Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:17])=[O:5])C.Cl.[CH:19]([CH2:22][C:23]([NH2:25])=N)(C)C.[CH2:26](O)C>>[CH:22]([C:23]1[NH:25][C:4](=[O:5])[C:6]2[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][S:8][C:7]=2[N:17]=1)([CH3:19])[CH3:26]
Reactant: CC(C)CC(=N)N
Reactant: CCO
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Agent: Cl
Product: CC(C)c1nc2scc(-c3ccccc3)c2c(=O)[nH]1
Temperature: 25 °C

Procedure:
A stirred mixture of 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ester (350.43 g, 1.54 mol), isopropylacetamidine hydrochloride (958.75 g, 7.7 mol) and ethanol (1500 ml) was heated under reflux for 18 hours then allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with a little cold ethanol, then crystallised from ethanol to give 2-Isopropyl-5-phenyl-3H-thieno[2,3-d]pyrimidin-4-one as a yellow solid which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1)[CH3:9].O.[OH-].[Li+].O.CO>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH3:9]
Reactant: COC(=O)c1ccc(C(C)Oc2ccccn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(Oc1ccccn1)c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
A mixture of methyl 4-(1-(pyridin-2-yloxy)ethyl)benzoate (590 mg, 2.3 mmol), lithium hydroxide monohydrate (482 mg, 11.5 mmol), water (4 mL) and methanol (4 mL) in tetrahydrofuran (12 mL) was stirred at 20° C. for 5 hours. The reaction mixture was concentrated. The residue was acidified to pH=2 with concentrated hydrochloride solution. The mixture was extracted with ethyl acetate (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give 4-(1-(pyridin-2-yloxy)ethyl)benzoic acid as a white solid (520 mg, 93%). LRMS (M+H+) m/z: 243.09. found 243.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:13][N:12]=[C:11]([CH3:14])[CH:10]=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2[O:24][CH2:25][CH2:26][N:27]=2)[CH:19]=[CH:20][C:21]=1[OH:22].CC1ON=C(CCC(OC)=O)C=1>>[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2[O:24][CH2:25][CH2:26][N:27]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:13][N:12]=[C:11]([CH3:14])[CH:10]=1
Reactant: Cc1cc(CCCCCCCBr)on1
Reactant: Oc1ccc(C2=NCCO2)cc1Cl
Agent: COC(=O)CCc1cc(C)on1
Product: Cc1cc(CCCCCCCOc2ccc(C3=NCCO3)cc2Cl)on1

Procedure:
5-{7-[2-Chloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole [IX; R=CH3, R2, R3, R4, R5 and R6 =H, R1 =2-Cl, Y=(CH2)7, oxazole at 4-position] was prepared from 5-(7-bromoheptyl)-3-methylisoxazole (Example 9, part c) and 4,5-dihydro-2-(3-chloro-4-hydroxyphenyl)oxazole according to the procedure of Example 9, part (d), and was obtained in the form of a colorless solid, m.p. 120°-120.5° C. when recrystallized from methanol and further purified by chromatography.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[C:17](=[O:18])[C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:32]5[NH:36][C:35](=[O:37])[O:34][N:33]=5)=[CH:22][CH:21]=4)=[C:15]([CH2:38][CH2:39][CH3:40])[N:14]=[C:13]3[CH3:41])[CH:10]=2)[O:5][C:4]([CH3:43])([CH3:42])[CH2:3]1.Cl>C(#N)C.C(OCC)(=O)C>[CH3:42][C:4]1([CH3:43])[CH2:3][CH:2]([NH:12][C:17](=[O:18])[CH3:16])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[C:17](=[O:18])[C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:32]5[NH:36][C:35](=[O:37])[O:34][N:33]=5)=[CH:22][CH:21]=4)=[C:15]([CH2:38][CH2:39][CH3:40])[N:14]=[C:13]3[CH3:41])[CH:10]=2)[O:5]1
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)C(O)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc3c(c2)C(NC(C)=O)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 153.1 %

Procedure:
3-(4-Hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (1.0 g) was dissolved in acetonitrile (10 mL), and concentrated hydrochloric acid (1.0 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.82 g, 76%) as a colorless solid.
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:40])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:18]([O:29][CH2:30][CH2:31][OH:32])=[C:17]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[F:39])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CO.CC[O:45]C(C)=O.CCOC(C)=O.[K+].[Br-]>C(O)=O>[CH2:1]([NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[F:39])[C:18]([O:29][CH2:30][C:31]([OH:45])=[O:32])=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[CH:20]=1)=[O:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(C)=O
Reactant: CCCCCCCCCCCCNC(=O)c1cc(-c2ccc(OC)cc2)c(OCCO)c(-c2ccccc2F)c1
Agent: [Br-]
Agent: [K+]
Solvent: O=CO
Solvent: CO
Product: CCCCCCCCCCCCNC(=O)c1cc(-c2ccc(OC)cc2)c(OCC(=O)O)c(-c2ccccc2F)c1

Procedure:
The tide compound was prepared as a white solid (0.229 g, 47%) from N-dodecyl-3-(2-fluorophenyl) 5-(4-methoxyphenyl)4-(2-hydroxyethoxy)benzamide using a procedure similar to step 3 of example 1. The product was purifed by preparatory plate chromatography (4% Methanol/EtOAc) followed by flash chromatography (15% EtOAc/Hex and 20% EtOAC/Hex, both with 1% formic acid); 1H NMR (400 MHz, DMSO-d6) δ0.84 (t, J=6.8 Hz, 3H), 1.17-1.27 (m, 18H), 1.44-1.51 (m, 2H), 3.22 (dd, J=6.8, 13.0 Hz, 2H), 3.78 (s, 3H), 3.81 (s, 2H), 6.99-7.02 (m, 2H), 7.23-7.28 (m, 2H), 7.42-7.47 (m, 2H), 7.50-7.57 (m, 2H), 7.71 (d, J=2.2 Hz, 1H), 7.84 (d, J=2.4 Hz, 1H), 8.47 (t, J=5.5, 1H), 12.48 (broad s, 1H); IR (KBr) 3375, 2925, 2850, 1730, 1615, 1200 cm−1; mass spectrum [(+)ESI], m/z 564 (M+H)+; Anal. Calcd. for C34H42FNO5: C, 72.44; H, 7.51; N, 2.48, Found: C, 72.48; H, 7.67; N, 2.46.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1>N1C=CC=CC=1>[F:21][C:18]([F:19])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:13][CH:14]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(F)(F)F)cn1)Oc1ccccc1
Temperature: 21 °C
Reaction time: 0.5 h

Procedure:
Phenyl chloroformate (1.92 g, 12.3 mmol) was added to a stirring solution of 2-amino-5-trifluoromethylpyridine (2.0 g, 12.3 mmol) in pyridine (20 mL) at a rate which maintained the temperature at 21° C. The mixture was stirred for an additional 0.5 hr and the resulting precipitate was collected by filtration, extracted with ether, then dried to obtain 2.33 g (67 percent of theory) of the title compound as white crystals melting at 203° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CC([O-])(C)C.[Na+].O(CCCC)CCCC>>[CH2:10]([NH:16][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCN
Reactant: COc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: CCCCCCNc1ccc(OC)cc1
Temperature: 85 °C
Yield: 88.2 %

Procedure:
Following general procedure D, a mixture of 4-chloroanisole (1.23 mL, 10 mmol), hexylamine (1.83 mL, 14 mmol), NaOt-Bu (1.15 g, 12 mmol), 10 (4 mg, 0.05 mol %), 1 (2.5 mg, 0.05 mol %), and Bu2O (3 mL) was heated to 85° C. for 1 h. The crude product was purified via the Biotage SP4 (silica-packed 100 g; 0-50% EtOAc/hexanes) to provide the title compound as a yellow oil (1.828 g, 88%). 1H NMR (300 MHz, CDCl3) δ: 6.84 (d, J=9.0 Hz, 2H), 6.62 (d, J=9.0 Hz, 2H), 3.78 (s, 3H), 3.40 (s, 1H), 3.09 (t, J=7.0 Hz, 2H), 1.64 (pentet, J=7.5 Hz, 2H), 1.42 (m, 6H), 0.97 (t, J=7.0 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 152.2, 143.2, 115.1, 114.2, 56.0, 45.3, 32.0, 30.0, 27.2, 23.0, 14.4 ppm. IR (neat, cm−1): 3394, 2929, 2857, 2831, 1513, 1466, 1237, 1180, 1040, 819, 520.
Reaction SMILES: [CH2:1]([CH:4]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH3:17])=[O:9])[C:5]([O-])=[O:6])[CH:2]=[CH2:3].[BH4-].[Li+].O.Cl>O1CCCC1>[CH2:1]([CH:4]([CH2:5][OH:6])[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH3:17])[OH:9])[CH:2]=[CH2:3]
Reactant: C=CCC(C(=O)[O-])C(=O)c1ccccc1CC
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC(CO)C(O)c1ccccc1CC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-allyl-3-(2-ethylphenyl)-3-oxopropionate (7.3 g.) in dry tetrahydrofuran (THF) (40 ml.) was added during 10 minutes to a stirred suspension of lithium borohydride (1.32 g.) in dry THF (40 ml.) at 0° C. under a nitrogen atmosphere. The mixture was then stirred at room temperature for 18 hours, cooled to 0°-5° C. and water (40 ml.) added. The aqueous mixture was acidified to pH 2 (concentrated hydrochloric acid) and extracted with ethyl acetate (3×120 ml.). The combined extracts were washed with saturated brine, dried (MgSO4) and evaporated. The residual oil (6.1 g.) was purified by chromatography on silica (180 g.) using 3:7 v/v ethyl acetate/petroleum ether (b.p.60°-80° C.) to give 2-allyl-1-(2-ethylphenyl)propane-1,3-diol (containing approximately 4:1 erythro- to threo-forms) as an oil (4.0 g.); NMR: 1.19 (3H,m), 2.04 (5H,m), 2.59 (2H,m), 3.76 (2H,m), 5.02 (3H,m), 5.67 (1H,m), 7.17 (3H,m), and 7.47 (1H,m)ppm.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[CH2:29]([N:36]1[CH2:41][CH2:40][N:39]([C:42](=[O:52])[CH2:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[OH:51])[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:8]([NH:26][C:27](=[O:28])[O:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[CH2:44][CH2:43][C:42]([N:39]1[CH2:40][CH2:41][N:36]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:37][CH2:38]1)=[O:52])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(CCc1ccccc1O)N1CCN(Cc2ccccc2)CC1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)Oc1ccccc1CCC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Triethylamine (0.84 ml) and octadecyl isocyanate (1.88 ml) were added to a solution containing 1-(4-benzylpiperazino)-3-(2-hydroxyphenyl)-1-propanone (1.76 g) in methylene chloride (18 ml) and stirred for 17 hours at room temperature. The insoluble matters were filtrated out and washed with chloroform. The filtrate and washings were combined and the mixture was washed with saturated sodium hydrogencarbonate aqueous solution and brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 75 g, chloroform:methanol=60:1), thereby yielding the entitled compound (2.32 g) as white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:14])[CH2:12][NH2:13])=[CH:7][CH:6]=1.CCN=C=NCCCN(C)C.Cl.[C:28]([N:35]([CH3:41])[C@H:36]([C:38](O)=[O:39])[CH3:37])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:15])[C:5]1[CH:6]=[CH:7][C:8]([C:11](=[O:14])[CH2:12][NH:13][C:38](=[O:39])[C@@H:36]([N:35]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH3:41])[CH3:37])=[CH:9][CH:10]=1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(C(=O)CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)CNC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)cc1
Reaction time: 2 h
Yield: 73.8 %

Procedure:
4-(2-Amino-acetyl)-benzoic acid methyl ester hydrochloride (2.22 mmol), WSC.HCl (2.44 mmol), Boc-N-methyl-(L)-alanine (2.44 mmol) and HOBt (2.77 mmol) were suspended in dichloromethane (10 ml). NMM (2.44 mmol) was added and the reaction stirred for 2 h. The reaction was diluted with ethyl acetate (50 ml) and washed with 10% citric acid (2×25 ml) and saturated sodium hydrogen carbonate (2×25 ml). The organic layer was dried (MgSO4) and the solvent removed in vacuo to give a brown oil residue. Purification by silica chromatography eluting with 10-50% ethyl acetate/iso-hexane gave the title compound (620 mg) as a pale yellow oil m/z=379 in MS ES+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[F:18][C:19]([F:24])([F:23])[C:20](O)=[O:21].Cl>O1CCCC1.C(N(CC)CC)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:20](=[O:21])[C:19]([F:24])([F:23])[F:18])=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)CCc1cc(N)ccc1O
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1cc(NC(=O)C(F)(F)F)ccc1O
Reaction time: 2 h

Procedure:
t-Butyl 3-(1-hydroxy-4-aminobenzen-2-yl)propionate was dissolved in a mixture of tetrahydrofuran (100 ml) and triethylamine (7.1 ml). Anhydrous trifluoroacetic acid (6.0 ml) was added to the solution at 0° C. in an atmosphere of argon gas. The solution was stirred for 2 hr. at 0° C. The reaction solution was poured into a mixture of ice and 1N hydrochloric acid (100 ml). The reaction mixture was extracted with ethyl acetate (300 ml). The extract was washed with water, saturated aqueous solution of sodium bicarbonate, followed by brine, dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from a mixture of ethyl acetate-n-hexane (1:5) to give the title compound having the following physical data.
Reaction SMILES: [CH3:1][C@@H:2]1O[C@@H:5]([O:7][C@H:8]2[C@H:13]([OH:14])[C@@H:12](O)[C@H:11](NC(N)=N)[C@@H:10](O)[C@@H:9]2NC(N)=N)[C@H:4]([O:25][C@@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2NC)[C@@:3]1(O)C=O.C[C:42]1(C)S[C@@H:45]2[C@H:47](NC(CC3C=CC=CC=3)=O)[C:48](=O)[N:44]2[C@H:43]1C([O-])=O.[K+].[C:65](=O)=O>>[CH:2]1[C:1]2[CH2:42][C@H:43]3[N:44]([CH2:45][CH2:47][C@@:9]45[C@H:10]3[CH:11]=[CH:12][C@H:13]([OH:14])[C@@H:8]4[O:7][C:5]([C:65]=25)=[C:4]([OH:25])[CH:3]=1)[CH3:48]
Reactant: O=C=O
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: [K+]
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Temperature: 37 °C

Procedure:
Human neuroblastoma SH-SY5Y cells were maintained as a monolayer culture in Dulbecco's modified eagle medium (DMEM) supplemented with 10% fetal calf serum, 100 μg/ml streptomycin and 100 units/ml penicillin in 5% carbon dioxide, incubator maintained at 37° C. (Wang et al., 2000). Cells were plated into flasks a week before experiments Treatments were terminated at the designated times by replacing the medium with ice-cold phosphate buffered saline (PBS) on ice and subsequently rinsed with PBS three times. Cells then were used for cAMP assay or harvested as described in Section C10
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[O-:18][C:19]#[N:20].[Na+].C(O)(=O)/C=C\C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:19]([NH2:20])=[O:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Reactant: N#C[O-]
Agent: O=C(O)/C=C\C(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: COC1=Cc2ccccc2N(C(N)=O)c2ccccc21
Reaction time: 24 h

Procedure:
50.0 g (0.224 moles) of 10-methoxyiminostilbene was dissolved in 750.0 ml of dichloromethane. 185.0 g (2.846 moles) of sodium cyanate and 75.0 g (0.65 moles) of maleic acid were added to the above solution at a temperature ranging from about 25° C. to about 30° C. The reaction mass was stirred for about 24 hours. After completion of the reaction (determined by HPLC/TLC) the reaction mass was filtered and washed three times with 100 mL of dichloromethane. The dichloromethane layer was evaporated to get a residue of about 150 g to about 200 g.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[OH:12][NH2:13].C([O-])([O-])=O.[K+].[K+]>CCO.CO>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N:13][OH:12]
Reactant: NO
Reactant: O=Cc1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CO
Product: ON=Cc1ccc(F)cc1F
Yield: 94.6 %

Procedure:
(Scheme 1, Compound C) To a mixture of 2,4-difluorobenzaldehyde (0.80 g, 5.6 mmol) and hydroxyamine HCl salt (0.43 g, 6.2 mmol) in EtOH (5 mL) was added K2CO3 (0.85 g, 6.2 mmol). The resultant mixture was stirred at rt for 24 hours. The mixture was diluted with MeOH (20 mL). The precipitates were filter off and washed with MeOH. The product from filtrate was purified by recrystalization (EtOAc/Hexanes). This compound was obtained as a white solid (0.84 g, 5.3 mmol, 94% yield). 1H NMR (DMSO-d6) δ 12.98 (br. s, 1H), 8.17 (s, 1H), 7.79 (m, 1H), 7.32 (m, 1H), 7.11 (m, 1H); Analytical HPLC 1.03 min. (95%); Mass Spec.: 158.06 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[CH:8]=[N:7][CH:6]=1.CC(C)([O-])C.[K+].C(O)(=O)C>O1CCCC1.CC(C)=O.Cl>[ClH:1].[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH:10]2[N:9]3[CH:8]=[N:7][CH:6]=[C:5]3[CH2:4][CH2:3][CH2:2]2)=[CH:12][CH:13]=1)#[N:18]
Reactant: N#Cc1ccc(Cn2cncc2CCCCl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1ccc(C2CCCc3cncn32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 8.1 g of 5-(3-chloropropyl)-1-(p-cyanophenylmethyl)-1H-imidazole in 50 ml of tetrahydrofuran is cooled to 0°. To this is added 7.0 g of potassium t-butoxide as a solid in portions. The mixture is stirred at room temperature for 2 h, neutralized with 10% acetic acid and partitioned between methylene chloride and water. The organic layer is washed with water, dried over magnesium sulfate and evaporated to yield an oil which is dissolved in a small volume of acetone and neutralized with ethereal hydrogen chloride. On cooling, the title compound is obtained as a white solid, m.p. 201°-203°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[C:7]([C:14](=[O:34])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][CH:16]=3)[C:6]=2[CH:35]=1.[CH3:36][S:37]([Cl:40])(=[O:39])=[O:38]>CC(C)=O>[CH3:13][CH2:12][CH2:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:35][C:6]=2[C:7]=1[C:14]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:17][CH:16]=1)=[O:34].[ClH:40]
Reactant: CCCCc1oc2ccc(N)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CC(C)=O
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Product: Cl
Temperature: 7.5 °C

Procedure:
Under a temperature range from room temperature to reflux temperature, preferably reflux temperature, 5-amino-2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)benzofuran is reacted with methanesulfonyl chloride in acetone solvent to provide a crude dronedarone hydrochloride, wherein an amount of acetone used is in the range of 0 to 15 parts by volume, preferably 4 to 10 parts by volume, more preferably 5 to 8 parts by volume based on 1 part by weight of the compound A, and an amount of methanesulfonyl chloride used is in the range of 1 to 5 equivalents, and preferably 1.5 to 3.5 equivalents, and more preferably 2 to 2.5 equivalents relative to the compound A to obtain a reaction mixture. When the reaction is terminated, the reaction mixture is cooled to −30 to 55° C., preferably −15 to 40° C., more preferably −10 to 25° C. to obtain crude dronedarone hydrochloride. Then the crude dronedarone hydrochloride can be purified to obtain highly pure dronedarone hydrochloride. If desired, the obtained dronedarone hydrochloride can be converted to highly pure dronedarone via alkaline solvent, or further converted to other pharmaceutically acceptable salts of dronedarone.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[CH2:11]=[O:12]>>[OH:12][CH2:11][C:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: Cn1cnc2ccccc21
Reactant: C=O
Product: Cn1c(CO)nc2ccccc21
Reaction time: 2 h
Yield: 43.5 %

Procedure:
A solution of 1-methylbenzimidazole (2.5 g, 19 mmol), (J. Chem. Soc. 1929, 2820-2828), and paraformaldehyde (2 g) was heated at 60° C. for 30 minutes. Further paraformaldehyde (1 g) was added and heating continued for 2 hours. The mixture was allowed to cool and was purified by column chromatography eluting with methylene chloride, followed by methylene chloride/methanol (95/5) to give 2-hydroxymethyl-1-methylbenzimidazole (1.34 g, 45%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:7](=[O:17])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:4].[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19].C(N(CC)CC)C>C(#N)C>[ClH:1].[CH2:18]([N:20]([CH2:21][CH3:22])[CH2:2][C:3]([NH:5][C:6]1[C:7](=[O:17])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:4])[CH3:19]
Reactant: Cc1cccc2cc(NC(=O)CCl)c(=O)[nH]c12
Reactant: CCNCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN(CC)CC(=O)Nc1cc2cccc(C)c2[nH]c1=O
Product: Cl
Temperature: 0 °C
Yield: 57.5 %

Procedure:
A suspension prepared by mixing 0.7 g of 3-chloroacetylamino-8-methylcarbostyril, 2.04 g of diethylamine, 1.16 ml of triethylamine in 30 ml of acetonitrile was refluxed by heating for 7.5 hours. The reaction mixture was poured in an ice-water, and the precipitate was collected by filtration, washed with water, and dried. Then the dried precipitate was dissolved in methanol, and converted into hydrochloride by using a concentrated hydrochloric acid-ethanol. Recrystallized from ethanol-water to obtain 0.52 g of 3-(2-diethylaminoacetyl)amino-8-methylcarbostyril hydrochloride. Light yellow powdery substance. Melting point: 250°-252° C. (decomposed).