9.8 g of zinc powder were added, followed by refluxing for 2 hours. After cooled to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the solid residue formed was washed with toluene to give 1.4 g (yield 77%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][CH2:21][CH2:22]O)[C:9]([C:11]1[NH:12][C:13](=[O:19])[C:14]([Br:18])=[CH:15][C:16]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:1]([N:8]1[CH2:20][CH2:21][CH2:22][N:12]2[C:13](=[O:19])[C:14]([Br:18])=[CH:15][C:16]([CH3:17])=[C:11]2[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)c(=O)[nH]c1C(=O)N(CCCO)Cc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(Br)c(=O)n2c1C(=O)N(Cc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of N-benzyl-5-bromo-N-(3-hydroxypropyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (4, 1.5 g, 3.9 mmol) in tetrahydrofuran (30 mL), triphenylphosphine (1.5 g, 5.9 mmol) and diisopropyl azodicarboxylate (1.2 g, 5.9 mmol) were added at 0° C. The reaction was stirred at room temperature for 16 h. After completion, solvent was removed under reduced pressure and crude was purified by flash chromatography eluting with 40% ethyl acetate in hexane. Appropriate fractions were concentrated under reduced pressure to afford 2-benzyl-8-bromo-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione (5) as yellow solid. Yield: 0.9 g, 64%; MS (ESI) m/z 361.18 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]([CH3:14])([CH3:13])[CH3:12].CO.O.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)c1cc(C(C)(C)C)c(Br)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1cc(C(=O)O)oc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of methyl 5-bromo-4-tert-butyl-furan-2-carboxylate (1.45 g, 5.57 mmol, prepared as described in the previous step) in a mixture of THF (15 mL), MeOH (10 mL), and H2O (5 mL) was treated with 3 M aqueous NaOH solution (3.00 mL, 9.00 mmol) and the resulting mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was dissolved in H2O (60 mL) and extracted with Et2O (2×30 mL). The aqueous layer was acidified to pH˜2 using 2 M HCl. The precipitate was isolated by filtration, washed with H2O (20 mL), and air-dried to yield 5-bromo-4-tert-butyl-furan-2-carboxylic acid. The filtrate was extracted with EtOAc (3×20 mL) and the combined extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure to yield a second crop of 5-bromo-4-tert-butyl-furan-2-carboxylic acid. 1H-NMR (400 MHz, CDCl3) δ: 7.25 (s, 1H), 1.35 (s, 9H).
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([OH:15])CC.Cl.N1C=C[CH:20]=[CH:19][CH:18]=1>>[C:1]([O:10][CH2:18][CH2:19][CH3:20])(=[O:15])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: CCCO
Reactant: c1ccncc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Product: CCCOC(=O)c1ccc(OC)cc1
Temperature: 110 °C

Procedure:
230 gm (1.32 mol) of anisoyl chloride were added drop by drop under agitation and cooling to a mixture of 316 gm (5.28 mol) of n-propanol and 300 ml of pyridine. The mixture was subsequently heated to 110° C. for three hours and then poured into a mixture of ice/water. The product was neutralized under cooling with half concentrated hydrochloric acid and extracted with ether. After drying, the ether phase was evaporated and the residue was fractionally distilled. The n-propyl anisate obtained had the following values: