Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1S(O)(=O)=O.[OH-:13].[K+]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:13]
Reactant: Cc1ccc(N)c(S(=O)(=O)O)c1
Reactant: [OH-]
Agent: [K+]
Product: Cc1ccc(N)c(O)c1

Procedure:
The Na salt of 2-amino-5-methyl-benzenesulphonic acid is reacted with 80% by weight of KOH to give the K salt of 2-amino-5-methyl-phenol (300° C.; 15 to 20 bar; 3h), the molar ratio of KOH to 2-amino-5-methyl-benzenesulphonic acid preferably being from 10:1 to 15:1. The reaction mixture is diluted to a content of approximately 5% by weight of 2-amino-5-methyl-phenol by direct expansion at 300° C. into water, or by pumping water into the autoclave after prior cooling to approximately 200° C. The resulting alkaline suspension of the K salt of 2-amino-5-methyl-phenol is metered into water at the same time as 36% by weight aqueous HCl at 90° C. at a pH of from 0.5 to 1.0. All the SO2 is expelled from the resulting, aqueous, approximately 4% by weight 2-amino-5-methyl-phenol hydrochloride solution using nitrogen or by applying a vacuum, the solution is if necessary clarified using activated carbon to remove tarry constituents, and the 2-amino-5-methyl-phenol is precipitated out by neutralization of the hydrochloric acid solution, for example using aqueous sodium hydroxide at a pH of from 4.5 to 6.0, and isolated in the usual manner, for example by filtration and washing with water.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][C:12]([S:14](N2C=CC=C2)(=[O:16])=[O:15])=[CH:11][CH:10]=1.[Na].S(Cl)([Cl:26])(=O)=O>>[Cl:26][S:14]([C:12]1[S:13][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:10][CH:11]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccccc1-c1ccc(S(=O)(=O)n2cccc2)s1
Agent: [Na]
Product: COc1ccccc1-c1ccc(S(=O)(=O)Cl)s1
Yield: 24 %

Procedure:
5-chlorosulfonyl-2-(2-methoxyphenyl)thiophene was prepared in the same manner as described in Example 65E from N-[5-(2-methoxyphenyl)thiophene-2-sulfonyl]pyrrole by hydrolysis of the sulfonamide to the sodium salt of sulfonic acid (83%) followed by conversion of the salt to the corresponding sulfonyl chloride, resulting in a 24% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([OH:32])[C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:31])[C@H:14]([CH:28]([CH3:30])[CH3:29])[NH:15][C:16](=[O:27])[C@H:17]([CH3:26])[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(Cl)(=O)C(Cl)=O.CS(C)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:31])[C@H:14]([CH:28]([CH3:30])[CH3:29])[NH:15][C:16](=[O:27])[C@H:17]([CH3:26])[NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[O:32]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(O)c1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)c1ccccn1

Procedure:
41 (0.29 g, 0.64 mmol), oxalylchloride (0.10 ml, 1.15 mmol), DMSO (0.11 ml, 1.59 mmol), TEA (0.36 ml, 2.55 mmol)
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1Br)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[Cu](C#N)[C:36]#[N:37]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:36]#[N:37])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: N#C[Cu]C#N
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Br)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C#N)n1
Temperature: 170 °C
Yield: 48.1 %

Procedure:
A solution of (3,5-bis-trifluoromethyl-benzyl)-(2-bromo-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine (6 g, 10.6 mmol) in DMF (20 mL) at room temperature was deoxygenated by bubbling nitrogen gas through the solution for 10 minutes. Copper cyanide (CuCN) (1.14 g, 12.8 mmol) was added to the reaction mixture and it was heated to 170° C. for 16 hours. The reaction was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed twice with saturated aqueous ammonium chloride solution and then washed with brine. It was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (silica gel, 320 g) (eluted over a gradient 5-25% ethyl acetate and hexane) to give 2.59 g (95%) of the title compound as yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.2 (s, 3H) 4.82 (s, 2H) 4.9 (s, 2H) 7.6 (dd, 1H) 7.7 (s, 2H) 7.8(s, 2H) 7.8 (dd, 1H). MS (ES+) Calc: 508.1, Found: 509.2 (M+1).
Reaction SMILES: CC([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([Br:14])=[C:12]([Cl:13])[C:7]=2[C:6]([O:15]C(C)=O)=[CH:5]1)=O.C[O-].[Na+]>CN(C)C=O>[Br:14][C:11]1[C:12]([Cl:13])=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:4][CH:5]=[C:6]2[OH:15]
Reactant: CC(=O)Oc1cn(C(C)=O)c2ccc(Br)c(Cl)c12
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1c[nH]c2ccc(Br)c(Cl)c12

Procedure:
To a stirred solution of 5-bromo-4-chloroindoxyl 1,3-diacetate (25) (1.0 g, 3.03 mmol) in anhydrous N,N-dimethylformamide (3 mL) was added sodium methoxide (270 mg, 5.00 mmol). The resulting dark-colored reaction mixture was degassed with nitrogen (g) for 30 min at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[OH:16])=[CH:5][CH:4]=1.[C:19]([O:22][C@@H:23]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@@H:24]1OC(=N)C(Cl)(Cl)Cl)(=[O:21])[CH3:20]>ClCCl>[C:19]([O:22][C@@H:23]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@H:24]1[O:16][C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[C:13]([CH3:14])[C:8]=1[CH2:7][C:6]1[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:21])[CH3:20]
Reactant: COc1ccc(Cc2c(C)cc(C)cc2O)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Product: COc1ccc(Cc2c(C)cc(C)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 2-(4-methoxybenzyl)-3,5-dimethylphenol (4.0 g) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroaceto-imidoyl-α-D-glucopyranose (8.9 g) in dichloromethane (100 mL) was added boron trifluoride diethyl-ether complex (2.5 mL) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: dichloromethane). The solvent was removed under reduced pressure, ethanol was added to the residue, and the resulting crystals were collected by filtration. The obtained crystals were dried under reduced pressure to give 2-(4-methoxybenzyl)-3,5-dimethylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (7.8 g).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([O:7][C:8](=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24]C)[O:15][N:14]=1)[CH3:6]>C(Cl)Cl>[CH2:5]([O:7][C:8](=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])[O:15][N:14]=1)[CH3:6]
Reactant: CCOC(=O)CCCCc1cc(-c2ccccc2OC)on1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CCCCc1cc(-c2ccccc2O)on1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Add boron tribromide (43 mL, 43 mmol, 1.0 M solution in CH2Cl2) dropwise over 30 minutes to a stirred 0° C. solution of 5-[5-(2-methoxy-phenyl)-isoxazol-3-yl]-pentanoic acid ethyl ester (5.20 g, 17.1 mmol) in CH2Cl2 (45 mL). Allow to warm to room temperature overnight. Add boron tribromide (17 mL, 17 mmol, 1.0 M solution in CH2Cl2) and stir at room temperature under N2. After 4 hours, add boron tribromide (17 mL, 17 mmol, 1.0 M solution in CH2Cl2) and stir at room temperature under N2. After 2 hours, quench via dropwise addition of ethanol (50 mL, absolute). Concentrate, dissolve residue in CHCl3, wash with saturated NaHCO3 solution (×2), dry over MgSO4 and concentrate to get 4.7 g of a tan solid. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 3-20% EtOAc/hexanes to afford the title compound (3.96 g, 80%). MS (IS) 290 (M+1)+.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.ClC1C(C(F)(F)F)=CC=CC=1C(NC(C1(N(C)C)CCCC1)C1C=CC=CC=1)=O.[Br:46][C:47]1[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[C:48]=1[C:49](O)=[O:50].ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[Br:46][C:47]1[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[C:48]=1[C:49]([NH:1][CH:2]([C:3]1([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:50]
Reactant: CN(C)C1(C(N)c2ccccc2)CCCC1
Reactant: Cc1cccc(Br)c1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)C1(C(NC(=O)c2cccc(C(F)(F)F)c2Cl)c2ccccc2)CCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1cccc(Br)c1C(=O)NC(c1ccccc1)C1(N(C)C)CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82 %

Procedure:
To {1-[amino(phenyl)methyl]cyclopentyl}dimethylamine D3 enantiomer 2 (50 mg, 0.23 mmol) in DCM (5 ml) was added 2-bromo-6-methylbenzoic acid (108 mg; 0.5 mmol), followed by 1-hydroxybenzotriazole (45 mg; 0.3 mmol) and PS-DCC (400 mg of 1.3 mmol/g loading, 0.52 mmol) and the mixture shaken at room temperature for ca. 2 days. The reaction mixture was filtered through a phase-separation cartridge and the filtrate stirred with saturated aqueous sodium bicarbonate for 30 min. The lower layer was removed, passed through another phase-separation cartridge and loaded onto an SCX cartridge which was eluted with 2 column volumes each of DCM, 50% methanol-DCM, methanol and 1M ammonia in methanol. The product containing fractions were evaporated to afford the title product (82 mg; 82%). 1H NMR (CDCl3) δ: 0.95-1.10 (2H, m), 1.40-1.60 (2H, m), 1.60-1.80 (2H, m), 1.80-1.90 (2H, m), 2.23 (6H, s), 2.33 (3H, m), 5.13 (1H, d J=6 Hz), 6.97 (1H, br s), 7.10-7.15 (2H, m), 7.24-7.34 (3H, m), 7.38-7.41 (1H, m), 7.46-7.48 (2H, m). Mass Spectrum (Electrospray LC/MS): Found 415 (MH+). C22H2779BrN2O requires 414. Ret. time 1.93 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)[Cl:31]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][Cl:31]
Reactant: OCc1ccc(Cl)c(Br)c1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClCc1ccc(Cl)c(Br)c1
Reaction time: 18 h
Yield: 88.6 %

Procedure:
To a solution of 3-bromo-4-chlorobenzyl alcohol (9.6 g, 43 mmol) in CH2Cl2 (100 mL) was added Ph3P (17.1 g, 1.5 mmol) and CCl4 (6.3 mL, 65 mmol). After 18 h, the solution was washed with brine (3×100 mL) and passed through a short silica gel column to afford the product as colorless oil (9.14 g, 88%). 1H NMR (400 MHz, CDCl3): 7.65 (d, J=2.1 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.27 (dd, J=8.3, 2.1 Hz, 1H), 4.51 (s, 3H).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:9][CH3:10])[CH2:5][C:6]([OH:8])=O)[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C=O)C.[N+:28]([C:31]1[C:40]2[N:41]=[CH:42][CH:43]=[CH:44][C:39]=2[C:38]2[C:33](=[N:34][C:35](=[O:46])[C:36](=[O:45])[N:37]=2)[CH:32]=1)([O-:30])=[O:29]>C1COCC1.C(N(CC)CC)C>[CH2:9]([N:4]([CH2:5][C:6]([N:41]1[CH2:42][CH2:43][C:44]2[C:31]([N+:28]([O-:30])=[O:29])=[CH:32][C:33]3[NH:34][C:35](=[O:46])[C:36](=[O:45])[NH:37][C:38]=3[C:39]=2[CH2:40]1)=[O:8])[CH2:2][CH3:3])[CH3:10]
Reactant: O=C1N=c2cc([N+](=O)[O-])c3ncccc3c2=NC1=O
Reactant: CCN(CC)CC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCN(CC)CC(=O)N1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 80 °C
Yield: 72.9 %

Procedure:
A mixture of N,N-diethylglycine hydrochloride (96 mg, 0.57 mmol) and carbonyldiimidazole (92 mg, 0.57 mmol) in THF (5 mL) were refluxed under a nitrogen atmosphere for 15 min. With the bath temperature at 70° C., DMF (7 mL) and 6-nitro-pyridoquinoxalinedione (0.1 g, 0.38 mmol) were added, and finally triethylamine (265 μL) was added and the reaction heated for 14 h at 80° C. The solvent was removed and the residue triturated with water, collected by filtration and washed with diethyl ether. An orange brown solid (104 mg) was obtained in 73% yield, mp 285-290° C. (dec); m/e M+1 376, nmR, IR.
Reaction SMILES: [NH2:1][C@H:2](C(O)=O)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:16]OC1C=C(C=CC=1)C=O.S(=O)(=O)(O)O>C(#N)C>[CH:16]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH:3]=[CH:2][N:1]=1
Reactant: COc1cccc(C=O)c1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: c1ccc2c(c1)[nH]c1cnccc12

Procedure:
Tryptophan A (1.0 g, 5.0 mmol) and 3-methoxybenzaldehyde (670 μL, 5.5 mmol) are suspended/dissolved in acetonitrile (100 mL) and concentrated sulfuric acid (100 μL) is added. The reaction is heated to reflux until all the aldehyde was consumed (overnight). The solvent was removed in vacuo and the residue was dissolved in 5 mL of ethanol. The product was precipitated out with ether, filtered, and washed with 10 mL of ether. The desired β-carboline product/intermediate B (1-(3-Methoxy-phenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid) is isolated as a beige solid (1.2 g, 76%). LC/MS RT=2.33 min. M/Z+323, 100%.
Reaction SMILES: CC1(C)O[CH2:8][CH2:7][C@H:6]2N1[C:4](=[O:12])[C@@H:5]2[N+]#[C-].[CH2:14]([SnH](CCCC)CCCC)[CH2:15][CH2:16]C.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[CH3:14][CH2:15][CH2:16][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[O:12]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: [C-]#[N+][C@H]1C(=O)N2[C@@H]1CCOC2(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CCCCCCCC=O

Procedure:
A mixture of (6R,7R)-2,2-dimethyl-7-isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-one (150 mg), tributyltinhydride (0.263 ml), and azobisisobutyronitrile (14 mg) in benzene (4.5 ml) was refluxed for 15 minutes. The resulting solution was chromatographed on silica gel (4.5 g) eluting with a mixture of benzene and acetone (15:1-16:1) to give the crude product (140 mg) as an oil, which was purified by silica gel (5 g) chromatography (eluate: a mixture of methylene chloride and ethyl acetate 30:1-5:1) to give (6R)-2,2-dimethyl-1-aza-3-oxabicycle[4.2.0]-octan-8-one (98 mg) as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]([CH3:45])([CH3:44])[CH2:10][C:11]([NH:13][C@H:14]1[C:20](=[O:21])[N:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:18]2[CH:40]=[CH:41][CH:42]=[CH:43][C:17]=2[S:16][CH2:15]1)=[O:12].[CH:46](=O)[C:47]1[O:51][CH:50]=[CH:49][CH:48]=1>>[O:51]1[CH:50]=[CH:49][CH:48]=[C:47]1[CH2:46][NH:8][C:9]([CH3:45])([CH3:44])[CH2:10][C:11]([NH:13][C@H:14]1[C:20](=[O:21])[N:19]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[CH:27][CH:28]=2)[C:18]2[CH:40]=[CH:41][CH:42]=[CH:43][C:17]=2[S:16][CH2:15]1)=[O:12]
Reactant: O=Cc1ccco1
Reactant: CC(C)(N)CC(=O)N[C@@H]1CSc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CC(=O)N[C@@H]1CSc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C1=O)NCc1ccco1

Procedure:
The title compound is prepared from 3-amino-3-methyl-N-[3,4-dihydro-4-oxo-5-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin-3(S)-yl]butanamide trifluoroacetate (prepared by the method of M. Fisher, et al, U.S. Pat. No. 5,206,235) and furfuraldehyde by the procedures described in Example 1.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH:18]([C:19]4[CH:23]=[CH:22][S:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[F:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[F:41])[C:35](Cl)=[O:36]>C(Cl)Cl>[F:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[F:41])[C:35]([N:16]1[CH2:17][CH:18]([C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[CH:14]([CH2:13][N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)[CH2:15]1)=[O:36]
Reactant: c1ccc(C2CCN(CC3CNCC3c3ccsc3)CC2)cc1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)c(F)c1)N1CC(CN2CCC(c3ccccc3)CC2)C(c2ccsc2)C1
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To a solution of 0.023 g (0.071 mmol) of 3-(SR)-(4-phenylpiperidinylmethyl)-4-(RS)-(3-thienyl)pyrrolidine and 0.079 mL of Et3N in 2 mL of CH2Cl2 was added 0.059 g (0.28 mmol) of 3,4-difluorobenzoyl chloride and the reaction mixture was stilled for 0.5 h. The reaction mixture was partitioned between CH2Cl2 and sat'd NaHCO3 solution. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (silica, acetone: hexanes, 1:3) to give 0.026 g of the title compound. 1H NMR (CDCl3) δ7.17-7.49 (m, 9H), 7.13 and 7.08 (s, 1H), 7.04 and 6.99 (d, 1H, J=4.6 Hz),4.08-4.15 (m, 2H); Mass Spectrum (CI) m/e=482 (M+1).
Reaction SMILES: [C:1](=[O:40])([O:3][CH2:4][CH:5]([NH:16][C:17](=[O:39])[CH2:18][N:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:21]([CH2:31][CH:32]([OH:37])[C:33]([F:36])([F:35])[F:34])[C:20]1=[O:38])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8](C(F)(F)F)[CH:7]=1)[NH2:2].ClC1C=CC(C2N(CC(O)[C:60]([F:63])([F:62])[F:61])C(=O)N(CC(O)=O)C=2)=CC=1.Cl.C(=O)(OCC(N)C1C=CC=CC=1C(F)(F)F)N>>[C:1](=[O:40])([O:3][CH2:4][CH:5]([NH:16][C:17](=[O:39])[CH2:18][N:19]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[N:21]([CH2:31][CH:32]([OH:37])[C:33]([F:35])([F:36])[F:34])[C:20]1=[O:38])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[C:60]([F:63])([F:62])[F:61])[NH2:2]
Reactant: O=C(O)Cn1cc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Reactant: NC(=O)OCC(NC(=O)Cn1cc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: NC(=O)OCC(N)c1ccccc1C(F)(F)F
Product: NC(=O)OCC(NC(=O)Cn1cc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O)c1ccccc1C(F)(F)F

Procedure:
In the same way as for the compound from Example 206, 58 mg (0.11 mmol) of [4-(4-chlorophenyl)-2-oxo-3-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydro-1H-imidazol-1-yl]acetic acid from Example 185A were reacted with 42 mg (0.12 mmol) of the compound from Example 180A. This gave 12 mg (18% of theory) of the target compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20])([CH3:15])[CH3:14])#[N:12]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:20])([CH3:15])[CH3:14])#[N:12]
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (7.85 g, 41.5 mmol) in tetrahydrofuran (80 mL) were added N,N-dimethylformamide (50 μL) and oxalyl chloride (4.33 mL, 49.8 mmol), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure to give 3-(cyano-1-methylethyl)benzoyl chloride as a pale-brown oil. To a solution of 3-nitroaniline (5.73 g, 41.5 mmol) and N,N-dimethylpyridine-4-amine (253 mg, 2.07 mmol) in pyridine (50 mL) was added dropwise a suspension of 3-(cyano-1-methylethyl)benzoyl chloride in pyridine (30 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and to the residue was added saturated aqueous sodium hydrogen carbonate solution (150 mL), and the mixture was extracted with ethyl acetate (200 mL, 50 mL). The combined organic layer was washed with saturated brine (30 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate/hexane mixture to give the title compound (11.46 g, 89%) as a pale-yellow solid.
Reaction SMILES: C([C@@:4]1([OH:29])[C@:8](C(=O)C)([OH:9])[C@@H:7]([CH2:13][O:14]C(=O)C)[O:6][C@H:5]1[N:18]1[CH:26]=[N:25][C:24]2[C:19]1=[N:20][C:21]([Cl:28])=[N:22][C:23]=2Cl)(=O)C.[OH-].[NH4+:31]>O1CCCC1>[Cl:28][C:21]1[N:22]=[C:23]([NH2:31])[C:24]2[N:25]=[CH:26][N:18]([C:19]=2[N:20]=1)[C@@H:5]1[O:6][C@H:7]([CH2:13][OH:14])[C@@H:8]([OH:9])[C@H:4]1[OH:29]
Reactant: [NH4+]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@@](O)(C(C)=O)[C@@]1(O)C(C)=O
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of the compound of Example 3 (271 g, 606 M), concentrated ammonium hydroxide (4 L) and tetrahydrofuran (0.5 L) is stirred at room temperature under nitrogen for 4 days. The solvent volume is reduced in vacuo and the resulting residue is triturated with absolute ethanol. The title compound is precipitated out of the ethanolic solvent to yield a light brown solid, (159 g, 87%).
Reaction SMILES: [Cl-:1].[Cl-:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:38]2[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=2)([C:34]([F:37])([F:36])[F:35])[C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1>ClCCl>[Cl:1][C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:38]2[CH:43]=[CH:42][C:41]([Cl:2])=[CH:40][CH:39]=2)([C:34]([F:37])([F:36])[F:35])[C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1
Reactant: [Cl-]
Reactant: Oc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)C(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)C(F)(F)F
Reaction time: 4 h

Procedure:
To a slurry of triphenylphosphine dichloride (0.2 moles) in dichloromethane (250 ml) under argon is added 2,2-bis(4-hydroxyphenyl)hexafluoropropane (0.1 mole). The solvent is removed by distillation to form an essentially solid reaction mixture in the reaction vessel. The reaction vessel is heated in a molten metal bath to form a molten reaction mixture and the mixture agitated for approximately four hours before cooling to obtain a solid reaction product. The resulting solid is dissolved in dichloromethane and washed first with dilute sodium hydroxide and second with deionized water. The resulting organic fraction is collected and purified passing it through a silica gel chromatographic column using hexane as the eluting solvent. The hexane is removed from the eluate with a rotary evaporator to yield 2,2-bis(4-chlorophenyl)hexafluoropropane.