Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[C:12]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:25][CH2:24][S:23][CH:22]2[C:26](Cl)=[O:27])(=[O:20])=[O:19])=[CH:14][CH:13]=1>O.C1COCC1>[C:12]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:25][CH2:24][S:23][CH:22]2[C:26]([NH:1][CH:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([OH:5])=[O:4])=[O:27])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: NC(C(=O)O)c1ccccc1
Reactant: O=C(Cl)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(NC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
Intermediate VIII (Scheme 3), e.g., 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid (1.747 g, 5 mmol) was dissolved in DCM (20 mL). The resulting solution was cooled down to −10° C. and oxalyl chloride (0.645 mL, 7.5 mmol) was added slowly. DMF (0.1 mL) was added carefully. The reaction mixture was allowed to warm to RT over 1 h and stirred an additional hour at RT. As the reaction was complete, the solvents were evaporated. Toluene was added and evaporated to remove residual oxalyl chloride. This process was repeated twice, affording intermediate XXX, e.g., 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carbonyl chloride as a yellow solid (1.839 g, quantitative yield). α-Aminophenylacetic acid (831 mg, 5.5 mmol) was dissolved in water (20 mL). TEA (2.77 mL, 20 mmol) was added carefully. THF (25 mL) was added to reaction mixture. The reaction mixture was cooled to 0° C. Acid chloride previously prepared XXX, e.g. 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carbonyl chloride dissolved in THF (25 mL) was added dropwise. The reaction mixture was stirred 15 min at 0° C. and overnight at RT. Solvents were concentrated and the resulting aqueous fraction was acidified with HCl 5N and extracted with 3 portions of EtOAc. Combined organic phases were dried over MgSO4, filtrated and evaporated. The crude product was recrystallized in acetone/Et2O mixture, affording carboxylic acid Ia, e.g., ({[3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)(phenyl)acetic acid in 97% purity by HPLC (943 mg, 39% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[F:10].C([Li])CCC.[CH:16]([CH:18]=[CH2:19])=[O:17].OS(O)(=O)=O>CCOCC.CCCCCC>[CH:18]([CH:16]([C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[F:10])[OH:17])=[CH2:19]
Reactant: Fc1cc(F)c(F)c(Br)c1
Reactant: C=CC=O
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: C=CC(O)c1cc(F)cc(F)c1F
Temperature: -73 °C
Reaction time: 0.03 h

Procedure:
A solution of 4.1 g (0.0194 mol) of 1-bromo-2,3,5-trifluorobenzene in 50 ml of anhydrous ether is cooled to -76 ° C. under a nitrogen atmosphere. 12.1 ml (0.0194 mol) of a 1.6M solution of n-butyllithium in hexane are added dropwise over 15 minutes at a temperature below -72° C. The mixture is stirred for 2 minutes at -73° C. and then a solution of 1.15 g (0.0205 mol) of acrolein in 5 ml of anhydrous ether is added dropwise. The mixture is stirred for 30 minutes at -70° C. and is then allowed to return to room temperature. The mixture is poured onto a mixture of 100 g of ice and 10 g of concentrated H2SO4. Extraction with ether, washing with water, drying over Na2SO4, filtration and concentration under vacuum are carried out. The residue obtained is used without other purification in the following stage. Weight obtained: 3.1 g (Yd.=86%)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH2:24][CH:25]3[CH2:27][S:26]3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:10][C:9]=1[O:28]COC)(C)(C)C>CO.Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH2:24][CH:25]3[CH2:27][S:26]3)(=[O:23])=[O:22])=[CH:19][CH:20]=2)=[CH:10][C:9]=1[OH:28]
Reactant: COCOc1cc(Oc2ccc(S(=O)(=O)CC3CS3)cc2)ccc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: Nc1ccc(Oc2ccc(S(=O)(=O)CC3CS3)cc2)cc1O
Yield: 95 %

Procedure:
To a solution of compound 21 (0.10 mg, 0.21 mmol) in methanol (5 mL) was added a few drops of conc. HCl. After the mixture was stirred at reflux for 1 h, the solvent was evaporated in vacuo. The crude product was taken up into water and EtOAc. Layers were separated and the aqueous layer was washed with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, the suspension was filtered and the filtrate was concentrated in vacuo. Purification by silica gel chromatography (hexanes/EtOAc=1/1) gave 22 in 95% yield (66 mg). 1H NMR (500 MHz, CDCl3) 82.14 (dd, J=1.3, 4.9 Hz, 1H), 2.18 (d, J=1.0 Hz, 1H), 2.56-2.49 (m, 1H), 3.08-3.00 (m, 1H), 3.17 (dd, J=7.8, 14.4 Hz, 1H), 3.51 (dd, J=5.6, 14.2 Hz, 2H), 6.54-6.46 (m, 2H), 6.80-6.73 (m, 1H), 7.07-6.97 (m, 2H), 7.80 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 24.4, 26.3, 62.8, 108.5, 113.1, 117.2, 117.9, 130.7, 131.1, 131.9, 145.9, 147.3, 164.1. HRMS (FAB) calcd for C15H16NO4S2 (M+H+) 338.0515. found 338.0507.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH:26]1([C:29]([NH:31][NH2:32])=[O:30])[CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([NH:32][NH:31][C:29]([CH:26]2[CH2:28][CH2:27]2)=[O:30])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)C1CC1
Reactant: O=C(O)Cc1cccc(Br)n1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(Br)n1)NNC(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(6-Bromopyridin-2-yl)acetic acid (Example 235, Step 2) (41% wt, 1.50 g, 2.85 mmol), EDC (1.64 g, 8.54 mmol), HOBT (872 mg, 5.69 mmol), and cyclopropanecarboxylic acid hydrazide (570 mg, 5.69 mmol) were combined in DMF (15 mL), and DIEA (994 μL, 5.69 mmol) was added. The reaction was stirred overnight at room temperature. After evaporation of the DMF, the residue was diluted with water and extracted with 5:1 CH2Cl2:MeOH (3×). The combined organic layers were dried (MgSO4), filtered, and evaporated. The solid residue was triturated with CH2Cl2 and filtered to isolate the title compound as a colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=1[CH3:18])C.Cl>[OH-].[K+]>[CH3:18][C:9]1[C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=1[CH2:7][CH2:6][CH2:5][C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)CCCc1ccc(C)c([N+](=O)[O-])c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(CCCC(=O)O)c(C)c1[N+](=O)[O-]
Temperature: 120 °C
Yield: 79.6 %

Procedure:
A suspension of 4-(2,4-dimethyl-3-nitro-phenyl)-butyric acid ethyl ester (4 g, 16.9 mmol) in 100 ml of 5% KOH was refluxed at 120° C. for 4 hours. This reaction was then cooled to 0° C. and neutralized with 10% HCl to pH 3-4. The resulting solid was filtered and washed with water. After drying under reduced pressure at 40° C., 3.19 g (80%) of pure product as a white solid was obtained. 1H-NMR δ (DMSO-d6, 300 MHz): 12.12 (brs, 1H, exchangeable with D2O), 7.26 (d, J=7.8 Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 2.61 (t, J=7.8 Hz, 2H), 2.25 (t, J=7.8 Hz, 2H), 2.17 (s, 3H), 2.13 (s, 3H), 1.70 (m, J=7.8 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[C:10]1[C:15](N)=[CH:14][CH:13]=[C:12](C)[C:11]=1[OH:18].Cl>[OH-].[Na+]>[CH:7]1[C:2](=[N:1][C:14]2[CH:13]=[CH:12][C:11]([OH:18])=[CH:10][CH:15]=2)[CH:3]=[CH:4][C:5](=[O:8])[CH:6]=1
Reactant: Cc1ccc(N)c(C)c1O
Reactant: Nc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1C=CC(=Nc2ccc(O)cc2)C=C1
Yield: 106.4 %

Procedure:
A first solution is prepared by dissolving 0.02 mole (2.18 g) of paraaminophenol in 200 cm3 of a 0.1 N NaOH solution. A second solution is prepared by dissolving 0.01 mole (1.37 g) of 2,6-dimethyl-3-amino phenol also in 100 cm3 of 0.1 N NaOH solution. The two solutions are mixed and air is bubbles for 2 hours in the resulting mixture at ambient temperature. The pH of the reaction mass in then brought to 5 by addition of an aqueous hydrochloric acid solution. The reaction mass is then filtered off to produce 2.12 g of said indophenol which, after recrystallization in a dimethylformamide-water mixture, melts at 248°C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:7]=[N+:8]([O-:12])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[Br:5][C:6]1[CH:7]=[N+:8]([O-:12])[CH:9]=[CH:10][C:11]=1[N+:1]([O-:4])=[O:2]
Reactant: [O-][n+]1cccc(Br)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc[n+]([O-])cc1Br
Temperature: 90 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Concentrated nitric acid (128 ml) and concentrated sulfuric acid (77 ml) were slowly added to a solution of 3-bromopyridin-N-oxide (31.9 g, 181.0 mmol) prepared in Step 1 in concentrated sulfuric acid (77 ml), while maintaining the temperature at 0° C.˜5° C. The reaction mixture was stirred at 90° C. for 2 hours and then cooled to room temperature. The reaction mixture was added to 1000 ml of ice water, which was then brought to pH 8 with 50% sodium hydroxide solution. The resulting precipitate was filtered and dried to give the titled compound as a yellow solid (29.3 g, 72.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([OH:15])[CH:10]=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.O1CCC[CH2:17]1.CC(C)([O-])C.[K+].CI>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([O:15][CH3:17])[CH:10]=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: N#Cc1ccn(O)c1-c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COn1ccc(C#N)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a stirred solution of 2-(p-chlorophenyl)-1-hydroxypyrrole-3-carbonitrile (2.88 g, 0.0132 mol) and anhydrous tetrahydrofuran is added potassium tert-butoxide (1.55 g, 0.0138 mol). After 30 minutes, methyl iodide (2.06 g, 0.9 mL, 0.0145 mol) is added and the resulting slurry is stirred at room temperature for 3 hours, diluted with water and extracted with ether. The combined ether extracts are washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a solid. Crystallization of the solid from ether/hexanes gives the title compound as a brown solid (2.35 g, 77%), mp 105° C.-106° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][S:16]([CH2:19][C:20]3[NH:21][C:22](=[O:25])[NH:23][N:24]=3)(=[O:18])=[O:17])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[O:26]=[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=[C:29]([C:37](OCC)=[O:38])[NH:28]1.C(N(CC)CC)C.CC(N(C)C)=O>CCO.C(OCC)(=O)C>[O:26]=[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=[C:29]([C:37]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:14]=[CH:13][C:12]([CH2:15][S:16]([CH2:19][C:20]4[NH:21][C:22](=[O:25])[NH:23][N:24]=4)(=[O:17])=[O:18])=[CH:11][CH:10]=3)[CH:6]=[CH:7][CH:8]=2)=[O:38])[NH:28]1
Reactant: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Reactant: NCc1cccc(-c2ccc(CS(=O)(=O)Cc3n[nH]c(=O)[nH]3)cc2)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: O=C(NCc1cccc(-c2ccc(CS(=O)(=O)Cc3n[nH]c(=O)[nH]3)cc2)c1)c1nc2ccccc2c(=O)[nH]1
Yield: 55 %

Procedure:
A solution of 5-[({[3′-(aminomethyl)biphenyl-4-yl]methyl}sulfonyl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one obtained in Reference Example 111 (0.060 g, 0.167 mmol), ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate obtained according to the methods described in Journal of Organic Chemistry (1978), 43(23), 4485-7 and the like (0.024 g, 0.112 mmol) and triethylamine (0.389 mL, 1.12 mmol) in EtOH (3 mL)-DMA (3 mL) was stirred at 90° C. for 24 hr. The reaction mixture was diluted with ethyl acetate, washed with 0.1N hydrochloric acid and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from EtOH-diethyl ether to give the title compound as a pale-yellow powder (0.032 g, 55%).
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([OH:8])[CH2:5][N:4]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[CH3:19]I.[H-].[Na+]>C1COCC1>[F:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][CH3:19])[CH2:5][N:4]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: CI
Reactant: O=C(OCc1ccccc1)N1C[C@H](O)C[C@H]1CF
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1C[C@@H](CF)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of benzyl (2S,4R)-2-(fluoromethyl)-4-hydroxypyrrolidine-1-carboxylate (500 mg, 1.97 mmol) in THF (6.6 mL) at 0° C. was added methyl iodide (0.43 mL, 3.44 mmol) followed by sodium hydride (104 mg, 4.34 mmol). The mixture was stirred for 2 hours at room temperature. The reaction was quenched with ice, and diluted with diethyl ether. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford benzyl (2S,4R)-2-(fluoromethyl)-4-methoxypyrrolidine-1-carboxylate. MS ESI calc'd. for C14H18FNO3 [M+H]+ 268. found 268.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[C:19](O)=[O:20].[CH3:22][O:23][C:24](=[O:42])[C@H:25]([NH2:41])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Cl:40])[CH:34]=2)=[CH:29][CH:28]=1>>[CH3:22][O:23][C:24](=[O:42])[C@H:25]([NH:41][C:19]([C:4]1[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:20])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Cl:40])[CH:34]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)[C@H](N)Cc1ccc(-c2ccc(F)c(Cl)c2)cc1
Reactant: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)O
Product: COC(=O)[C@@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1OC
Yield: 76.1 %

Procedure:
3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(R)-[(4-methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester (223 mg) was prepared from 4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (141 mg, 0.5 mmol) and-2-(R)-amino-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester (155 mg, 0.5 mmol) following the general procedure A.
Reaction SMILES: C(N)C1C=CC=CC=1.O1CC1COC1C2C3C(=CC=CC=3)NC=2C=CC=1.[CH3:27][O:28][C:29]1[C:34]([O:35][CH2:36][CH2:37][N:38]([CH2:46][CH:47]([OH:63])[CH2:48][O:49][C:50]2[C:55]3[C:56]4[C:61]([NH:62][C:54]=3[CH:53]=[CH:52][CH:51]=2)=[CH:60][CH:59]=[CH:58][CH:57]=4)CC2C=CC=CC=2)=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OC(=O)C)C.C(O)(=O)C.[Pd].[Cl-].[Cl-].[Zn+2]>[CH3:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][NH:38][CH2:46][CH:47]([OH:63])[CH2:48][O:49][C:50]1[CH:51]=[CH:52][CH:53]=[C:54]2[NH:62][C:61]3[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=3[C:55]=12
Reactant: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2[nH]c3ccccc3c12
Agent: [Pd]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: NCc1ccccc1
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 400 ml ethylacetate, 70 g (0.27 moles) anhydrous N-2-[2-(methoxy)-phenoxy]-ethyl]-benzylamine, 10.25 g (0.075 moles) of anhydrous ZnCl2 and 50 g (0.21 moles) of 4-(oxiranylmethoxy)-9H-carbazole are added and the reaction mixture is heated to 70-75° C. for 3 hrs (TLC control for checking conversion to N-benzyl carvedilol). The reaction mixture is cooled to ambient temperature and quenched into 100 ml of ˜12-15% aqueous ammonia. The aqueous layer separated, and the product enriched organic layer is washed with water till neutral pH. The organic layer is charcoalised, filtered and the filtrate subjected to hydrogenation reaction. To this solution of N-benzyl carvedilol in ethylacetate, 5 ml acetic acid is added, followed by (7 g) of wet Pd/C catalyst (5% Pd content and 50% moisture content) is added. The reaction mixture is hydrogenated at 4.0 Kg/cm2 at temperature of 60-70° C. for a period of about 8 hours. The reaction mixture is filtered and the filtrate is washed with 40 ml of 12-15% v/v aqueous ammonia. The product enriched organic layer is separated and concentrated to remove ethylacetate. To the resultant syrupy mass n-butanol (100 ml) is added and the solution is stirred for about 10 hours, the crystals separated by filtration, washed successively with n-butanol (50 ml) and toluene (100 ml) to obtain carvedilol (55.4 g). The product is recrystallized from 3 volumes of ethyl acetate to obtain carvedilol (49 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[CH:16]=[C:17](/[CH:22]=[CH:23]/[S:24](Cl)(=[O:26])=[O:25])[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:14][C:15]1[CH:16]=[C:17](/[CH:22]=[CH:23]/[S:24]([NH:1][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=2[S:10]([NH2:13])(=[O:12])=[O:11])(=[O:26])=[O:25])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: Nc1cc(F)cc(F)c1S(N)(=O)=O
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)c(Cl)c1
Product: NS(=O)(=O)c1c(F)cc(F)cc1NS(=O)(=O)/C=C/c1ccc(Cl)c(Cl)c1
Yield: 49 %

Procedure:
The title compound was synthesized as described for Example 194 a) in 49% yield, starting from 2-amino-4,6-difluorobenzenesulfonamide and (E)-2-(3,4-dichlorophenyl)ethenesulfonyl chloride (1.5 equiv.). Purification by column chromatography, using chloroform/methanol (95:5) as the eluent.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10](C(OC(C)(C)C)=O)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][C:5]=1[Cl:25].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:25][C:5]1[CH:6]=[C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:8]=[CH:9][C:4]=1[CH2:3][OH:2]
Reactant: COC(=O)c1ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(CO)c(Cl)c1
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a 0° C. solution of methyl-2-chloro-4-(bis-Boc-amino)-benzoate (491 mg) in THF (4 mL) was added lithium aluminum hydride (1.27 mL, 2M in THF), dropwise, the reaction mixture was stirred for 30 min and quenched with MeOH. The reaction mixture was diluted with EtOAc, the organic layer washed with saturated NH4Cl (1×), brine (1×), dried over Na2SO4 and volatiles removed. The residue was purified by column chromatography using 0-60% EtOAc/Hexanes to provide compound 2-chloro-4-(boc-amino)-benzylalcohol as a clear syrup (259 mg).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:34])[CH2:8][C:9]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=2)([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[C@H:4]([C:35]([N:37]2[CH2:41][CH2:40][CH2:39][C@@H:38]2[C:42]([NH:44][CH2:45][C@H:46]2[CH2:51][CH2:50][CH2:49][NH:48][CH2:47]2)=[O:43])=[O:36])[CH2:3]1.[CH2:52](I)[CH3:53]>>[CH2:52]([N:48]1[CH2:49][CH2:50][CH2:51][C@H:46]([CH2:45][NH:44][C:42]([C@H:38]2[CH2:39][CH2:40][CH2:41][N:37]2[C:35]([C@@H:4]2[CH2:3][C@@H:2]([OH:1])[CH2:6][N:5]2[C:7](=[O:34])[CH2:8][C:9]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=2)([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH3:17])=[CH:14][CH:15]=2)[C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=2)=[O:36])=[O:43])[CH2:47]1)[CH3:53]
Reactant: CCI
Reactant: CCc1ccc(C(CC(=O)N2C[C@H](O)C[C@H]2C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCNC2)(c2ccc(CC)cc2)c2ccc(CC)cc2)cc1
Product: CCc1ccc(C(CC(=O)N2C[C@H](O)C[C@H]2C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC)C2)(c2ccc(CC)cc2)c2ccc(CC)cc2)cc1

Procedure:
The title compound was prepared by a method similar to Example 77, using (2R)-1-((2S,4R)-4-hydroxy-1-{3,3,3-tris(4-ethylphenyl)propanoyl}pyrrolidin-2-yl)carbonyl-N-{((3S)-3-piperidyl)methyl}pyrrolidine-2-carboxamide and ethyl iodide. The compound was obtained as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][S:9]([O-])(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:17]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][S:9]([Cl:17])(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(CS(=O)(=O)Cl)cc1
Yield: 100 %

Procedure:
To a suspension of 28.3 g (118 mmol, 1.0 equiv.) of finely ground sodium 4-nitrobenzyl sulfonate in 250 mL of toluene was added 24.6 g (118 mmol, 1.0 equiv) of finely ground phosphorous pentachloride as the solid in portions. After addition the mixture was heated to reflux for one hour. The mixture was cooled, and volatile material was removed in vacuo. The residue was dissolved in 500 mL chloroform and 250 mL of water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to give 27.8 g (100%) of 4-nitrobenzyl sulfonyl chloride, pure by 1H NMR.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.C1C=C(Cl)C=C(C(OO)=[O:22])C=1.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N+:4]([O-:22])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2cc(Br)cnc2c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2cc(Br)c[n+]([O-])c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
in CPBA (2.9 g, 16.8 mmol) was added to a solution of 3-bromo-7-methoxyquinoline (2.0 g, 8.40 mmol) in DCM (42 mL) at RT, and the reaction mixture was stirred at RT for 1 h. A second portion of mCPBA (2.9 g, 16.8 mmol) was then added, and the reaction mixture was stirred at RT for 18 h. The reaction mixture was poured onto 10% aqueous Na2SO3 and DCM, and the layers were separated. The organic layer was washed with NaHCO3, dried over MgSO4, filtered and concentrated. The resulting product was used with no further purification. LRMS (M+H)+=254.2.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2)#N.[OH-].[Na+].Cl>CO.O>[C:4]([C:17]1[CH:22]=[CH:21][C:1]([C:3]2[C:4]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:5][C:6]3[C:11]([N:12]=2)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=3)=[CH:19][CH:18]=1)#[N:5]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(C#N)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(-c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
A solution of methyl 3-cyano-2-phenylquinoxaline-6-carboxylate (50 mg, 0.17 mmol, 1.00 equiv) and NaOH (16 mg, 0.40 mmol, 3.00 equiv) in MeOH/H2O (5/5 mL) in a 50-mL round-bottom flask was allowed to react, with stirring, for 1 hr at room temperature, followed by a further 1 hr at 50° C. in an oil bath. The reaction progress was monitored by TLC (ethyl acetate:petroleum ether (1:2)). The pH value of the solution was adjusted to 4 with 1N HCl, and the resulting mixture was concentrated under vacuum. The solids were collected by filtration and dried in an oven under reduced pressure, giving 30 mg (46%) of 3-(4-cyanophenyl)-2-phenylquinoxaline-6-carboxylic acid as a white solid.