Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([F:31])[CH:25]=4)[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:41]1([NH2:44])[CH2:43][CH2:42]1.O.CN(C)[CH:48]=[O:49]>N1C=CC=CC=1.C(Cl)(=O)OC1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([NH:30][C:48]([NH:44][CH:41]5[CH2:43][CH2:42]5)=[O:49])=[C:26]([F:31])[CH:25]=4)[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc(N)c(F)c3)ncnc21
Reactant: NC1CC1
Agent: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc(NC(=O)NC4CC4)c(F)c3)ncnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
After dissolving 261 mg of 4-[6-(4-benzyloxyphenyl)-7-(trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-fluorophenylamine in 3 ml of dimethylformamide, 0.053 ml of pyridine and 0.082 ml of phenyl chlorocarbonate were added, the mixture was stirred at room temperature for 2 hours, 0.081 ml of cyclopropylamine was added and the mixture was further stirred overnight. Water was added, liquid separation and extraction were performed with ethyl acetate, and the organic layer was washed with saturated saline, dried over sodium sulfate, concentrated and subjected to silica gel column chromatography (hexane-ethyl acetate) to obtain 265 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[N:18]=[C:17]([CH3:20])[CH:16]=[C:15]3[N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)=[C:6]([Cl:26])[CH:5]=[CH:4][C:3]=1[N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]=O.Cl.[NH2:35][OH:36].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[N:18]=[C:17]([CH3:20])[CH:16]=[C:15]3[N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)=[C:6]([Cl:26])[CH:5]=[CH:4][C:3]=1[N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1/[CH:32]=[N:35]/[OH:36].[Cl:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[N:18]=[C:17]([CH3:20])[CH:16]=[C:15]3[N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)=[C:6]([Cl:26])[CH:5]=[CH:4][C:3]=1[N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1/[CH:32]=[N:35]\[OH:36]
Reactant: NO
Reactant: Cc1cc(-n2cccn2)c2cccc(OCc3c(Cl)ccc(-n4cccc4C=O)c3Cl)c2n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(-n2cccn2)c2cccc(OCc3c(Cl)ccc(-n4cccc4/C=N/O)c3Cl)c2n1
Product: Cc1cc(-n2cccn2)c2cccc(OCc3c(Cl)ccc(-n4cccc4/C=N\O)c3Cl)c2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 1-[2,4-dichloro-3-[2-methyl-4-(pyrazol-1-yl)quinolin-8-yloxymethyl]phenyl]-2-formylpyrrole (80 mg), hydroxylamine hydrochloride (18 mg), sodium acetate (21 mg) and ethanol (60% solution in water, 1.5 ml) was stirred at 60° C. for 1 hour. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (n-hexane:ethyl acetate=1:1, V/V) to give 1-[2,4-dichloro-3-[2-methyl-4-(pyrazol-1-yl)quinolin-8-yloxymethyl]phenyl]-2-((E)-hydroxyiminomethyl)pyrrole (45 mg) as an amorphous powder and 1-[2,4-dichloro-3-[2-methyl-4-(pyrazol-1-yl)quinolin-8-yloxymethyl]phenyl]-2-((Z)-hydroxyiminomethyl)pyrrole (14 mg) as an amorphous powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])[NH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:19][O-].[Na+].Cl>>[CH2:1]([O:8][C:9]1[C:10](=[O:16])[C:11]([Cl:19])=[C:12]([CH3:15])[NH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c[nH]1
Reactant: [O-]Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1[nH]cc(OCc2ccccc2)c(=O)c1Cl
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of 5-(benzyloxy)-2-methylpyridin-4(1H)-one (9.00 g, 41.8 mmol) in 2M sodium hydroxide (62.5 mL, 125 mmol) under ice-water bath, a solution of 10-14% sodium hypochlorite (62.5 mL) was added slowly during 20 minutes. The reaction mixture was stirred at room temperature for another hour. The reaction mixture was carefully neutralized with 6N HCl to pH about 7 with external cooling to keep the internal temperature below 25° C. The solid was filtered and washed with water (3×), then dried in a vacuum oven for overnight. Thus, 5-(benzyloxy)-3-chloro-2-methylpyridin-4(1H)-one (9.03 g) was obtained as a white solid. Yield=86%; 1H NMR (DMSO-D6, 90 MHz) δ (ppm): 11.74 (br. s, 1H), 7.14-7.68 (m, 6H), 5.02 (s, 2H) and 2.33 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][CH:17]=3)[CH2:12][CH2:11][C:10]2=[O:26])=[CH:5][CH:4]=1.C(N(CC)CC)C.C(O[C:37]1(O[Si](C)(C)C)[CH2:39][CH2:38]1)C.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH:37]1([N:23]2[CH2:22][CH2:21][CH:20]([O:19][C:15]3[CH:14]=[C:13]4[C:18](=[CH:17][CH:16]=3)[N:9]([C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=3)[C:10](=[O:26])[CH2:11][CH2:12]4)[CH2:25][CH2:24]2)[CH2:39][CH2:38]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: O=C1CCc2cc(OC3CCNCC3)ccc2N1c1ccc(F)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC(=O)O
Product: O=C1CCc2cc(OC3CCN(C4CC4)CC3)ccc2N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
A suspension of 1-(4-fluorophenyl)-6-(piperidin-4-yloxy)-3,4-dihydroquinolin-2(1H)-one hydrochloride prepared in Example 7-(3) (0.30 g), triethylamine (0.080 g), [(1-ethoxycyclopropyl)-oxy]trimethylsilane (0.69 g), acetic acid (0.48 g) and molecular sieves 3A (1.0 g) in methanol (10 mL) was stirred at room temperature for 1 hour, followed by addition of sodium cyanoborohydride (0.25 g) and stirring at the same temperature for 16 hours. The reaction mixture was warmed to 95° C., heated under reflux for 7 hours, and then cooled to room temperature, followed by filtration to remove insoluble materials. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform→chloroform/methanol=4/1) and preparative TLC (on a single plate of 2 mm thickness, developing solvent: chloroform/methanol=9/1) to give the titled compound (0.11 g, 37%) as a colorless amorphous substance.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Br[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][C:44]([CH3:49])([CH3:48])[CH2:43]1)=O>>[CH3:48][C:44]1([CH3:49])[CH2:45][CH2:46][CH2:47][N:42]([CH2:40][CH2:39][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[C@@H:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:43]1
Reactant: CC1(C)CCCN(C(=O)CBr)C1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCCC(C)(C)C3)cc2)c1
Yield: 92.4 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-bromo-1-(3,3-dimethylpiperidin-1-yl)ethanone (19 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (10 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH2:35][C:36]([O:38]C)=[O:37])=[O:33])=[CH:4][N:3]=1.[OH-].[Na+].O.Cl>O1CCOCC1>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:33])=[CH:4][N:3]=1
Reactant: COC(=O)CNC(=O)c1cnc(N)c2c(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)csc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2csc3c(C(=O)NCC(=O)O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 50 °C
Yield: 50.6 %

Procedure:
To a mixture of methyl ({[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)thieno[3,2-c]pyridin-7-yl]carbonyl}amino)acetate (0.130 g, 0.239 mmol) in 1,4 dioxane (10 mL) was added 2M sodium hydroxide in water (0.260 mL, 0.521 mmol). The resulting solution was heated at 50° C. for 3 hours. 1M hydrochloric acid was added until pH of the mixture was 4 and solvent was removed under reduced pressure. The resulting white solid was washed with water (2 mL) and filtered and dried to furnish the title compound (64 mg, 0.121 mmol): LCMS (Conditions b): MH+=530 RT=2.03 min; 1H NMR (DMSO-d6, 400 MHz) δ 12.65 (1 H), 9.50 (1 H), 8.95 (1 H), 8.60 (1 H), 8.02 (1 H), 7.71 (2 H), 7.58 (1 H), 7.35 (2 H), 7.21 (1 H), 7.15 (1 H), 7.09 (1 H), 6.29 (2 H), 4.04 (3 H), 3.97 (2 H), 3.92 (3 H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=O)=[CH:23][CH:24]=2)[N:19]=[C:18]([CH3:28])[CH:17]=1.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1.C(O)(=O)C>ClCCCl>[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][NH:29][C:30]3[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=3)=[CH:23][CH:24]=2)[N:19]=[C:18]([CH3:28])[CH:17]=1
Reactant: Cc1cc(Cl)c2ccc(C=O)cc2n1
Reactant: N#Cc1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1cc(Cl)c2ccc(CNc3ccc(C#N)cc3)cc2n1
Yield: 65 %

Procedure:
Sodium triacetoxyborohydride (74 mg, 0.34 mmol) was added to a solution of 4-chloro-2-methyl-quinoline-7-carbaldehyde (example 13a, 50 mg, 0.24 mmol), 4-aminobenzonitrile (29 mg, 0.24 mmol), and acetic acid (88 mg, 1.5 mmol) in 1,2-dichloroethane (0.5 mL), then after 16 h the reaction mixture was partitioned between ethyl acetate and 2 M aq. sodium hydroxide solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. Flash chromatography (SiO2, hexane/ethyl acetate 1:1) afforded the title compound (48 mg, 64%); White solid, ISP-MS: m/e=308.2 ([M+H]+).
Reaction SMILES: [C:1]([S:4][CH:5]1[N:8]([CH:9]([C:13]([CH3:15])=C)[C:10]([OH:12])=[O:11])[C:7](=[O:16])[CH:6]1[N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])(=[O:3])[CH3:2].[O:28]=[O+][O-]>CO>[C:1]([S:4][CH:5]1[N:8]([CH:9]([C:13](=[O:28])[CH3:15])[C:10]([OH:12])=[O:11])[C:7](=[O:16])[CH:6]1[N:17]1[C:18](=[O:27])[C:19]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:20]2[C:21]1=[O:22])(=[O:3])[CH3:2]
Reactant: O=[O+][O-]
Reactant: C=C(C)C(C(=O)O)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1SC(C)=O
Solvent: CO
Product: CC(=O)SC1C(N2C(=O)c3ccccc3C2=O)C(=O)N1C(C(C)=O)C(=O)O
Yield: 63 %

Procedure:
To a solution of α-[4 -acetylthio-3-phthalimido-2-oxoazetidin-1-yl]-α-isopropenyl acetic acid (100 mg) in methanol (10 ml) at 0° C. is introduced excess ozone. After the gas at the outlet makes a potassium iodide starch paper coloured, the reaction mixture is bubbled with sulfur dioxide gas. The reaction mixture is concentrated, and the obtained residue is dissolved in aqueous solution of sodium hydrogen carbonate, washed with ether, neutralized with hydrochloric acid, and extracted with methylene chloride. The extract solution is washed with water, dried, and evaporated to give α-[4-acetylthio-3-phthalimido-2-oxoazetidin-1-yl]-α-acetylacetic acid (64 mg). Yield: 63%. Foam. IR: νmaxCHCl3 1780, 1730, 1680 cm-1.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH:18]4[CH2:19][CH2:20][CH:14]3[CH2:15][O:16][CH2:17]4)[N:10]=[C:9]([C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.ClC(Cl)(O[C:32](=[O:38])OC(Cl)(Cl)Cl)Cl.[NH2:40][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1>>[CH3:47][C:44]1[CH:45]=[CH:46][C:41]([NH:40][C:32]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([C:9]3[N:8]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:12]=[C:11]([N:13]4[CH:14]5[CH2:20][CH2:19][CH:18]4[CH2:17][O:16][CH2:15]5)[N:10]=3)=[CH:22][CH:23]=2)=[O:38])=[CH:42][CH:43]=1
Reactant: Cc1ccc(N)cc1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: Cc1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)nc(N4C5CCC4COC5)n3)cc2)cc1
Yield: 30.6 %

Procedure:
Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and p-toluidine (20 mg, 0.18 mmol) gave the title compound as off-white solid (9.2 mg, 31% yield). MS (ESI) m/z 502.5.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]#[N:29])[CH2:22][CH2:21]1.O>CN(C=O)C>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]#[N:29])[CH2:22][CH2:21]2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: N#CCCN1CCC(N)CC1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)C(NC2CCN(CCC#N)CC2)=C(c2ccccc2)S1(=O)=O
Yield: 88.7 %

Procedure:
A solution of 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.200 g, 0.700 mmol), TEA (0.283 g, 2.800 mmol) and 3-(4-aminopiperidin-1-yl)propanenitrile (0.161 g, 1.050 mmol) in DMF (3 mL) was heated in a microwave reactor at 120° C. for 10 mins. Water was added and the mixture was extracted with EtOAc. The organic phase was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using a mixture of heptane and EtOAc (20:80) to 100% EtOAc, then a mixture of MeOH and EtOAc (1:99) as eluant, to give the title compound (0.25 g, 89%); 1H NMR (500 MHz, CDCl3): δ 7.54-7.51 (m, 2H), 7.49-7.44 (m, 3H), 5.20 (br d 1H), 4.46-4.38 (m, 1H), 3.01-2.91 (br m, 1H), 2.70-2.65 (br m, 2H), 2.55 (t, 2H), 2.41 (t 2H), 1.74-1.63 (m 4H), 1.60 (d 6H) 1.44-1.35 (m 2H); 13C NMR (125 MHz, CDCl3): δ 158.7, 134.5, 131.8, 130.1, 128.9, 125.3, 118.8, 106.8, 53.3, 51.5, 50.0, 47.8, 32.4, 20.4, 16.4: Mass Spectrum: M−H+ 403.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:18])[CH:4]=1)=O.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:19]([NH:23][CH2:1][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:18])[CH:4]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCNCc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.4 %

Procedure:
To a solution of ethyl 2-(4-formyl-2-methylphenoxy)-2-methylpropanoate (0.56 g, 2.25 mmol) in anhydrous CH2Cl2 (10 mL) was added n-butylamine (0.33 mL, 3.38 mmol). After stirring for 90 mins under nitrogen at room temperature, sodium triacetoxyborohydride (0.668 g, 3.15 mmol) was added and stirring continued for 18 h. The reaction was quenched by cautious addition of sat. sodium carbonate aq. (20 mL) and then extracted CH2Cl2 (2×40 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo to afford the title compound as a pale yellow oil (0.48 g).
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]>C(#N)C>[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: CS(=O)(=O)Cl
Reactant: CCCCc1oc2ccc(N)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Solvent: CC#N
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Product: Cl
Temperature: 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 acetonitrile solvent to provide a crude dronedarone hydrochloride, wherein an amount of acetonitrile used is in the range of 0 to 10 parts by volume, preferably 1 to 8 parts by volume, more preferably 3 to 6 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 1.1 to 3 equivalents, and more preferably 1.2 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 50° C., preferably −20 to 35° C., more preferably −15 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: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[OH:18])=[N:16][C:12]=3[CH:11]=[C:10]([C:34]3[NH:38][C:37](=[O:39])[O:36][N:35]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])=[O:18])=[N:16][C:12]=3[CH:11]=[C:10]([C:34]3[NH:38][C:37](=[O:39])[O:36][N:35]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(C(O)c3ccccc3F)nc3cc(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1CC[C@H](Cn2c(C(=O)c3ccccc3F)nc3cc(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a room temperature slurry of 3-{4-(5-chloropyridin-3-yl)-2-[(2-fluorophenyl)(hydroxy)methyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (Example 7.4 in Table 7, 150 mg, 0.273 mmol) in dichloromethane (4 mL) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (127 mg, 0.301 mmol). The mixture was stirred at room temperature for 1 hour during which time it became a homogeneous solution. Saturated aqueous sodium thiosulfate was added, and the resulting mixture was extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification via mass guided reverse phase HPLC (acetonitrile/water+0.1% TFA modifier) afforded 3-{4-(5-chloropyridin-3-yl)-2-[(2-fluorophenyl)carbonyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (TFA salt) as a white solid. MS ESI calcd. for C28H24ClFN6O3 [M+H]+ 547. found 547. 1H NMR (500 MHz, DMSO-d6) δ 13.01 (s, 1H), 8.96 (s, 1H), 8.89 (s, 1H), 8.51 (s, 1H), 8.45 (s, 1H), 7.85-7.87 (m, 2H), 7.45-7.41 (m, 2H), 4.25 (d, J=6.5 Hz, 2H), 1.43-1.40 (m, 2H), 1.15-1.02 (m, 2H), 0.86-0.80 (m, 2H), 0.73-0.65 (m, 5H), 0.55-0.50 (m, 2H).
Reaction SMILES: [N+:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([O-:3])=[O:2].[CH2:11]=[O:12].O.[C:14](=[O:17])([O-])[O-].[Na+].[Na+]>>[N+:1]([C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH2:14][OH:17])[CH2:11][OH:12])([O-:3])=[O:2]
Reactant: C=O
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])Cc1ccccc1
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])C(CO)(CO)c1ccccc1
Temperature: 38 °C
Reaction time: 1 h

Procedure:
100 g. (0.73 mole) of nitromethylbenzene, 131.5 g. (1.61 mole) of 37% formaldehyde and 1.8 g. of sodium carbonate monohydrate are placed in a 500 ml. beaker equipped with a mechanical stirrer. The mixture is stirred, the temperature rises to 38° C. and is maintained at 38° C. by using a cold water bath. After 1 1/2 hours, crystals begin to form. The mixture is diluted with 210 ml. of ice water and stirred at 10° C. for about 2 hours. The mixture is filtered and the filtrate washed with water. The damp cake is placed back in the beaker and 280 ml. of ice water is added. The mixture is stirred for 1 hour, filtered and air dried overnight. The solid is stirred with 250 ml. of toluene for about 1 hour at 10° C. and filtered, then washed with cold toluene and dried. The yield is 112.6 g. of nitrophenyldiol (78%), M.P. 96°-97.5° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.CCN(CC)CC.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].C([O-])(O)=O.[Na+]>ClCCl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(I)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(I)cn1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 106.3 %

Procedure:
5-Iodopyridin-2-amine (5 g, 22.7 mmol) was dissolved in 50 ml of dichloromethane and Et3N (6.3 ml, 45.5 mmol, 2 equiv.) was added at room temperature. The mixture was cooled to 0-5° C. and pivaloyl chloride (3.4 ml, 27.3 mmol, 1.2 equiv.) was added dropwise. The reaction mixture was stirred for 1 hour at 0-5° C. Saturated NaHCO3-solution was added and the mixture was extracted with dichloromethane. The organic extracts were dried with sodium sulfate, filtered and evaporated to dryness. The desired N-(5-iodopyridin-2-yl)pivalamide (7.34 g, 99.8% yield) was obtained as a brown oil, MS: m/e=305.0 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([O:25][CH3:26])[C:17]=1[CH:18]=[O:19]>C1COCC1>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([CH:18]([C:17]2[C:20]([O:25][CH3:26])=[CH:21][CH:22]=[C:23]([F:24])[C:16]=2[F:15])[OH:19])=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: COc1ccc(F)c(F)c1C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1C(O)c1cnc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 5-bromo-2,4-dichloropyrimidine (Aldrich, 3.02 g, 13.25 mmol) in 20 mL of THF at −30° C., isopropyl magnesium chloride (Aldrich, 2M solution in THF, 7.12 mL, 13.25 mmol) was added dropwise and the mixture was stirred for 20 minutes. Then 2,3-difluoro-6-methoxy-benzaldehyde (Matrix, 2.28 g, 13.25 mmol) was added and the mixture was warmed to 0° C. and stirred for 40 minutes. The reaction was quenched with saturated ammonium chloride solution and the resulting mixture was extracted with EtOAc. The extract was dried with sodium sulfate. The solvent was removed on a rotary evaporator and the solid was treated with hexane (8 mL). The solid was filtered and dried to give an off-white solid. 3.42 g; Yield, 80.5%. MS (M+H)+, 322.