Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.Br[CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1C=CC=CC=1.CCOCC.[Zn]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]([OH:10])[CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:3][CH:4]=1
Reactant: CCOC(=O)C(C)Br
Reactant: COc1ccc(C=O)cc1
Agent: [Zn]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C(C)C(O)c1ccc(OC)cc1

Procedure:
To 36.2 g. (0.55 mole) of purified zinc dust is added portionwise a solution of 80 g p-anisaldehyde (0.58 mole) in 80 ml of anhydrous benzene, 20 ml anhydrous ether and 98 g (0.54 mole) of ethyl 2-bromopropionate from a separatory funnel. About 15 ml of this solution is added to the zinc and the flask is warmed until the reaction starts and then heating is removed and allowed to continue exothermally. The addition takes about an hour. The reaction mixture is refluxed for 40 minutes and then cooled in an ice bath and hydrolyzed by the addition of 250 ml of cold 10% sulfuric acid with vigorous stirring. The acid layer is drawn off and the benzene solution is extracted twice with 63 ml of 5% sulfuric acid followed by 30 ml of 10% sodium carbonate solution, then with 3 × 30 ml of 5% sulfuric acid, and finally with 2 × 30 ml of water. The combined acid solution is extracted with 2 × 100 ml of ether and the combined ether and benzene solution is washed with 2 × 50 ml of saturated sodium chloride, then it is dried over sodium sulfate for 11/2 hours and filtered. Most of the solvent is removed on an evaporator. The rest is distilled under vacuum to obtain ethyl β-(p-methoxyphenyl)-β-hydroxy-α-methylpropionate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH:21]=[CH2:22])=[CH:18][CH:19]=2)[CH2:14][O:13]1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH2:21][CH2:22][N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)=[CH:18][CH:19]=2)[CH2:14][O:13]1
Reactant: C=Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Product: CN1CCN(CCc2ccc3c(n2)COC3=C2C(=O)Nc3ccc(F)cc32)CC1
Temperature: 100 °C
Yield: 101.4 %

Procedure:
Following the method described in Example 19, 5-fluoro-3-(2-vinyl-7H-furo[3,4-b]pyridin-5-ylidene)-1,3-dihydro-indol-2-one (60 mg, 0.20 mmol) and N-methylpiperazine (300 mg, 3.00 mmol) are heated 100° C. for 2 h. The reaction mixture is cooled and treated with triethylamine (10 drops). The reaction mixture is loaded onto silica gel and purified by chromatography (silica gel, gradient elution, 2% MeOH/Chloroform to 20% MeOH/chloroform ) to provide the title compound (80 mg, 100%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:11]2[N:12]=[C:13](Cl)[C:14]3[N:15]([C:17](=[O:24])[N:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:19]=3)[CH:16]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:26]([NH2:29])([CH3:28])[CH3:27]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([C:11]2[N:12]=[C:13]([NH:29][CH:26]([CH3:28])[CH3:27])[C:14]3[N:15]([C:17](=[O:24])[N:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:19]=3)[CH:16]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)C1(c2cn3c(=O)n(C(C)(C)C)nc3c(Cl)n2)CCCC1
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2cn3c(=O)n(C(C)(C)C)nc3c(NC(C)C)n2)CCCC1

Procedure:
A solution of 365 mg of 1-(2-tert-butyl-8-chloro-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-cyclopentanecarboxylic acid ethyl ester and 590 mg of isopropylamine in THF (5.0 mL) was heated at reflux for two h. The solvent was removed and the residue was purified by silica gel chromatography to afford 1-(2-tert-butyl-8-isopropylamino-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-cyclopentanecarboxylic acid ethyl ester as an oil. MS (M+H+)=390.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[C:10]([CH3:12])=[CH2:11].CCN(C(C)C)C(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5](/[CH:11]=[C:10](\[CH3:12])/[C:9]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:7]=1
Reactant: C=C(C)C(=O)OCC
Reactant: Nc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCOC(=O)/C(C)=C/c1ccc(N)nc1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
To a stirred solution of 2-amino-5-bromopyridine (25 g, 140 mmole) in propionitrile (150 mL) was added ethyl methacrylate (50 mL, 400 mmole), DIEA (50 mL, 287 mmole), palladium(II) acetate (1.57 g, 7 mmole), and tri-o-tolylphosphine (4.3 g, 14 mmole). The reaction was purged with argon and heated at reflux for 6 hr, then was cooled to RT and concentrated to dryness under vacuum. The residue was taken up in 80% ethyl acetate/hexanes (100 mL), and the solution was filtered through a pad of silica gel, eluting with 80% ethyl acetate/hexanes (400 mL) until all the product was eluted off. The yellowish filtrate was concentrated under vacuum, and the residue was taken up in a small volume of 1:1 Et2O/petroleum ether. The precipitate which formed was collected and dried under vacuum to give ethyl (E)-3-(6-aminopyridin-3-yl)-2-methylacrylate (10.77 g, 37%) as a pale yellow solid: LCMS (ES) m/e 207.0 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=1.7 Hz, 1H), 7.63 (dd, 1H), 7.48 (s, 1H), 6.75 (d, J=8.8 Hz, 1H), 5.79 (br s, 2H), 4.26 (q, 2H), 2.10 (s, 3H), 1.34 (t, 3H). The filtrate was concentrated to dryness and purified by flash chromatography on silica gel (4:1 ethyl acetate/hexanes) to give additional ethyl (E)-3-(6-aminopyridin-3-yl)-2-methylacrylate (0.87 g, 3%) and ethyl 2-(6-aminopyridin-3-ylmethyl)acrylate (5.77 g, 20%) as a yellow oil: LCMS (ES) m/e 207.0 (M+H)+; 1H NMR (300 MHz, CDCl3) 57.86 (d, J=2.1 Hz, 1H), 7.32 (dd, 1H), 6.53 (d, J=8.5 Hz, 1H), 6.21 (d, J=1.8 Hz, 1H), 5.48 (d, J=1.4 Hz, 1H), 4.17 (q, 2H), 3.47 (s, 2H), 1.27 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][C@@H:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:26].Cl.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][C:35](O)=[O:36].CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:15]1([CH2:14][C@H:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:12][C:11]2[CH:10]=[CH:9][C:8]3[C:7](=[O:26])[CH2:6][CH2:5][CH2:4][C:3]=3[C:2]=2[NH:1][C:35](=[O:36])[CH2:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: O=C(O)Cc1ccccn1
Reactant: Nc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Cc1ccccn1)Nc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a solution of 5-amino-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (100 mg, 0.288 mmol) and 2-pyridylacetic acid HCl (67 mg, 0.386 mmol) in DMF (3 mL) was added EDCI HCl (111 mg, 0.576 mmol, 2 equiv). The yellow solution turned orange overnight. Some of the DMF was removed under reduced pressure. The residue was dissolved in H2O and 1 M NaOH was added until the solution was basic (pH 10). The mixture was extracted thoroughly with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give a bright yellow oil. Purification by chromatography (7% MeOH/CH2Cl2) afforded the title compound as a pale yellow foam (107 mg, 0.229 mmol, 80%). The structure was confirmed by NMR and mass spectrometry. MS m/z 467 (M++H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[I:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]Br.C1CCN2C(=NCCC2)CC1>C1COCC1>[I:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: BrCc1ccccc1I
Reactant: c1nc[nH]n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Ic1ccccc1Cn1cncn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.4 %

Procedure:
To a stirring solution of 1,2,4-triazole (1.02 g, 14.8 mmol) and 2-iodobenzyl bromide (6.05 g, 20.3 mmol) in THF (10 mL) was added a solution of DBU (2.65 g, 17.4 mmol) in THF (2 mL) dropwise over a 1 hour period. The mixture was stirred at ambient temperature for 12 hours after which it was filtered. The filtrate was concentrated in vacuo and the resultant residue was dissolved in ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 50-60% ethyl acetate/isohexane to give the title compound as a white solid (1.45 g). 1H NMR (360 MHz, CDCl3): δ 8.15 (1H, s), 8.00 (1H, s), 7.89 (1H, d, J=7.9 Hz), 7.36 (1H, t, J=7.6 Hz), 7.13 (1H, d, J=7.7 Hz), 7.08-7.04 (1H, m), 5.43 (2H, s).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[C:3]1=[O:23].[CH2:24]([O:26][C:27](=[O:50])[C@H:28](OS(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:25].C(OCC)(=O)C.CCCCCC.Cl>C(OCC)(=O)C.O1CCCC1>[CH2:24]([O:26][C:27]([C@@H:28]([NH:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]([CH3:21])[CH3:22])=[CH:18][CH:19]=2)[C:3]1=[O:23])[CH2:29][CH2:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)=[O:50])[CH3:25]
Reactant: CC(C)c1ccc(CN2C(=O)C(N)CCc3ccccc32)cc1
Reactant: CCOC(=O)[C@@H](CCc1ccccc1)OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CCC1CCCCC1)NC1CCc2ccccc2N(Cc2ccc(C(C)C)cc2)C1=O

Procedure:
Was prepared analogously to Example 1c) starting from 3-(R/S)-amino-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one and (R)-alpha-[[(4-nitrophenyl)sulfonyl]-oxy]-4-phenylbutyric acid ethyl ester (Helv. Chim. Acta 71 (2), 337, 1988). Flash chromatography (eluant: ethyl acetate/hexane: 1:4) yields the two pure diastereoisomeric forms which, after being dissolved in ethyl acetate/tetrahydrofuran, are each converted separately into the corresponding hydrochloride by treatment with 3 equivalents of 1N hydrochloric acid. Rf values of the free bases (eluant ethyl acetate/hexane):
Reaction SMILES: [CH2:1]([C:7]1[N:8]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([C:7]1[N:8]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:33])=[O:32])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1nc2cnc3ccccc3c2n1CCCCN
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CCCCCCc1nc2cnc3ccccc3c2n1CCCCNS(=O)(=O)c1ccccc1
Yield: 43.6 %

Procedure:
Using the general method of Example 233 Part B except that the reaction was run at ambient temperature, 4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine (1.20 g, 3.7 mmol) was reacted with benzenesulfonyl chloride (429 μL, 3.7 mmol) to provide 0.75 g of N-[4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide as a light yellow solid, m.p. 137.0–138.1° C.
Reaction SMILES: C(O[C:6](=[O:19])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[CH:10][CH:9]=1)(C)(C)C.[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:29]=1)C(O)=O.O[CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][C:40]1=[O:44]>>[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([N:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[CH:29]=1)[C:6]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:37][CH2:38][N:39]2[CH2:43][CH2:42][CH2:41][C:40]2=[O:44])=[CH:10][CH:9]=1)=[O:19]
Reactant: O=C1CCCN1CCO
Reactant: O=C(O)c1cc(F)cc(N2CCCCC2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Product: O=C(Nc1ccc(OCCN2CCCC2=O)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from tert-butyl(4-hydroxy-1-naphthyl)carbamate, 3-fluoro-5-piperidin-1-yl-benzoic acid and 1-(2-hydroxyethyl)-pyrrolidin-2-one according to conditions described in general procedure D. A white solid is produced (27 mg). Mp: 161-162° C.; 1H NMR (300 MHz, CDCl3) δ 1.62-1.70(m, 6H), 1.99-2.09(m, 2H), 2.35-2.44(m, 2H), 3.16-3.27(m, 2H), 3.63-3.68(m, 2H), 3.84(d, J=5.1 Hz, 2H), 4.26(d, J=4.8 Hz, 2H), 6.73-6.79(m, 2H), 6.70(d, J=8.4 Hz, 1H), 7.32(s, 1H), 7.49-7.58(m, 2H), 7.68(d, J=8.1 Hz, 1H), 7.84(d, J=7.8 Hz, 1H), 8.03(s, 1H), 8.24-8.27(m, 1H); MS 476 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:35])[C@H:13]([O:14][Si](C)(C)C)[C@@H:12]([O:19][Si](C)(C)C)[C@H:11]([O:24][Si](C)(C)C)[C@@H:10]([CH2:29][O:30][Si](C)(C)C)[O:9]2)=[CH:4][C:3]=1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]([F:48])([F:47])[F:46])=[CH:39][CH:38]=1.[CH3:49]S(O)(=O)=O.C(=O)(O)[O-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:35][CH3:49])[C@H:13]([OH:14])[C@@H:12]([OH:19])[C@H:11]([OH:24])[C@@H:10]([CH2:29][OH:30])[O:9]2)=[CH:4][C:3]=1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]([F:48])([F:47])[F:46])=[CH:39][CH:38]=1
Reactant: C[Si](C)(C)OC[C@H]1O[C@@](O)(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Reactant: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2S,3R,4S,5R,6R)-2-[4-chloro-3-[[4-(2,2,2-trifluoroethoxyl)phenyl]methyl]phenyl]-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-ol 17d (45.0 g, 58.0 mmol) in anhydrous methanol (120 mL) was added methylsulfonic acid (11.3 mL, 174 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate till pH becomes 7 and concentrated in vacuo to remove most of the solvent. The residue was partitioned between water (200 mL) and ethyl acetate (200 mL). The aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by re-crystallization from a toluene/n-hexane mixture (v/v)=1/1 to give the title compound 17e as yellow solid powder (12.5 g, 54.3%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 537.1 [M+HCOO]−.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[F:13][C:14]1[CH:15]=[C:16]([N:21]2[CH2:25][CH2:24][CH2:23][CH:22]2[C:26]2[CH:27]=[C:28]([C:43]([OH:45])=O)[CH:29]=[C:30]3[C:35]=2[O:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][C:31]3=[O:42])[CH:17]=[C:18]([F:20])[CH:19]=1.OC1C=CC=C[N+]=1[O-].[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>C(Cl)Cl>[F:20][C:18]1[CH:17]=[C:16]([N:21]2[CH2:25][CH2:24][CH2:23][CH:22]2[C:26]2[CH:27]=[C:28]([C:43]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[O:45])[CH:29]=[C:30]3[C:35]=2[O:34][C:33]([N:36]2[CH2:37][CH2:38][O:39][CH2:40][CH2:41]2)=[CH:32][C:31]3=[O:42])[CH:15]=[C:14]([F:13])[CH:19]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: ClCCl
Product: O=C(c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCOCC1
Reaction time: 4 h
Yield: 58.1 %

Procedure:
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (71.4 mg, 0.37 mmol) was added portionwise to a stirred solution of 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (85 mg, 0.19 mmol), 2-hydroxypyridine 1-oxide (41.4 mg, 0.37 mmol) and morpholine (0.033 mL, 0.37 mmol) at room temperature under nitrogen and stirred for 4 h. The reaction mixture was diluted with DCM, washed with water, brine, dried over MgSO4 and concentrated. The reaction mixture was purified by preparative HPLC. The fractions were evaporated to dryness, and the residue was dissolved in DCM, dried over MgSO4 and concentrated. The remaining solid was triturated with diethyl ether, filtered, washed with diethyl ether and dried under vacuum at 50° C. to afford 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-6-(morpholine-4-carbonyl)-2-morpholino-4H-chromen-4-one (58.0 mg, 59.3%) as a pale beige solid.
Reaction SMILES: CC1[N:3]([C:8]2[CH:18]=[C:11]3[CH:12]([CH3:17])[N:13]([CH3:16])[CH2:14][CH2:15][N:10]3[N:9]=2)C(C)=CC=1.NO.Cl>C(O)C>[CH3:17][CH:12]1[N:13]([CH3:16])[CH2:14][CH2:15][N:10]2[N:9]=[C:8]([NH2:3])[CH:18]=[C:11]12
Reactant: Cc1ccc(C)n1-c1cc2n(n1)CCN(C)C2C
Agent: Cl
Agent: NO
Solvent: CCO
Product: CC1c2cc(N)nn2CCN1C
Temperature: 25 °C
Yield: 18.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a reflux condenser was charged with 287h (1.63 g, 1.0 eq., 6.70 mmol), NH2OH.HCl (2.33 g, 5.0 eq., 33.5 mmol), and ethanol (50 mL). The mixture was refluxed for 2 days. It was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 287i as a yellow solid (211 mg, 19%). MS-ESI: [M+H] 167.1. 1H NMR (500 MHz, CDCl3) δ 5.36 (s, 1H), 4.04-4.00 (m, 1H), 3.94-3.92 (m, 1H), 3.61 (bs, 2H), 3.30 (q, J=6.5 Hz, 1H), 3.10-3.08 (m, 1H), 2.81-2.75 (m, 1H), 2.43 (s, 3H), 1.38 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([OH:13])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]1[O:17][CH:15]1[CH3:16]>C(O)C>[CH2:1]([N:8]([CH2:14][CH:15]([OH:17])[CH3:16])[CH2:9][CH:10]([OH:13])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CO1
Reactant: CCC(O)CNCc1ccccc1
Solvent: CCO
Product: CCC(O)CN(Cc1ccccc1)CC(C)O
Temperature: 150 °C

Procedure:
To a solution of 1-benzylamino-butan-2-ol (Intermediate 482, 8.5 g, 47.48 mmol) in ethanol (150 mL) was added propylene oxide (8.8 g, 151 mmole) and the mixture was heated at 150° C. for 2 h in autoclave. After concentration of the mixture under reduced pressure, the residue was purified by column chromatography using methanol in dichloromethane to give product as an oil.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2)=[O:4]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CCl)Nc1ccc2[nH]ncc2c1
Yield: 24.2 %

Procedure:
Chloroacetyl chloride (3.14 ml, 39.4 mmol) was added to a solution of 5-aminoindazole (5.0 g, 37.5 mmol) in tetrahydrofuran (100 ml) at room temperature, followed by adding thereto a solution of triethylamine (5.76 ml, 41.3 mmol) in tetrahydrofuran (30 ml) at 0° C., and the resulting mixture was stirred at 0° C. for 30 minutes. Subsequently, a saturated aqueous sodium carbonate solution and then water were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was suspended in ethanol and stirred, followed by filtration. To a solution of the solid collected by the filtration and dissolved in a mixture of tetrahydrofuran (25 ml) and methanol (25 ml) was added a 2N-aqueous lithium hydroxide solution (9.3 ml) at 0° C., and stirred at room temperature for 30 minutes. Then, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2-chloro-N-(1H-indazol-5-yl)acetamide (1.90 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]1([CH2:16][C:17]([OH:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OC(=O)C)(=O)C>C(N(CC)CC)C>[C:10]1([C:16](=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:17]([OH:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C(O)Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)C(=Cc1ccc(Cl)cc1)c1ccccc1

Procedure:
A mixture of 56.2 g 4-chlorobenzaldehyde, 54.4 g phenylacetic acid, 80 ml acetic anhydride and 40 ml triethylamine was refluxed for 5 hours. Unreacted 4-chlorobenzaldehyde was removed by steam distillation and the residue dissolved in aqueous alcohol and treated with decolourising carbon. Crystals of α-phenyl-4-chlorocinnamic acid were obtained on acidification of the solution. The product was recrystallised from alcohol and found to have a melting point of 202°-4° C. The chlorosulphonyl derivative was prepared according to the method described in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]2=[N:8][C:9]([C:11]3[O:12][C:13]4[C:14](=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=4)[CH:15]=3)=[CH:10][N:5]2[N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]1([C:46]2[S:47][CH:48]=[C:49]([CH2:51]O)[N:50]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][O:2][C:3]1[S:7][C:6]2=[N:8][C:9]([C:11]3[O:12][C:13]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:51][C:49]5[N:50]=[C:46]([C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)[S:47][CH:48]=5)[C:14]=4[CH:15]=3)=[CH:10][N:5]2[N:4]=1
Reactant: COc1nn2cc(-c3cc4c(O)cccc4o3)nc2s1
Reactant: OCc1csc(-c2ccccc2)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1nn2cc(-c3cc4c(OCc5csc(-c6ccccc6)n5)cccc4o3)nc2s1
Temperature: 2 °C
Reaction time: 4 h
Yield: 17.4 %

Procedure:
A mixture of 2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 38G, 0.100 g, 0.349 mmol), triphenylphosphine (0.165 g, 0.627 mmol) and (2-phenylthiazol-4-yl)methanol (Example 3B, 0.080 g, 0.418 mmol) in a 50 ml flask was maintained under vacuum for 10 min and then purged with nitrogen. Dry tetrahydrofuran (10 mL) was added and the resulting mixture was slightly warmed and maintained in an ultrasonic bath for 5 min. The cooled mixture (still heterogeneous) was treated at 22° C. with a solution of diisopropyl azodicarboxylate (0.113 g, 0.558 mmol) in tetrahydrofuran (2 mL) added dropwise over 1 h. The mixture was then stirred at 2° C. for 4 h. The clear reaction mixture was quenched by the addition of dichloromethane (100 mL) and saturated sodium bicarbonate (10 mL). The organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Chromatography of the residue on silica gel (2.5×12 cm, elution dichloromethane-ethyl acetate 0-3%) followed by crystallization of the desired fraction from ethyl acetate (8 mL) gave 0.028 g (24% yield) of the title material as a white solid. LC (Method A): 2.426 min. HRMS (ESI) calcd for C23H17N4O3S2 [M+H]+ m/z 461.0737. found 461.0926. 1H NMR (CDCl3, 400 MHz) δ ppm: 4.22 (s, 3H), 5.45 (d, J=0.78 Hz, 2H), 6.80 (dd, J=7.04, 1.57 Hz, 1H), 7.15-7.21 (m, 2H), 7.22 (s, 1H), 7.38 (s, 1H), 7.42-7.51 (m, 3H), 7.92 (s, 1H), 7.95-8.03 (m, 2H).
Reaction SMILES: CN(C=O)C.[C:6](Cl)(=O)[C:7]([Cl:9])=[O:8].[CH3:12][O:13][C:14]([C:16]1[C:25]2[C:20](=[CH:21][C:22](CC(O)=O)=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)=[O:15]>C(Cl)Cl>[CH3:12][O:13][C:14]([C:16]1[C:25]2[C:20](=[CH:21][C:22]([CH2:6][C:7]([Cl:9])=[O:8])=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1cccc2cc(CC(=O)O)ccc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cccc2cc(CC(=O)Cl)ccc12
Temperature: 0 °C

Procedure:
140 μl (1.8 mMol) DMF are added to an ice-cooled solution of 3.6 ml (43 mMol) oxalylchloride in 150 CH2Cl2. Then a suspension of 8.8 g (36 mMol) 6-carboxymethyl-naphthalene-1-carboxylic acid methyl ester in 400 ml CH2Cl2 is added during 1 h. After 1.5 h stirring in the ice-bath, the reaction mixture is concentrated in vacuo, yielding the title compound.