Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:23]([C:24]([O:26]C)=[O:25])=[C:7]3[CH:8]=[C:9]([CH3:22])[CH:10]=[C:11]([O:12][CH2:13][C:14]4[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=4[F:21])[N:6]3[N:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCOCC1>[CH:1]1([C:4]2[C:23]([C:24]([OH:26])=[O:25])=[C:7]3[CH:8]=[C:9]([CH3:22])[CH:10]=[C:11]([O:12][CH2:13][C:14]4[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=4[F:21])[N:6]3[N:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1c(C2CC2)nn2c(OCc3c(F)cccc3F)cc(C)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C3CC3)c(C(=O)O)c2c1
Temperature: 100 °C
Reaction time: 7 h
Yield: 98.8 %

Procedure:
A solution of 384 mg (1.02 mmol) of methyl 2-cyclopropyl-7-[(2,6-difluorobenzyl)oxy]-5-methylpyrazolo[1,5-a]pyridine-3-carboxylate from Example 99A in 10.6 ml of dioxane was admixed with 10.2 ml (10.2 mmol) of 1 N sodium hydroxide solution and the mixture was stirred at 100° C. for 7 h. The reaction solution was cooled and adjusted to pH 2 with 1 N hydrochloric acid. The solids that precipitated out were filtered off and dried under high vacuum. The filtrate was admixed once again with 1 N hydrochloric acid. The solids that precipitated out were filtered off and dried under high vacuum together with the previously isolated solids. A total of 361 mg of the title compound (74% by LC-MS, 73% of theory) were obtained and were converted without further purification.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[CH2:14]O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.S(Cl)([Cl:24])=O.C(O)=O>C1C=CC=CC=1>[C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[CH2:14][Cl:24])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: COc1ccc(CO)cc1OS(=O)(=O)c1ccc(C)cc1
Reactant: O=S(Cl)Cl
Solvent: O=CO
Solvent: c1ccccc1
Product: COc1ccc(CCl)cc1OS(=O)(=O)c1ccc(C)cc1
Temperature: 17.5 °C
Yield: 90 %

Procedure:
To a cooled solution of 3-[(p-Toluenesulfonyl)oxy]-4-methoxybenzyl alcohol 22 (8.0 g, 26 mmol) in benzene (25 mL) was added thionyl chloride (1.9 mL, 26 mmol) slowly over a period of 5-10 min maintaining the temperature around 15-20° C. The reaction was maintained at those conditions for 2 h and checked TLC for the completion. The flask is connected to a high vacuum through a trap containing formic acid under mild heating to remove excess thionyl chloride. The slurry formed after complete removal of thionyl chloride and benzene, filtered, washed with hexane and dried to afford 23. Yield: 90%; white solid mp 102-105° C. 1H NMR: δ 2.43 (s, 3H, CH3), 3.61 (s, 3H, OCH3), 4.50 (s, 2H, CH2), 6.80-7.79 (m, 7H, Ar—H). Anal. Calcd for C15H15ClO4S: C, 55.13, H, 4.63. Found: C, 53.20, H, 4.59.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:16])[CH:8]=2)[CH:6]=1.I[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20]>[Cu].CS(C)=O>[CH3:16][C:9]1[CH:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH:3]=[N:4]2)[CH:12]=[CH:11][C:10]=1[N+:13]([O-:15])=[O:14]
Reactant: FC(F)(F)C(F)(F)I
Reactant: Cc1cc(-n2cc(I)cn2)ccc1[N+](=O)[O-]
Agent: [Cu]
Solvent: CS(C)=O
Product: Cc1cc(-n2cc(C(F)(F)C(F)(F)F)cn2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
4-Iodo-1-(3-methyl-4-nitrophenyl)-1H-pyrazole (1.98 g), copper powder (1.14 g), iodopentafluoroethane (8.85 g) and DMSO (9 ml) were set in an autoclave and heated and stirred for 8 hours, maintaining the inside temperature of 100° C. After finishing the reaction, the reaction mixture was poured into ice water and an insoluble matter was filtered with Celite, and then, it was extracted with ethyl acetate. The extracted solution was washed with water and dried with anhydrous sodium sulfate. After distilling off the solvent, the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitrophenyl)-4-pentafluoroethyl-1H-pyrazole (0.72 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=2)[N:6]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21]>>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:11][C:10]([S:12]([NH:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])(=[O:14])=[O:13])=[CH:9][CH:8]=2)[N:6]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: Cc1nc(-c2ccc(S(=O)(=O)Cl)s2)cs1
Product: Cc1nc(-c2ccc(S(=O)(=O)Nc3cccc(C(=O)O)c3)s2)cs1
Yield: 13.7 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting with 5-(2-methylthiazol-4-yl)thiophene-2-sulfonyl chloride (15.4 mg, 0.055 mmol) and 3-aminobenzoic acid (6.9 mg, 0.05 mmol) affording 2.6 mg (14%) of the title compound. MS (ESI+) calcd for C15H21N2O4S3 379.995919, found 379.995859.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([N:17]([CH3:39])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[C@@H:27]([CH3:38])[CH2:26]4)=[CH:20][CH:19]=3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([N:17]([CH3:39])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][C@@H:27]([CH3:38])[CH2:26]4)=[CH:20][CH:19]=3)=[O:16])[CH2:13][CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)N3CCC(Nc4cccc(F)c4)CC3)cc2)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)N3CCC(Nc4cccc(F)c4)CC3)cc2)CCN1
Reaction time: 2.5 h
Yield: 102.7 %

Procedure:
1,1-Dimethylethyl (2S)-4-({4-[({4-[(3-fluorophenyl)amino]-1-piperidinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D33) (9.337 g, 17.322 mmol) was dissolved in DCM (144 mL) and cooled in an ice bath. TFA (36 mL) was added slowly and the mixture was allowed to stir for 2.5 h under argon. The solvent was removed under vacuum and the residue partitioned between DCM and saturated aqueous NaHCO3. The organic layer was separated and the aqueous layer extracted twice with DCM. The combined organic extracts were dried and concentrated to give the title compound as a cream coloured foam (7.82 g). MS (ES): MH+ 440.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][NH2:26])[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:26][CH2:25][CH2:24][N:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2
Reactant: CN1CCN(CCN)CC1
Reactant: Clc1ccc2c(Cl)c3c(nc2c1)CCCC3
Product: CN1CCN(CCNc2c3c(nc4cc(Cl)ccc24)CCCC3)CC1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-1,2,3,4-tetrahydroacridine and 2-(4-methylpiperazin-1-yl)ethanamine, the title compound was obtained; MS (Found M+1=359). 1H NMR (CDCl3, 300 Hz): 7.97-7.95 (m, 2H, J=9 Hz), 7.95-7.91 (d, 1H, J=9 Hz), 7.28-7.25 (m, 1H), 5.25 (b, 1H), 3.58-3.49 (m, 2H), 3.05 (m, 2H), 3.73 (m, 2H), 2.63-2.59 (m 10H), 2.39 (s, 3H), 1.94-1.90 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:13]=O.[OH:15][C:16]1[C:17]([C:26]([NH:28][NH2:29])=[O:27])=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>>[OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:13]=[N:29][NH:28][C:26]([C:17]1[C:16]([OH:15])=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)=[O:27]
Reactant: O=Cc1c(O)cc(O)c2ccccc12
Reactant: NNC(=O)c1cc2ccccc2cc1O
Product: O=C(NN=Cc1c(O)cc(O)c2ccccc12)c1cc2ccccc2cc1O
Yield: 83 %

Procedure:
Following the general procedure of Example 1, condensation of 2, 4-dihydroxy-1-naphthaldehyde and 3-hydroxy-2-naphthoic hydrazide yielded a yellow crystal (83%) [recrystallized from DMSO/H2O (8:2, v/v)]: mp>280° C. (dec); 1H NMR d 12.42 (br s, 1 H), 11.65 (s, 1 H), 10.96 (br s, 1 H), 10.59 (s, 1 H), 8.99 (s, 1H), 8.07 (s, 1H), 7.77 (d, 1 H, J=8.4 Hz), 7.67 (d, 1 H, J=8.4 Hz), 7.48 (d, 1 H, J=8.1 Hz), 7.32 (d, 1H, J=8.4 Hz), 7.13 (t, 1H, J=7.5 Hz), 7.06 (t, 1 H, J=7.5 Hz), 6.91 (s, 1 H), 6.90 (m, 2 H); 13C NMR d 162.92, 160.47. 157.70, 154.20, 148.22, 135.97, 132.99, 130.33, 128.72, 128.33 (2 C), 126.84, 125.92, 123.91, 122.94, 122.55, 120.80, 120.32, 119.66, 110.70, 101.38, 100.49; HRMS Calcd for C22H16N2O4 :372.1110, found 372.1095; Anal. (C22H16N2O4 2DMSO H2O) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[CH:4]=[N:5][OH:6].ClCl.[C-:11]#[N:12].[Na+]>CCOCC.CO.O>[CH3:1][O:2][C:3]([CH3:8])([CH3:7])[C:4](=[N:5][OH:6])[C:11]#[N:12]
Reactant: COC(C)(C)C=NO
Reactant: [C-]#N
Agent: ClCl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: COC(C)(C)C(C#N)=NO
Reaction time: 1 h

Procedure:
53.6 g (0.46 mol) of 2-methoxy-2-methylpropionaldehyde oxime in ether (about 1 M) are initially taken at from −5 to −10° C. 35.8 g (0.5 mol) of chlorine gas are passed in, after which stirring is carried out for 1 hour at this temperature and the mixture is then evaporated down at 10° C. and the residue is taken up in diethyl ether. 24.7 g (0.5 mol) of sodium cyanide in 375 ml of 20:1 methanol/H2O are initially taken at 10° C. and the above ethereal solution is rapidly added dropwise. After 4 hours at room temperature, the mixture is filtered under suction and the residue is washed with twice 100 ml of methanol. The combined solutions are evaporated down and the residue is partitioned between methyl tert-butyl ether and water. Drying the organic phase over Na2SO4, evaporating down and crystallizing from dichloromethane/n-hexane give 41.1 g (63% of theory) of a white powder of melting point 102-104° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[NH:13][C:12](=O)[C:11]=2[CH:10]=[CH:9]1.P(Cl)(Cl)([Cl:25])=O>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([Cl:25])[C:11]=2[CH:10]=[CH:9]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccccc1-n1ccc2c(=O)[nH]c3c(C)cccc3c21
Product: Cc1ccccc1-n1ccc2c(Cl)nc3c(C)cccc3c21

Procedure:
1-(2-Methylphenyl)-4-oxo-6-methyl-4,5-dihydropyrrolo[3,2-c]quinoline (4.75 g) and phosphoryl chloride (40 ml) were heated at reflux for 1.5 hours. The phosphoryl chloride was evaporated in vacuo, the residue poured onto ice and extracted with dichloromethane, which was dried and evaporated. Crystallisation from ethanol yielded 1-(2-methylphenyl)-4-chloro-6-methylpyrrolo[3,2-c]quinoline (4.76 g), m.p.135°-137°.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27]>C(O)C>[OH:27][CH2:26][CH:25]([NH:24][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]([CH3:21])[CH3:22])=[CH:13][CH:12]=2)=[O:7])[CH2:28][OH:29]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccc(OC(C)C)cc2c1O
Reactant: NC(CO)CO
Solvent: CCO
Product: CC(C)Oc1ccc2c(Cl)nc(C(=O)NC(CO)CO)c(O)c2c1
Yield: 114.3 %

Procedure:
0.035 gm of 1-chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid butyl ester and 0.088 g of 2-amino-propane-1,3-diol were dissolved in 1 ml of ethanol and the mixture was refluxed for 24 h. The reaction mixture was concentrated and the residue was dissolved in 10 ml of ethyl acetate. The ethyl acetate solution was extracted with 5 ml of aqueous 1 M HCl and water, dried (sodium sulfate) and concentrated to give 0.042 g of a white solid: MS-(+)-ion: 355.1.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([CH3:21])[CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].CC(O)C.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=2)=[C:14]([CH3:21])[CH:13]=1
Reactant: O=C(O)c1cccc(I)c1
Reactant: Cc1cc(Cl)ccc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(Cl)ccc1-c1cccc(C(=O)O)c1
Temperature: 80 °C

Procedure:
To a mixture of 3-iodobenzoic acid (11.9 g, 48 mmol), 4-chloro-2-methylphenylboronic acid (9.8 g, 57.7 mmol) and sodium carbonate (6.1 g, 57.7 mmol) under nitrogen atmosphere, was added i-PrOH-water (1/1, 180 mL) followed by 10% Pd—C (2 g, 19.2 mmol) with caution. The reaction mixture was heated at 80° C. under nitrogen overnight. The catalyst was removed by filtration, and the filtered catalyst was washed with EtOH (60 mL). Most of organic solvent was removed under reduced pressure. The resulting aqueous residue was treated with 2N HCl (aq) to bring the pH <2. The resulting mixture was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water and saturated brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Compound 9.7 was obtained as white solid (12 g), which was used directly in the next step. MS ESI (neg.) m/e: 245 (M−H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH:17]2[CH2:26][C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]([O:32][C:33]([N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[CH2:44]Cl)=[O:34])([CH3:31])([CH3:30])[CH3:29].CCN(C(C)C)C(C)C>CC#N>[C:28]([O:32][C:33]([N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[CH2:44][N:16]([CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])=[CH:10][CH:11]=1)[CH:17]1[CH2:26][C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNC2CCc3cccnc3C2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1ccc(CN(Cc2nc3ccccc3n2C(=O)OC(C)(C)C)C2CCc3cccnc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
{4-[(5,6,7,8-Tetrahydro-quinolin-7-ylamino)-methyl]-benzyl}-carbamic acid tert-butyl ester (88 mg, 0.24 mmol), 2-Chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (80 mg, 0.30 mmol), DIPEA (0.10 mL, 0.54 mmol), and KI (19 mg, 0.11 mmol) were heated to 80° C. in CH3CN (1.5 mL) for 2 h under N2, then it was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, washed with NH4Cl (aq), NaCl (aq), and dried (MgSO4). Evaporation of the solvent and purification of the residue by flash chromatography on silica gel (1:1:98 CH3OH—NH3 H2O—CH2Cl2) afforded the title compound (80 mg, 56%) as a white foam.
Reaction SMILES: [BH4-].[K+].[OH:3][C:4]1([CH3:16])[CH2:8][S:7][C:6](=[S:9])[N:5]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl>O.CO>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:5][C:6](=[S:9])[S:7][CH2:8][CH:4]([OH:3])[CH3:16]
Reactant: CC1(O)CSC(=S)N1c1ccccn1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(O)CSC(=S)Nc1ccccn1
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
A solution of potassium borohydride (5.4 g) in distilled water (80 cc) is added, at a maximum of 35° C., to a solution of 4-hydroxy-4-methyl-3-(pyrid-2-yl)-thiazolidine-2-thione (22.6 g) in methanol (320 cc). The reaction is allowed to proceed for 30 minutes at 25°-35° C. A 3 N aqueous solution of hydrochloric acid (33.2 cc) is added. The methanol is evaporated off under reduced pressure (20 mm Hg) at 45° C. The aqueous phase is extracted with ethyl ether (800 cc). The ether solution is washed twice with distilled water (300 cc in total), treated with decolourising charcoal (1 g), dried over sodium sulphate and evaporated. The resulting product (23.0 g) is purified by recrystallisation from a mixture of ethyl ether (100 cc) and isopropyl ether (100 cc). 2-Hydroxypropyl pyrid-2-yldithiocarbamate (11.1 g), which melts at 78° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[C:4]([OH:19])[CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Cl)(Cl)=[O:27].C1(C)C=CC=CC=1.N1CCCC1>O.C1(C)C=CC=CC=1>[N:20]1([C:21]([O:19][C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=2[O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=C(Cl)Cl
Reactant: c1ccncc1
Reactant: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Solvent: O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1OC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.4 %

Procedure:
200 mg (0.722 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was mixed with toluene (3 mL) and the mixture was ice-cooled. To the mixture were added 60 ìL (0.742 mmol) of pyridine, then 0.67 mL (0.724 mmol) of 1.08 mol/L phosgene-toluene solution under nitrogen atmosphere with stirring, and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was ice-cooled, 60 ìL (0.722 mmol) of pyridine, then 60 ìL (0.719 mmol) of pyrrolidine were added to the mixture, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 4 plates were used, developed by hexane:ethyl acetate=2:1) to obtain 190 mg (0.508 mmol, Yield: 70.7%) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 1-pyrrolidinecarboxylate (Compound No. 1937).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:18][C@@H:19]1[C@@:23]([CH2:43]OS(C2C=CC(C)=CC=2)(=O)=O)([CH2:24][O:25][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:22][C@@H:21]([N:55]2[C:70]3[N:69]=[C:62]([NH:63][C:64](=[O:68])[CH:65]([CH3:67])[CH3:66])[NH:61][C:59](=[O:60])[C:58]=3[N:57]=[CH:56]2)[C@@H:20]1[OH:71])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:11]([O:18][C@@H:19]1[C@@:23]2([CH2:43][O:71][C@H:20]1[C@H:21]([N:55]1[C:70]3[N:69]=[C:62]([NH:63][C:64](=[O:68])[CH:65]([CH3:67])[CH3:66])[NH:61][C:59](=[O:60])[C:58]=3[N:57]=[CH:56]1)[O:22]2)[CH2:24][O:25][Si:26]([C:39]([CH3:42])([CH3:40])[CH3:41])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@]2(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)C(C)C)nc43)[C@H](O)[C@@H]2OCc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@@]3(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 156.9 %

Procedure:
In a stream of nitrogen, sodium bis(trimethylsilyl)amide (1.0 M in THF, 0.31 ml, 0.315 mmol) was added to a tetrahydrofuran solution (3.0 ml) of Compound 45 (92.1 mg, 0.102 mmol) at room temperature, and the mixture was stirred for 3 hours at room temperature. A saturated sodium bicarbonate solution was added to the reaction mixture, and then the system was extracted 3 times with methylene chloride. The organic phase was washed with a saturated sodium chloride solution, and then dried over sodium sulfate. The solvents were distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (CHCl3-MeOH, 25:1) to obtain a white powder, Compound 46 (31.4 mg, 0.160 mmol, 44%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[C:3]=1F.O.[NH2:15][NH2:16]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[C:3]=1[NH:15][NH2:16]
Reactant: NN
Reactant: Fc1cc(C(F)(F)F)cc(F)c1F
Solvent: O
Solvent: CCO
Product: NNc1c(F)cc(C(F)(F)F)cc1F

Procedure:
A mixture of 1,2,3-trifluoro-5-(trifluoromethyl)benzene (300 g, 1.5 mmol) and hydrazine monohydrate (300 g, 6.0 mmol) in ethanol (1200 ml) was heated at reflux overnight. The reaction mixture was concentrated in vacuo and the residue was re-crystallised from 2-propanol to give Preparation 21 (194 g).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[O:13][C:12]2[CH:11]=[CH:10][C:9]([NH:14]S(C)(=O)=O)=[CH:8][C:7]=2[C:6]=1C(C1C=CC(OCCCN(CCCC)CCCC)=CC=1)=O.C(C1OC2C=CC([N+]([O-])=O)=CC=2C=1)CCC.[H][H]>[Pt]=O>[CH2:4]([C:5]1[O:13][C:12]2[CH:11]=[CH:10][C:9]([NH2:14])=[CH:8][C:7]=2[CH:6]=1)[CH2:3][CH2:2][CH3:1]
Reactant: [H][H]
Reactant: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Agent: O=[Pt]
Agent: CCCCc1cc2cc([N+](=O)[O-])ccc2o1
Product: CCCCc1cc2cc(N)ccc2o1

Procedure:
A process for synthesizing dronedarone was described in patent application WO 02/48132, mentioned previously, using 2-n-butyl-5-nitrobenzofuran, which is reduced, under pressure with hydrogen in the presence of platinum oxide as catalyst to form 2-n-butyl-5-aminobenzofuran. This benzofuran derivative is then subjected to the action of methanesulfonyl chloride, which gives 2-n-butyl-5-methanesulfonamidobenzofuran, which is treated with 4-[3-(di-n-butylamino)propoxy]benzoyl chloride to obtain dronedarone.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]([NH2:8])=[S:7])=[NH:4].[Br:9][CH2:10][C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]>C(O)C>[BrH:9].[CH3:1][N:2]=[C:3]([NH2:4])[NH:5][C:6]1[S:7][CH:10]=[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[C:17](=[O:26])[C:18]3=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]3[C:20]2=[O:21])[N:8]=1
Reactant: CNC(=N)NC(N)=S
Reactant: O=C(CBr)CCCCN1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: Br
Product: CN=C(N)Nc1nc(CCCCN2C(=O)c3ccccc3C2=O)cs1

Procedure:
To a solution of (N-methylamidino)thiourea (0.4 g.) in hot ethanol (20 ml.) was added N-(6-bromo-5-oxohexyl)phthalimide (1.5 g.). The mixture was heated under reflux for 1 hour, cooled and evaporated to dryness. The residue was triturated with acetonitrile and the resulting solid was filtered and dried to give 2-(2-methylguanidino)-4-(4-phthalimidobutyl)thiazole hydrobromide, m.p. 210°-212° C.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:6]([CH2:17][OH:18])=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(N(CC)CC)C>[C:24]([O:18][CH2:17][C:6]1[C:7]([CH2:13][CH:14]2[CH2:15][CH2:16]2)=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:3]([CH:2]([F:1])[F:23])=[N:4][C:5]=1[C:19]([F:22])([F:20])[F:21])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(CO)c1CC1CC1
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(COC(=O)c2ccccc2)c1CC1CC1

Procedure:
Reaction of methyl 2-(difluoromethyl)-5-(hydroxymethyl)-4-(cyclopropylmethyl)-6-(trifluoromethyl)-3-pyridine-carboxylate (U.S. Pat. No. 5,169,432 example A compound A4) with Benzoyl chloride and triethylamine according to the procedure in example 99 of U.S. Pat. No. 5,169,432 gave the product.