Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1>C1COCC1.C(OCC)(=O)C.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:29][C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([C:41]4[CH:40]=[N:39][N:38]([CH3:37])[CH:42]=4)=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@@H]1CCCC[C@H]1O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(Cc3cc4c(=O)n([C@@H]5CCCC[C@H]5O)cnc4c4ccccc34)cn2)cn1
Temperature: 100 °C

Procedure:
To a solution of rac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one (0.080 g, 0.19 mmol) in 3 mL of THF under an atmosphere of nitrogen was added cesium carbonate (0.38 mL, 1 N aqueous, 0.38 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.079 g, 0.38 mmol), and bis(tri-tert-butylphosphine)palladium(0) (10 mol %). The reaction was heated at 100° C. for 20 h, cooled to rt, and diluted with ethyl acetate and water. The organic layer was removed and washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 100% ethyl acetate, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 466.0 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 9.02-8.99 (m, 1H), 8.67 (br s, 1H), 8.61 (s, 1H), 8.33 (s, 1H), 8.23 (d, J=7.5 Hz, 1H), 8.03-8.00 (m, 2H), 7.82-7.62 (m, 4H), 4.60 (s, 2H), 4.10-4.04 (m, 1H), 3.89 (s, 3H), 2.08-2.00 (m, 1H), 1.93-1.83 (m, 1H), 1.90-1.72 (m, 3H), 1.38-1.30 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].C(Cl)(=O)C([Cl:18])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([Cl:18])=[O:13])[S:10][C:3]=12
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2nccc(Cl)c2s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 100 mL round bottom flask was charged with lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (0.500 g, 2.28 mmol), methylene chloride (15 ml), and 6 drops of DMF. Oxalyl chloride (0.248 ml, 2.85 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 3 hours then concentrated in vacuo to yield 7-chlorothieno[3,2-b]pyridine-2-carbonyl chloride as a brown solid. This material was suspended in chloroform (5 mL). N′-hydroxyacetamidine (0.186 g, 2.50 mmol), triethylamine (0.347 ml, 2.50 mmol), and chloroform (15 mL) were stirred together in a 50 mL flask to form a slurry, which was slowly added to the 7-chlorothieno[3,2-b]pyridine-2-carbonyl chloride suspension, then stirred for 1.5 hours at room temperature. The reaction mixture was diluted with chloroform (50 mL) and washed with water (50 mL), sat. aq. NaHCO3 (50 mL) and brine (50 mL). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo. The resulting brown solid was triturated with toluene, and the precipitate collected to obtain the title compound (0.282 g, 46% yield) as a tan solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C@@H:33]2[CH2:37][NH:36][CH2:35][C@H:34]2[OH:38])[CH2:29][CH2:28]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:36]3[CH2:37][C@@H:33]([N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)[C@H:34]([OH:38])[CH2:35]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: CN1CCN([C@@H]2CNC[C@H]2O)CC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3C[C@@H](O)[C@H](N4CCN(C)CC4)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 8-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3R,4R)-4-(4-methylpiperazin-1-yl)pyrrolidin-3-ol. MS obsd. (ESI+) [(M+H)+] 522, 1H NMR (400 MHz, CD3OD) δ ppm 7.99-7.86 (m, 1 H), 7.84-7.75 (m, 1 H), 7.73 (s, 1 H), 7.64-7.52 (m, 1 H), 7.47 (d, J=8.59 Hz, 1 H), 7.43-7.32 (m, 1 H), 7.27 (d, J=8.59 Hz, 1 H), 6.27-6.09 (m, 1 H), 5.10 (brs, 2 H), 4.50 (brs, 1 H), 4.43-4.33 (m, 1 H), 3.81-3.62 (m, 2 H), 3.56 (dd, J=9.85, 4.55 Hz, 3 H), 3.45-3.35 (m, 1 H), 3.02-2.92 (m, 1 H), 2.84 (brs, 2 H), 2.76-2.62 (m, 3 H), 2.57 (brs, 3 H), 2.39 (s, 3 H), 2.32 (s, 3 H).
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[C:17][Si](C)(C)C)[C:11]=1[F:22])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].CCO.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)(Cl)Cl>[C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[CH:17])[C:11]=1[F:22])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(C#C[Si](C)(C)C)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: C#Cc1cccc(CO[Si](C)(C)C(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
tert-Butyl({2-fluoro-3-[(trimethylsilyl)ethynyl]benzyl}oxy)dimethylsilane (4.13 g) was mixed with EtOH (61 ml), and potassium carbonate (847 mg) was added thereto, followed by stirring at room temperature for 1 hour. Water and CHCl3 were added to the reaction mixture at 0° C., and the organic layer was washed with water and saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain tert-butyl[(3-ethynyl-2-fluorobenzyl)oxy]dimethylsilane (3.19 g).
Reaction SMILES: [H-].[Li+].[CH3:3][O:4][C:5]([C:7]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[F:21])=[C:11]([F:22])[C:10](=[O:23])[NH:9][CH:8]=1)=[O:6].Br.Br[CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[F:21])=[C:11]([F:22])[C:10](=[O:23])[N:9]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:8]=1)=[O:6]
Reactant: BrCc1cccnc1
Reactant: COC(=O)c1c[nH]c(=O)c(F)c1Nc1ccc(Br)cc1F
Agent: Br
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(Cc2cccnc2)c(=O)c(F)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Lithium hydride (14 mg, 1.64 mmol) was added to a stirred solution of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (0.190 g, 0.529 mmol) in DMF (5 mL) at 0° C. After stirring for 30 minutes, 3-bromomethyl-pyridine hydrobromide (0.14 g, 0.53 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours. After quenching with ice water, the reaction mixture was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (1% MeOH in methylene chloride) yielded 4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylic acid methyl ester. The methyl ester was dissolved in 4:1 THF:MeOH (5 mL) and 1 M LiOH solution (1.1 mL) was added. After 1 hour, the reaction mixture was acidified to pH 1 with 10% aqueous HCl solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Trituration with diethyl ether gave 0.160 g (69% two step yield) clean desired product. MS APCI (−) m/z 434, 436 (M−, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 9.40 (bs, 1H), 8.65 (s, 1H), 8.61 (s, 1H), 8.51 (d, 1H), 7.74 (d, 1H), 7.58 (d, 1H), 7.39 (m, 1H), 7.34 (s, 1H), 7.16 (m, 1H), 0.525 (s, 1H).
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])(=O)=O.[Br:19][C:20]1[CH:21]=[CH:22][C:23](=O)[NH:24][CH:25]=1.N1C(C)=CC=CC=1C.O>ClCCl>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[N:24][CH:25]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O=c1ccc(Br)c[nH]1
Solvent: O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)[Si](Oc1ccc(Br)cn1)(C(C)C)C(C)C
Reaction time: 0.25 h
Yield: 100.7 %

Procedure:
Triisopropylsilyl trifluoromethanesulfonate (65.4 g) was added dropwise to a solution of 5-bromo-2(1H)-pyridinone (33.8 g) and 2,6-lutidine (31.1 g) in 775 ml of dichloromethane at 0° C. The resulting solution was stirred for 15 minutes, and then it was poured into water and the layers were separated. The aqueous phase was extracted with dichloromethane, and the combined organic layers were dried over magnesium sulfate and concentrated to give a liquid. The product was slurried with silica gel and hexanes. Filtration gave 64.6 g of oil.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH:12]=[C:11]([CH3:18])[N:10]=2)=CC=1.S(=O)(=O)(O)O.O.N>FC(F)(F)C(O)=O>[NH2:8][C:9]1[C:14]2[CH:15]=[CH:16][S:17][C:13]=2[CH:12]=[C:11]([CH3:18])[N:10]=1
Reactant: COc1ccc(CNc2nc(C)cc3sccc23)cc1
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2sccc2c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.2 %

Procedure:
To a solution of 24 g of 4-(4-methoxybenzyl)amino-6-methylthieno[3,2-c]pyridine in 80 ml of trifluoroacetic acid was added 15 ml of concentrated sulfuric acid, and the mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was poured into ice water, rendered alkaline by the addition of 28% ammonia water and extracted with chloroform. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel and recrystallized from chloroform/petroleum ether to give 15 g of the title compound as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C:10]23[C:16]([CH3:18])([CH3:17])[C:13]([CH3:19])([CH2:14][CH2:15]2)[C:12](=[O:20])[CH2:11]3)[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[CH:31]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:29]=[CH:28][C:25]=1[CH:26]=O.C([O-])(=O)C.[NH4+]>CCO>[Cl:21][C:5]1[C:6]([NH:9][C:10]23[C:16]([CH3:17])([CH3:18])[C:13]([CH3:19])([CH2:14][CH2:15]2)[C:12](=[O:20])[CH2:11]3)=[C:7]2[N:8]=[C:26]([C:25]3[CH:28]=[CH:29][C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:31][C:24]=3[O:23][CH3:22])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CC12CCC(Nc3c(Cl)cnc(N)c3N)(CC1=O)C2(C)C
Reactant: COc1cc(N2CCOCC2)ccc1C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1cc(N2CCOCC2)ccc1-c1nc2c(NC34CCC(C)(C(=O)C3)C4(C)C)c(Cl)cnc2[nH]1
Temperature: 70 °C

Procedure:
4-(2,3-diamino-5-chloropyridin-4-ylamino)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (10) (300 mg, 0.97 mmol), 2-methoxy-4-morpholinobenzaldehyde (193 mg, 0.873 mmol) were taken in EtOH (15 ml) to which ammonium acetate (112 mg) was added and the reaction mixture was heated at 70° C. for 48 h. Crude LCMS showed the desired product along with trace of starting material. The reaction mixture was allowed to come to rt and the precipitated was filtered and washed well with ethanol to afford the desired product (495 mg, 24%) as an off white solid. NMR: δ (1H, 400M Hz, DMSO-d6): 0.91 (6H, s), 1.09 (3H, s), 1.40-1.50 (1H, m), 1.70-1.90 (2H, m), 2.40-2.60 (1H, m), 3.00-3.10 (1H, m), 3.20-3.40 (4H, m), 3.60-3.80 (5H, m), 3.94 (3H, s), 5.36 (1H, s), 6.64 (1H, s), 6.72 (1H, d, J=8.8 Hz), 7.94 (1H, d, J=8.8 Hz), 8.01 (1H, s), 12.29 (1H, s). LCMS (254 nm): [M+H]+ 510.25 (98.08%). HPLC: (220 nm) 97.36%
Reaction SMILES: [OH-].[K+].[SH2:3].[CH3:4][O:5][C:6](=[O:18])[C:7]([C:14]([O:16][CH3:17])=[O:15])=[C:8]([CH2:12]Cl)[CH:9]=[CH:10]Cl>C(O)C.O.CCOCC>[S:3]1[CH:10]=[CH:9][C:8]([CH:7]([C:14]([O:16][CH3:17])=[O:15])[C:6]([O:5][CH3:4])=[O:18])=[CH:12]1
Reactant: S
Reactant: COC(=O)C(C(=O)OC)=C(C=CCl)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: COC(=O)C(C(=O)OC)c1ccsc1
Reaction time: 1 h
Yield: 74 %

Procedure:
Potassium hydroxide (0.14 g, 2.0 mmol) in ethanol (50 ml) was saturated with hydrogen sulphide at 0° C. To this was added methyl-2-methoxycarbonyl-5-chloro-3-chloromethylpenta-2,4-dienoate (0.62 g, 2.45 mmol) and addition of hydrogen sulphide was continued for 1 hour at room temperature. The reaction mixture was stirred for a further 4 hours. Potassium hydroxide (0.20 g, 2.8 mmol) was added and hydrogen sulphide passed for 0.5 hours. The reaction mixture was stirred at room temperature for 16 hours, diluted with water and ether extracted. The extracts were washed with saturated brine, dried and evaporated to give the title compound (0.39 g, 74%), b.p. 96°-98° C./0.3 mm. δ (CDCl3) 3.77 (6H, s, 2×CH3), 4.82 (1H, s, CH), 7.11-7.48 (3H, m, thienyl protons). νmax (film) 1740 cm-1C9H10O4S requires M,214. Found: M+, 214.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:16])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Br)=[C:8]([O:14][CH3:15])[CH:7]=[CH:6][CH:5]=2.[NH3:17]>O1CCCC1>[NH2:17][C:11]1[C:10](=[O:13])[C:9]2[C:4]([C:3](=[O:16])[C:2]=1[Br:1])=[CH:5][CH:6]=[CH:7][C:8]=2[O:14][CH3:15]
Reactant: COc1cccc2c1C(=O)C(Br)=C(Br)C2=O
Reactant: N
Solvent: C1CCOC1
Product: COc1cccc2c1C(=O)C(N)=C(Br)C2=O
Yield: 82 %

Procedure:
To a solution of 500.0 mg (1.5 mmol) of 2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methoxynaphthalene in 25 mL of tetrahydrofuran, a drop of ammonia is added. The color of the reaction medium turns black. A current of ammonia is passed through the medium for 2 h at 20° C. The raw product obtained after evaporation of the solvent is purified on cake (support: silica; eluant: dichloromethane/heptane, 80/20) to produce 347.3 g of a mixture of 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methoxynaphthalene and 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methoxynaphthalene.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH3:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[O:23][CH2:24][CH2:25][NH2:26].[C:31]([OH:40])(=[O:39])[C:32]1[C:33](=[CH:35][CH:36]=[CH:37][CH:38]=1)[OH:34]>CC(O)C>[CH3:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[O:23][CH2:24][CH2:25][NH:26][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]=12.[C:31]([O-:40])(=[O:39])[C:32]1[C:33](=[CH:35][CH:36]=[CH:37][CH:38]=1)[OH:34]
Reactant: O=C(O)c1ccccc1O
Reactant: COc1ccccc1OCCN
Reactant: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Solvent: CC(C)O
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Product: O=C([O-])c1ccccc1O
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A mixture of 4-(oxiran-2-ylmethoxy)-9H-carbazole (II) (25.0 g, 104.60 mmole) and 62.5 ml 2-propanol is heated to 70° C. to 80° C. To this 2-(2-methoxyphenoxy)ethylamine (III) (25.33 g, 151.67 mmole) is added in one lot. The temperature of the reaction mass is then raised to 80° C. to 82° C. and refluxed for 1 hour. The reaction mixture is added into the preheated (80° C. to 85° C.) solution of salicylic acid (18.77 g, 135.98 mmoles) in 187.5 ml of 2-propanol. The reaction mass is further refluxed for 2 hours, cooled to 50° C. to 55° C. and stirred for 1 hour at this temperature. The solid is filtered, followed by three 33 ml wash with hot (50° C. to 55° C.) 2-propanol. The wet product dried at 60° C. to 65° C. for 6 hours or till constant weight gives 39.75 g (Yield 70%) of Carvedilol salicylate, which contains about 2-2.5% of compound (IV) as an impurity.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:8][C:7]=1[CH3:22].[OH-].[Na+].C1COCC1.Cl>CO>[F:35][C:2]([F:1])([F:34])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][N:17]=2)=[CH:8][C:7]=1[CH3:22]
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-c3ncc(C(F)(F)F)cn3)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2ncc(C(F)(F)F)cn2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)O)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A reaction mixture of methyl 4-((4,4,4-trifluoro-1-(2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)phenyl)butyl)amino)benzoate (4.93 g), 1M aqueous sodium hydroxide solution (39.6 mL), THF (40 mL) and methanol (40 mL) was stirred at 70° C. overnight. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a crudely purified product. This compound was used in step C without further purification.
Reaction SMILES: [Cl:1]C1C=CC(S)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].S([N:25]1[CH2:30][CH2:29][CH2:28][CH:27]([S:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[CH2:26]1)(C1C=CC(C)=CC=1)(=O)=O.C1(O)C=CC=CC=1>CN(C)C=O.Br>[ClH:1].[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([S:31][CH:27]2[CH2:28][CH2:29][CH2:30][NH:25][CH2:26]2)=[CH:37][CH:36]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(Sc3ccc(Cl)cc3)C2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: Cl
Product: Clc1ccc(SC2CCCNC2)cc1
Temperature: 100 °C

Procedure:
A mixture of 54 g (0.375 mole) of p-chlorothiophenol, 51.4 g (0.126 mole) of 1-[(4-methylphenyl)sulfonyl]-3-piperidinol-4-methylphenylsulfonate ester and 35 g of sodium carbonate in 500 ml of dimethylformamide was heated at 100° C. for 18 hr. The mixture was cooled and quenched in excess 1M sodium hydroxide solution. The aqueous mixture was extracted with several portions of methylene chloride and the combined methylene chloride extracts were extracted with several portions of 1M sodium hydroxide solution and dried over magnesium sulfate. The solvent was removed in vacuo to give an oil which was shown by NMR, mass spectrum and TLC to be impure N-tosyl-3-(p-chlorothiophenoxy)piperidine. (See Preparation 13 for the pure compound). A mixture of this compound and excess phenol in 75 ml of 48% hydrobromic acid was refluxed for 1 hr and quenched in an ice-water mix. The mixture was made basic with sodium hydroxide and was extracted with several portions of methylene chloride. The aqueous layer was discarded. The combined methylene chloride extracts were dried over magnesium sulfate and the methylene chloride was removed in vacuo to give an oil, the free base of the title compound. The free base was reacted with hydrogen chloride using the solvent pair diethyl ether-methanol for crystallization and recrystallization to obtain the white crystalline hydrochloride salt, m.p. 159°-161° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].N[C@@H:14](C1CCCC1)[C:15](O)=O>>[CH:7]1([C@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[C:10]([OH:12])=[O:11])[CH2:9][CH2:15][CH2:14][CH2:8]1
Reactant: N[C@H](C(=O)O)C1CCCC1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Product: COC(=O)N[C@H](C(=O)O)C1CCCC1

Procedure:
(S)-2-cyclopentyl-2-(methoxycarbonylamino)acetic acid was synthesized similar to N-methoxycarbonyl-L-Valine, using (S)-2-amino-2-cyclopentylacetic acid instead of L-Valine.
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([OH:14])=[O:13])[CH2:4]1.[CH3:15][C:16](Cl)([CH3:18])[CH3:17].CN1CCCC1=[O:26]>C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC>[OH:26][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:16]([CH3:18])([CH3:17])[CH3:15])=[O:13])[CH2:4]1
Reactant: CC(C)(C)Cl
Reactant: CN1CCCC1=O
Reactant: CC1(C)O[C@H](CCl)C[C@H](CC(=O)O)O1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Temperature: 85 °C
Reaction time: 0.75 h

Procedure:
Solid tetra-n-butylammonium acetate prepared in step (e) (i) of Example 1 above (106.2 g, 0,352 mole) was added in one portion to a mechanically stirred solution of the chloride (4R-cis)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid, 1,1-dimethylethyl ester prepared in step (d) of Example 1 above (32.7 g, 0. 117 mole) in HPLC grade 1-methyl-2-pyrrolidinone (471 ml) under argon. The resulting solution was stirred at 85° C. (internal temperature). After 30 to 60 minutes the reaction mixture became homogeneous and brown in color. The progress of the reaction was followed by TLC and GC analysis. (TLC: Rf =0.54 for the title compound; Rf =0.63 for the chloride starting material (silica gel, Ethyl acetate: Hexane, 1:1, visualization by Ce(SO4)2 spray).) After 9 hours the reaction was completed.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12]([O:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=1[F:26])(=[O:14])=[O:13])=[CH:7][CH:6]=2.OO.NC(N)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.P(Br)(Br)([Br:48])=O>O.C(Cl)Cl>[Br:48][C:4]1[C:5]2[C:10](=[CH:9][C:8]([S:12]([O:15][C:16]3[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=3[F:26])(=[O:14])=[O:13])=[CH:7][CH:6]=2)[CH:11]=[C:2]([Cl:1])[N:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2cnc(Cl)cc2c1
Agent: NC(N)=O
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Br)nc(Cl)cc2c1
Reaction time: 15 h
Yield: 33.4 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 3-chloroisoquinoline-6-sulfonate (1.21 g, 2.95 mmol) and DCM (11.81 ml) to give a clear solution. Urea compound with hydrogen peroxide (1:1) (0.556 g, 5.91 mmol) was added, resulting in a suspension. The flask was cooled in an ice-water bath for 10 min, then 2,2,2-trifluoroacetic anhydride (0.834 ml, 5.91 mmol) was added over 20 s. The cooling bath was removed, the flask was sealed, and the mixture was stirred overnight for 15 h. An additional portion of TFAA (0.3 mL) was added, and the mixture was stirred for 5 h. The mixture was carefully quenched with saturated aq. sodium bicarbonate solution (50 mL), then diluted with water and extracted with DCM (3×). The cloudy organic layer was stirred over sodium sulfate for 2 min, which resulted in the formation of an orange solution. The mixture was filtered, and the filtrate was concentrated under a vacuum. The residue was dissolved in DCM (5 mL) to give an orange solution. Phosphoryl tribromide (1.693 g, 5.91 mmol) was added in one portion, and the mixture was stirred further at room temperature. After 1 h, the mixture was poured into ice, then diluted with water and DCM. When it had achieved room temperature, the layers were separated. The aq. layer was extracted with DCM (2×), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The aq. layer was further diluted with water and extracted with DCM (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated with residue from the first organic extraction. The combined residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 25-g loading column, 0-40% EtOAc/Heptane) to give perfluorophenyl 1-bromo-3-chloroisoquinoline-6-sulfonate (0.482 g, 0.986 mmol, 33.4% yield) as a white solid: m/z (ESI) 488.0 (M+H)+.