Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[O:20][CH3:21])[CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]([O:31]C)=[O:30])[CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.[OH-].[Na+]>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=2)=[O:8])=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[O:20][CH3:21])[CH:3]=1
Reactant: COC(=O)c1cc(N)ccn1
Reactant: COc1cc(F)ccc1Oc1cc(Cl)c(Cl)cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1Oc1cc(Cl)c(Cl)cc1C(=O)Nc1ccnc(C(=O)O)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 7 %

Procedure:
4,5-Dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoic acid (40 mg, 0.12 mmol), methyl 4-aminopicolinate (36.5 mg, 0.24 mmol) and HATU (45.9 mg, 0.12 mmol) were combined in DMF (1 mL) and heated at 50° c. for 2 hours. The reaction was treated with 10 drops of 3 M NaOH and heated at 50° C. for 16 h. The reaction was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water containing HCl (5 mM) as a modifier (10-99%) to yield 4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid (76) (3.80 mg, 7%). ESI-MS m/z calc. 450.02. found 451.1 (M+1)+; Retention time: 1.47 minutes (3 minutes run).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[Cl-].[C:7]([O:12][CH2:13][CH2:14][N+:15](C)([CH3:17])[CH3:16])(=[O:11])[C:8]([CH3:10])=[CH2:9]>>[C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[C:7]([O:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: C=C(C)C(=O)OCC[N+](C)(C)C
Agent: C=CC(N)=O
Agent: [Cl-]
Product: C=C(C)C(=O)OCCN(C)C

Procedure:
The crosslinked copolymer of acrylamide and of methacryloyloxyethyltrimethylammonium chloride used according to the invention is more particularly a copolymer obtained by copolymerization of acrylamide and of dimethylaminoethyl methacrylate quaternized with methyl chloride, followed by crosslinking with an olefinically unsaturated compound, in particular methylenebisacrylamide. A crosslinked acrylamide/methacryloyloxyethyltrimethylammonium chloride copolymer (about 50/50 by weight) in the form of a dispersion is more particularly used. This dispersion is sold under the name Salcare SC92 by the company Ciba.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH:10]([C:21](OC)=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH:10]([CH2:21][OH:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccccc2)CC1CO
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
Compound 111a (1 g, 2.99 mmol) was dissolved in 100 mL of anhydrous tetrahydrofuran and lithium aluminum hydride (342 mg, 8.98 mmol) was added carefully at 0° C. and the mixture was stirred for 30 min. Then, it was refluxed for 3 h and the reaction mixture was poured onto ice portion-wise. It was then filtered and the filtrate was evaporated in vacuo. After addition of 100 mL brine, it was extracted with dichloromethane (100 mL×3). The combined organic layer was dried over Na2SO4, filtered and concentrated to afford 111b as yellow oil (0.6 g, yield 91%)
Reaction SMILES: [C:1]1(=[O:7])[CH:5]=[CH:4][C:3](=[O:6])[CH2:2]1.[CH3:8][C:9]([C:11]([CH3:13])=[CH2:12])=[CH2:10].C(C1C=C(O)C(C(C)(C)C)=CC=1O)(C)(C)C>C1C=CC=CC=1>[CH3:8][C:9]1[CH2:10][C@@H:5]2[C@H:4]([CH2:12][C:11]=1[CH3:13])[C:3](=[O:6])[CH2:2][C:1]2=[O:7]
Reactant: C=C(C)C(=C)C
Reactant: O=C1C=CC(=O)C1
Agent: CC(C)(C)c1cc(O)c(C(C)(C)C)cc1O
Solvent: c1ccccc1
Product: CC1=C(C)C[C@H]2C(=O)CC(=O)[C@H]2C1
Reaction time: 96 h

Procedure:
A solution of 4-cyclopentene-1,3-dione (5.48g; 0.06 mole) and 2,3-dimethyl butadiene (10.4g; 0.127 mole) in dry benzene (20ml) were treated with a few crystals of 2,5-di-t-butyl hydroquinone and allowed to stand at ambient temperature for 4 days. After refluxing for 15 mins the mixture was cooled and the pale orange solid filtered. Recrystallisation from benzene, methanol afforded the title product as a white solid, m.p. 157°-158° C.
Reaction SMILES: C([O:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1)C.[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCCC>[OH:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1
Reactant: CCOc1ccc2nc(S(N)(=O)=O)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Product: NS(=O)(=O)c1nc2ccc(O)cc2s1

Procedure:
A stirred mixture of 6-ethoxy-2-benzothiazolesulfonamide (20 g.) and aluminum chloride (40 g.) in heptane (500 ml) is heated at reflux for 4 hours and cooled. The heptane is decanted from the reaction mixture which is then treated with ice water (500 ml.). After 1/2 hour the crude product is filtered, dissolved in warm dilute sodium hydroxide, filtered and acidified with concentrated hydrochloric acid to give 7.5 g. of 6-hydroxy-2-benzothiazolesulfonamide which melts at 225°-228° C. after recrystallization from acetic acid.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([C:12]([CH3:14])=[CH2:13])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[CH:29])=[N:26][CH:27]=2)=[CH:18][CH:17]=1>CCOC(C)=O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[C:29][C:2]3[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([C:12]([CH3:14])=[CH2:13])[CH:3]=3)=[N:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: C=C(C)c1cc(I)ccc1OCCO
Solvent: CCOC(C)=O
Product: C=C(C)c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCO

Procedure:
The product was prepared analogously to Example 7.1e starting from 2-(4-iodo-2-isopropenylphenoxy)ethanol and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 1.00 g (60% of theoretical); C24H20ClNO2 (M=389.874); calc.: molpeak (M+H)+: 390/392 (Cl); found: molpeak (M+H)+: 390/392 (Cl); Rf value: 0.30 (silica gel, PE/EtOAc 1:1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([NH:32][CH3:33])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1.CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]5[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:30])[NH:32][CH3:33])=[CH:25][CH:24]=5)[CH:18]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CNS(=O)(=O)c1ccc(-c2cccc(N)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)c1ccc(-c2cccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)c2)cc1
Reaction time: 16 h

Procedure:
To a solution of 1-benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl chloride (0.97 mmol) in CH2Cl2 (3 mL) at ambient temperature was added a solution of 3′-amino-N-methylbiphenyl-4-sulfonamide (0.25 g, 0.97 mmol), Et3N (0.68 mL, 4.9 mmol), DMAP (0.050 g, 0.058 mmol), and CH2Cl2 (1 mL) dropwise. The mixture was allowed to stir for 16 h before it was diluted with CH2Cl2 (50 mL). The solution was washed with 1N HCl (2×25 mL), sat. aq. NaHCO3 (2×25 mL), then brine (25 mL). The organics were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (5-25% EtOAc/hexanes) to provide 1-benzo[1,3]dioxol-5-yl-N-[3-[4-(methylsulfamoyl)phenyl]phenyl]-cyclopropane-1-carboxamide as a white solid. ESI-MS m/z calc. 450.5, found 451.3 (M+1)+. Retention time of 3.13 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:55]=[CH:54][C:6]([CH2:7][N:8]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:31]([OH:44])[C:32]4[CH:37]=[CH:36][C:35]([S:38]([N:41]([CH3:43])[CH3:42])(=[O:40])=[O:39])=[CH:34][CH:33]=4)[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:62][S:63](Cl)(=[O:65])=[O:64]>C(Cl)Cl.O.CCOC(C)=O.O1CCOCC1>[CH3:62][S:63]([O:44][CH:31]([C:18]1[CH:19]=[N:20][C:21]([NH:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[C:16]([C:11]2[N:10]=[C:9]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:55][CH:54]=3)[CH2:45][C:46]3[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=3)[N:14]=[C:13]([CH3:15])[N:12]=2)[CH:17]=1)[C:32]1[CH:37]=[CH:36][C:35]([S:38](=[O:40])(=[O:39])[N:41]([CH3:43])[CH3:42])=[CH:34][CH:33]=1)(=[O:65])=[O:64]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(O)c4ccc(S(=O)(=O)N(C)C)cc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(OS(C)(=O)=O)c4ccc(S(=O)(=O)N(C)C)cc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Reaction time: 8 h

Procedure:
A solution of 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)(hydroxy)methyl)-N,N-dimethylbenzenesulfonamide (12.9 mg, 0.017 mmol) in DCM (0.2 mL) was treated with pyridine (20 μL, 0.25 mmol) followed by methanesulfonyl chloride (20 μL, 0.258 mmol). The mixture was allowed to stand overnight. Some crystals formed. The crystals were colorless and insoluble in DCM, but soluble in water. The mixture was diluted with DCM (10 mL) and washed with saturated aqueous NaHCO3 (5 mL). The DCM layer was dried and concentrated to give a yellow solid which was soluble in DCM, but insoluble in EtOAc and sparingly soluble in dioxane. The crude product was taken on directly to the next step.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]([N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[CH2:30][CH2:29]2)=[C:17]([NH:19][C:20]([C:22]2[O:23][C:24](Br)=[CH:25][CH:26]=2)=[O:21])[CH:18]=1)=[O:12].C([O-])([O-])=O.[K+].[K+].OO.O.[CH3:50][C:51](N(C)C)=O>CS(C)=O.[C-]#N.[C-]#N.[Zn+2].[Zn].CC(P(C(C)(C)C)C(C)(C)C)(C)C.CC(P(C(C)(C)C)C(C)(C)C)(C)C.[Pd]>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]([N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[CH2:30][CH2:29]2)=[C:17]([NH:19][C:20]([C:22]2[O:23][C:24]([C:50]#[CH:51])=[CH:25][CH:26]=2)=[O:21])[CH:18]=1)=[O:12]
Reactant: CC(=O)N(C)C
Reactant: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2ccc(Br)o2)CC1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: C#Cc1ccc(C(=O)Nc2cc(C(=O)NCCCN3CCCC3=O)ccc2N2CCN(c3ccccc3C)CC2)o1
Temperature: 85 °C
Reaction time: 5 h
Yield: 47 %

Procedure:
Furan-2,5-dicarboxylic acid 2-amide 5-{[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide} (compound no. 216) was prepared as follows: 5-Bromo-furan-2-carboxylic acid [5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide (0.1 g, 0.164 mmol), Zn(CN)2 (0.038 g, 0.33 mmol), Zn (2.1 mg, 0.033 mmol) were taken in DMA (5.0 mL) and the solution was degassed for 5 min. Pd(t-Bu3P)2 (8.0 mg, 0.016 mmol) was added to this, and the solution was degassed and nitrogen purged again. The reaction mixture was stirred at 85° C. under nitrogen for 5 h. It was cooled, dissolved in MeOH and purified on preparative HPLC using water/methanol as eluent to the intermediate nitrile (0.07 g, 79%). The above nitrile (0.05 g, 0.09 mmol) was taken in DMSO (2.0 mL). K2CO3 (0.074 mg, 0.54 mmol) was added to this followed by H2O2 (0.031 g, 0.27 mmol) and the reaction was stirred at room temperature for 4 h. LC-MS indicated the completion of the reaction. Water (2.0 mL) was added and the product crashed out. It was filtered and dried to give the desired product (0.025 g, 47%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.C([Li])CCC.CN([CH:18]=[O:19])C>C(OCC)C>[F:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([Br:8])[CH:5]=1)[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1cc(F)cc(Br)c1
Yield: 100 %

Procedure:
To a solution of 3,5-dibromofluorobenzene in diethyl ether (100 cm3) at −78° C. was added n-butyl lithium (2.5 M, 8 cm3, 20 mmol) dropwise. After 30 min. the mixture was treated with DMF (20 cm3 diethyl ether (10 cm3 stirring was continued at −78° C. After 30 min. the mixture was quenched with dilute HCl aq., separated and the aqueous layer was extracted with EtOAc. The combined organic layers were combined, washed with water, brine, dried (MgSO4) and evaporated to give 3-fluoro-5-bromobenzaldehyde (4.0 g, 19.7 mmol, 100%) as an oil: 1H NMR (CDCl3) δ inter alia 7.50-7.53 (m, 2H), 7.82 (s, 1H) and 9.93 (m, 1H); MS (EI) m/z 202, 204 [M+].
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17]1[N:18]([CH:23]2[CH2:26][CH2:25][CH2:24]2)[N:19]=[C:20]([CH3:22])[CH:21]=1)=[O:4].[OH-].[Li+]>>[CH:23]1([N:18]2[C:17]([N:6]3[CH2:7][C@H:8]([S:10]([CH2:13][CH:14]4[CH2:16][CH2:15]4)(=[O:11])=[O:12])[CH2:9][C@H:5]3[C:3]([OH:4])=[O:2])=[CH:21][C:20]([CH3:22])=[N:19]2)[CH2:26][CH2:25][CH2:24]1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1c1cc(C)nn1C1CCC1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)CC3CC3)C[C@H]2C(=O)O)n(C2CCC2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-4-cyclopropylmethanesulfonyl-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as off-white solid which was used in the next step without further purification. MS (ESI): m/z=367.2 [M+H]+.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]([N:15]=[C:16]=[O:17])[CH2:12][CH2:13][CH2:14][C:7]1=2>>[CH3:5][O:4][N:3]([CH3:2])[C:16]([NH:15][CH:11]1[C:8]2[CH:9]=[CH:10][S:6][C:7]=2[CH2:14][CH2:13][CH2:12]1)=[O:17]
Reactant: CNOC
Reactant: O=C=NC1CCCc2sccc21
Agent: Cl
Product: CON(C)C(=O)NC1CCCc2sccc21

Procedure:
Following the procedure described in Example 6, N,O-dimethyl hydroxylamine hydrochloride and 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate are allowed to react to give 1-methoxy-1-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, which is crystallized from acetone-hexane-ether to give product melting at 60° C. to 62.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:28])[C:15](=[O:27])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([OH:26])[CH:17]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.Br[CH2:32][CH2:33][O:34][CH3:35].CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:28])[C:15](=[O:27])[C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[C:18]([O:26][CH2:32][CH2:33][O:34][CH3:35])[CH:17]=2)=[C:4]([O:29][CH3:30])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(O)cc(C(F)(F)F)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCCOc1cc(C(=O)N(C)c2cnccc2-c2ccc(F)cc2OC)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of N-[4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-3-hydroxy-N-methyl-5-trifluoromethyl-benzamide (0.06 g, 143 μmol) in acetonitrile (1 mL) were added 1-bromo-2-methoxyethane (19.8 mg, 143 μmol) and DIPEA (22.1 mg, 29.9 μL, 171 μmol) and the light yellow suspension was stirred at room temperature for 45 minutes. To the reaction mixture was added potassium carbonate (23.7 mg, 171 μmol) and stirring was continued for 2.75 hours at room temperature. Then the reaction mixture was stirred at reflux temperature for 16 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Light brown solid (0.048 g; 70%). MS (ESI): m/z=479.16 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([N:16]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN.Cl>C1COCC1.C(O)C>[C:1]1([CH2:7][CH2:8][O:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12][CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](OCCc2ccccc2)CC1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: N[C@H]1CC[C@H](OCCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 9 g of trans-2-(4-phenylethyloxy-cyclohexyl)-isoindole-1,3-dione in 60 mL of THF and 150 mL of ethanol was added 3.75 mL of hydrazine hydrate and the mixture heated to reflux for 4 h, then 80 mL of 6N HCl was added and the reflux was continued for 1 h. The cooled mixture was concentrated under reduced pressure to remove ethanol and filtered. The filter pad was washed with 2×50 mL of dilute HCl and the combined filtrates basified to pH 10 with 20% sodium hydroxide and extracted with 3×150 mL portions of chloroform. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Further drying under vacuum gave 6 g of product as an oil. MS (m+1)=220.2; 1H NMR (400 MHz, CDCl3) 7.3-7.1 (m, 5H), 3.7 (t 2H), 3.2 (m, 1H), 2.9 (t, 2H), 2.7 (m, 1H), 2.0 (d, 2H), 1.85 (d, 2H), 1.4 (br s, 2H), 1.3 (dd, 2H), 1.15 (dd, 2H).
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=1Cl)=[S:6])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.O>CS(C)=O>[C:1]([C:5]1[S:6][C:9]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]([Cl:14])=[CH:13][C:8]=2[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C(=S)Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc2cc(Cl)c([N+](=O)[O-])cc2s1

Procedure:
A mixture of 94 g of N-tert-butylthiocarbonyl-2,5-dichloro-4-nitroaniline, described in Example 1, in 360 ml of dimethylsulphoxide and 160 ml of triethylamine is heated at 140° for 10 hours under nitrogen. The reaction mixture is cooled and poured into water. The solid obtained is filtered and washed with water and air-dried to yield 2-tert-butyl-5-chloro-6-nitrobenzothiazole, melting at 65°-69°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]([CH3:15])[CH3:14])[C:5]([O:7]C)=O.[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:28][CH:27]=3)[S:23][C:22]=2[CH:40]=1>>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[C:25]([C:5]([C:4]3[CH:9]=[CH:10][C:11]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:2]([Br:1])[CH:3]=3)=[O:7])=[C:24]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:30][CH:31]=3)[S:23][C:22]=2[CH:40]=1
Reactant: COc1ccc2cc(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Reactant: COC(=O)c1ccc(CN(C)C)c(Br)c1
Product: COc1ccc2c(C(=O)c3ccc(CN(C)C)c(Br)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Yield: 66 %

Procedure:
By essentially following the procedure used to prepare Example 137, Part C, the title compound was prepared from methyl 3-bromo-4-[(dimethylamino)methyl]benzoate (Part A) and 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Example 1, Part B) in 66% yield.
Reaction SMILES: O.[S:2](=[O:6])(=[O:5])([OH:4])[OH:3].[CH3:7][CH2:8][CH2:9][CH2:10][C:11]1[O:19][C:18]2[CH:17]=[CH:16][C:15]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:14][C:13]=2[C:12]=1[C:25]([C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][CH2:36][N:37]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:31][CH:32]=1)=[O:26].Cl>CC(C)=O>[CH3:7][CH2:8][CH2:9][CH2:10][C:11]1[O:19][C:18]2[CH:17]=[CH:16][C:15]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:14][C:13]=2[C:12]=1[C:25]([C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][CH2:36][N:37]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:31][CH:32]=1)=[O:26].[S:2]([O-:6])([O-:5])(=[O:4])=[O:3]
Reactant: O=S(=O)(O)O
Agent: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=S(=O)([O-])[O-]
Temperature: 52 °C
Reaction time: 1 h

Procedure:
The obtained oily product was dissolved in 12 mL acetone to obtain a mixture, then 2 mL water were added to the mixture. Then, a solution of 1.1 mL concentrated sulfuric acid in 3 mL acetone was added dropwise under 10˜15° C. in about 20 min. Then, the mixture was heated to 52° C. and stirred for 1 h. The mixture was cooled by ice water bath under stirring for crystallization. After about 3.5 h later, lots of solid was precipitated. The solid obtained was filtered and dried at 50° C. under vacuum to obtain 5.5 g targeted compound. Yield: 84%, (Calculation by dronedarone hydrochloride), Purity of HPLC: 99.85%.
Reaction SMILES: C[C@@]12[C@H]3[C@@H](O)C[C@]4(C)[C@@](O)(C(CO)=O)CC[C@H]4[C@@H]3CCC1=CC(=[O:6])CC2.C(N(CCC)C(=O)CCC(O)=O)CC.[CH:41]1([N:47]=[C:48]=[N:49][CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.ClCCl>N1C=CC=CC=1>[C:48]([NH:47][CH:41]1[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]1)([NH:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)=[O:6]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Agent: CCCN(CCC)C(=O)CCC(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
To a solution of hydrocortisone (5 g, 0.014 mole) and N,N-di-n-propylsuccinamic acid (2.78 g, 0.014 mole) in 25 ml pyridine at room temperature was added dicyclohexylcarbodiimide (2.85 g, 0.014 mole). After the reaction was stirred 10 minutes, 25 ml dichloromethane was added to it to keep the suspension which had formed sufficiently fluid for stirring. After the reaction was stirred overnight, it was filtered. The residue was washed twice with CH2Cl2 and dried in the air to give 2.46 g (91% yield) dicyclohexylurea. The filtrate was concentrated in vacuo to a residue which was dissolved in 25 ml hot THF. After the THF solution was filtered while hot, the resulting filtrate was diluted to 150 ml with Et2O. The product crystallized overnight and was filtered and dried to give 3.49 g of light brown crystals, which a preliminary NMR showed to be contaminated with solvent. The crystals were dried in vacuo (50° C., 2 hours) to give 2.81 g (37% yield) of the desired product: mp 157°-162° C.; NMR (CDCl3) δ5.64 (s, 1, O=C-CH=), 4.98 (m, 2, O=C-CH2O), 4.46 (m, 1, CHOH), 3.8-4.2 (m, 2, OH), 3.24 (t, 4, J=7 Hz, N CH2), 2.70 (s, 4, OCCH2CH2CO), 1.46 (s, 3, C-CH3), 0.96 (s, 3, C-CH3), 0.94 (m, 6, N(CH2CH2CH3)2), 2.9-0.8 (m, 21, CH, CH2); TLC (silica gel, 10% MeOH/Et2O) Rf 0.56; [α]25D=+127° (C=0.5, dioxane); IR (KBr) 3400 cm-1 (s) (OH), 1730, 1710, 1640 and 1610 cm-1 (s) (C=O).