Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[C:14]([O:22]C)[CH:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[OH:24].B(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[C:14]([OH:22])[CH:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[OH:24]
Reactant: COC(=O)c1ccc(-c2cc3ccccc3c(O)c2C)cc1OC
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cc3ccccc3c(O)c2C)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a cooled (-78° C.) suspension of 7.0 g of 2-methyl-3-(4'-methoxycarbonyl-3'-methoxyphenyl)-1-naphthol in 100 mL of methylene chloride was added, dropwise over 10 minutes, 26 mL of 1 M boron trichloride in methylene chloride. The resulting mixture was stirred overnight at 25° C. and then quenched with 25 mL of methanol. The solution was washed with 3×40 mL of 1 N hydrochloric acid and then 2×50 mL of saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residual oil was purified by flash chromatography (2:1 methylene chloride:hexane as eluent) to give 4.8 g of 2-methyl-3-(4'-methoxycarbonyl-3'-hydroxyphenyl)-1-naphthol as a white solid.
Reaction SMILES: [Si]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2c1ccn2C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)n1ccc2c(O)cccc21
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 70.5 %

Procedure:
A solution of 10 (28.62 g, 75 mmol) in tetrahydrofuran (375 mL) containing acetic acid (4.5 g, 75 mmol) was treated at 0° C. with 1 M tetrabutylammonium fluoride (75 mL, 75 mmol) and the mixture was stirred at 0° C. for 40 min. The solvent was evaporated and the residue was dissolved in diethyl ether (250 mL) and washed with saturated aq. sodium bicarbonate and brine, dried and evaporated to give a brown solid which was washed with cold hexanes to give 11 as white fluffy needles (14.13 g, 70%), mp 118-120° C. (from dichloromethane-hexanes), (lit.11 mp 121-124° C.).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([CH3:13])=[CH:8][N:7]=1)=[O:5].[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+].CCOC(C)=O>C1COCC1>[NH2:12][C:11]1[C:6]([C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:5])=[N:7][CH:8]=[C:9]([CH3:13])[N:10]=1
Reactant: CON(C)C(=O)c1ncc(C)nc1N
Reactant: Br[Mg]c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cnc(C(=O)c2ccccc2)c(N)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3-Amino-5-methyl-pyrazin-2-carboylic acid methoxy-methyl-amide (0.3 g, 1.53 mmol) is dissolved in anhydrous THF (30 ml) under N2. The clear yellow solution is cooled to −78° C., and a 1M solution of phenyl magnesium bromide in THF (7.6 ml, 7.6 mmol) is added. The resulting reaction mixture is stirred at −78° C. for 1 hour, and is then allowed to warm to room temperature and stirred for a further 2.5 hours. The reaction mixture is poured onto aq. NaHCO3 and EtOAc. The phases are separated and the aqueous layer is washed with EtOAc. The combined organic layers are washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (SiO2, 0-7% MeOH in DCM) yields (3-amino-5-methyl-pyrazin-2-yl)-phenyl-methanone as a yellow solid. [M+H]+ 214.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8](Br)[S:7][CH:6]=1)=[O:4].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1csc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1csc(-c2ccccc2)c1
Temperature: 80 °C
Yield: 51.6 %

Procedure:
Prepare a mixture of 5-bromo-thiophene-3-carboxylic acid methyl ester (1.86 g, 8.41 mmol), phenylboronic acid (2.05 g, 16.83 mmol), and 1 M aqueous potassium carbonate (12.5 mL, 25.23 mmol) in 1,2-dimethoxyethane (70 mL) and purge with nitrogen for 20 minutes. Add Pd(PPh3)4 (485 mg, 0.42 mmol) and again purge the mixture with nitrogen for 10 minutes. Heat to 80° C. for 24 hours. Evaporate the solvent and redissolve the residue in ethyl acetate. Extract the aqueous phase with ethyl acetate (2×20 mL), wash the combined organic phases brine (40 mL), dry (magnesium sulfate), filter and concentrate. Perform flash chromatography on silica-gel eluting with 10:1 hexane/ethyl acetate to afford 947 mg of 5-phenylthiophene-3-carboxylic acid methyl ester as a white solid. MS: m/e=219 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:30])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:28][CH3:29])=[C:16]([CH2:19][NH:20][CH:21]4[CH2:26][CH2:25][CH2:24][NH:23][C:22]4=[O:27])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C=O.S([O-])([O-])(=O)=O.[Mg+2].[C:39]([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[C:3]([F:30])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:28][CH3:29])=[C:16]([CH2:19][N:20]([CH3:39])[CH:21]4[CH2:26][CH2:25][CH2:24][NH:23][C:22]4=[O:27])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [BH3-]C#N
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1CCCNC1=O
Agent: C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1CCCNC1=O
Temperature: 50 °C
Yield: 61.5 %

Procedure:
3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]piperidin-2-one (160 mg, 0.37 mmol prepared as described in Example 10), para-formaldehyde (112 mg, 3.72 mmol) and magnesium sulfate (90 mg, 0.74 mmol) were stirred in methanol (15 ml) and sodium cyanoborohydride (94 mg, 1.49 mmol) added. The mixture was heated at 50° C. for 1.5 hours, cooled, filtered and concentrated under reduced pressure. The resulting material was purified by flash chromatography on silica, eluting with increasingly polar mixtures of methanol/methylene chloride (2/98 to 5/95) to give the title product (101 mg, 61%) as a white solid; 1H NMR spectrum: (DMSO d6) 1.77 (m, 3H), 2.02 (m, 1H), 2.40 (s, 3H), 3.09 (m, 2H), 3.29 (dd, 1H), 3.95 (s, 5H), 7.18 (s, 1H), 7.28 (t, 1H), 7.40 (brs, 1H), 7.48 (t, 1H), 7.55 (m, 1H), 8.35 (s, 1H), 8.42 (s, 1H), 9.76 (s, 1H); Mass Spectrum: (M+H)+ 444.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:14][CH2:13]2)[N:7]=1)=[O:5])C.[Li+].[OH-].O.Cl>C1COCC1>[CH:12]1([C:8]2[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:11]=[CH:10][CH:9]=2)[CH2:13][CH2:14]1
Reactant: CCOC(=O)c1cccc(C2CC2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(C2CC2)n1

Procedure:
1.00 g (5.23 mmol) 6-cyclopropyl-pyridine-2-carboxylic acid ethyl ester was suspended in 10 mL THF and treated with 350 mg (14.6 mmol) LiOH and 5 mL water at RT for 2.5 h. The reaction mixture was acidified with 4 M aqueous hydrochlorid acid and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]1[CH2:24][CH2:23][O:22][CH:21]1[OH:25])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[C:27](OC(=O)C)(=[O:29])[CH3:28]>CN(C)C1C=CN=CC=1>[C:27]([O:25][CH:21]1[C@@H:20]([NH:19][C:17](=[O:18])[C@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:24][CH2:23][O:22]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H]1CCOC1O
Agent: CN(C)c1ccncc1
Solvent: O
Product: CC(=O)OC1OCC[C@@H]1NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 29 %

Procedure:
(3S)-3-[[N-tert-Butoxycarbonyl-(L)-phenylalanyl]amino]-2-hydroxytetrahydrofuran (0.1 g) was dissolved in acetic anhydride (3 ml) followed by addition of 4-dimethylaminopyridine (DMAP) (0,012 g) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with 10% aqueous citric acid, water, saturated aqueous sodium hydrogen carbonate, and saturated aqueous sodium chloride in the order mentioned and dried (MgSO4) and the solvent was distilled off to give (3S)-2-acetoxy-3-[[N-tert-butoxycarbonyl-(L)-phenylalanyl]amino]tetrahydrofuran (chemical formula below) (0,035 g, 29%). This product was recrystallized from ethyl acetate-hexane. Colorless crystals, m.p. 156°-157° C. Optical rotation [α]D -49.9° (C=0.15, CHCl3). ##STR45##
Reaction SMILES: I[C:2]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:14]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>>[CH:14]([C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:19][CH:18]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=C(O)c1cccc(C(=O)O)c1I
Product: CC(C)c1ccc(Nc2c(C(=O)O)cccc2C(=O)O)cc1
Yield: 62 %

Procedure:
Similar reaction of 2-iodoisophthalic acid and 4-isopropylaniline gave 2-[(4-isopropyl)phenylamino]isophthalic acid (62%), mp (EtOAc/petroleum ether) 208° C. (dec). 1H NMR [(CD3)2SO] δ 1.16 (d, J=6.9 Hz, 6 H, 2×CH3), 2.78-2.82 (m, 1 H, CH), 6.83 (d, J=8.4 Hz, 2 H, H-2' and H-6' or H-3' and H-5'; 6.97 (t, J=7.7 Hz, 1 H, H-5), 7.07 (d, J=8.5 Hz, 2 H, H-3' and H-5' or H-2' and H-6'), 7.92 (d, J=7.7 Hz, 2 H, H-4 and H-6), 9.66 (br s, 1 H, NH), 12.89 (br s, 2 H, 2×COOH). Anal. (C17H17NO4) C, H, N.
Reaction SMILES: Cl[Mg][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:11]([C:13]1[N:14]=[C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[S:16][CH:17]=1)=[O:12].[Cl-].[NH4+]>O1CCCC1>[OH:12][CH:11]([C:13]1[N:14]=[C:15]([CH:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]2)[S:16][CH:17]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Reactant: Cl[Mg]CCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C(O)CCc3ccccc3)cs2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere and at −78° C., chloro(2-phenylethyl)magnesium (1M in diethyl ether, 3.77 ml) was added dropwise to a solution of tert-butyl 4-(4-formyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (1.0 g) in tetrahydrofuran (10 ml). The reaction mixture was stirred at −78° C. for one hour, and more chloro(2-phenylethyl)magnesium (3M in diethyl ether, 0.20 ml) was then added dropwise. The reaction mixture was then stirred for 20 minutes. Saturated ammonium chloride solution was then added to the reaction mixture, and the aqueous phase was separated off. After extraction of the aqueous phase with ethyl acetate, the combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure. This gave tert-butyl 4-[4-(1-hydroxy-3-phenylpropyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (790 mg).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C:31](=[O:37])[C@@H:30]([OH:38])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C:31](=[O:37])[C:30](=[O:38])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4C(=O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4C(=O)C(=O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
Using the procedure described in Org. Syn., 1976, 55, 84, (3β,5α,12β,25R)-3-(t-butyldimethylsilyloxy)-spirostan-12-ol-11-one was oxidized with chromium trioxide and pyridine in methylene chloride to give the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[CH:4][CH:3]=1.[Cu][C:19]#[N:20]>CN1CCCC1=O>[C:19]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[CH:4][CH:3]=1)#[N:20]
Reactant: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Yield: 99.7 %

Procedure:
A mixture of 7-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (51.7 g, 0.168 mol), copper (I) cyanide (31.8 g, 0.35 mol) and N-methyl-2-pyrrolidinone (620 ml) was heated at reflux for 4 h, cooled, then partitioned between dilute aqueous ammonia (1.5 L) and dichloromethane (5×300ml). The combined organic extracts were dried (Na2O4) and evaporated in vacuo to give the title compound (42.6 g, 100%) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18]O)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[CH2:16]([C@@:13]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:32]=[N:33][CH:34]=[C:29]([Cl:28])[CH:30]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1)[CH:17]=[CH2:18]
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: OB(O)c1cncc(Cl)c1
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3cncc(Cl)c3)cc2)C(=O)O1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and 5-chloropyridine-3-boronic acid following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.97 min, m/z=451 (M+1); 1H NMR (CDCl3) 8.68 (d, 1H, J=2 Hz), 8.59 (d, 1H, J=2 Hz), 7.94 (t, 1H, J=2.2 Hz), 7.33-7.27 (m, 4H), 7.04 (ap q, 2H, J=9, 17 Hz), 5.75-5.65 (m, 2H), 5.12-5.02 (m, 2H), 3.03-2.98 (m, 1H), 2.66-2.54 (m, 2H), 2.41-2.17 (m, 3H), 1.56 (d, 3H, J=7 Hz).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([S:21](Cl)(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].C(N(CC)CC)C>ClCCl>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([S:21]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)(=[O:22])=[O:23])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: c1ccc2c(c1)CCCN2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1,2,3,4-Tetrahydroquinoline (0.29 ml) was added to a suspension of 3,4-dimethoxybenzene sulphonyl chloride (0.50 g) in dichloromethane (15 ml) at room temperature. Triethylamine (0.44 ml) was added and the resulting mixture stirred for 24 hours at room temperature. The reaction mixture was then diluted with dichloromethane (20 ml) and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 ml), 2N hydrochloric acid (10 ml) and saturated aqueous sodium chloride solution (10 ml). Drying over magnesium sulphate and concentration in vacuo provided a yellow oil. Purification by column chromatography eluting with 30% ethyl acetate in hexane provided the title compound as a colourless oil (0.60 g) which solidified on standing.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([OH:10])[C:7]([CH3:12])([CH3:11])[C:6]=2[CH:13]=1.Cl.[CH3:15][N:16](C)C=O>O>[C:15]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([OH:10])[C:7]([CH3:12])([CH3:11])[C:6]=2[CH:13]=1)#[N:16]
Reactant: CN(C)C=O
Reactant: CC1(C)c2cc(Br)ccc2OC1O
Agent: Cl
Solvent: O
Product: CC1(C)c2cc(C#N)ccc2OC1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Bromo-2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran (7.3 g), prepared as in Example 5(e) and cuprous cyanide (3.2 g) were heated under reflux in dimethylformamide (10 ml) with stirring for 51/2 hours. The mixture was cooled to room temperature and a solution of ferric chloride (6 g) in water (20 ml) containing hydrochloric acid (3.7 ml conc) was added. After heating at 60°-70° C. for 20 minutes the mixture was extracted with ether. The extracts were washed with water (twice), dried over magnesium sulphate and run down under vacuum to give 4.6 g of product, which on recrystallisation from toluene gave 2.0 g pure title product, mp 124°-127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:15].OO>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][N+:3]=1[O-:15]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: OO
Solvent: ClCCl
Product: [O-][n+]1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the 2-chloro-5-trifluoromethylpyridine (1.8 g, 0.01 mol) in methylene chloride (20 ml) was mixed with trifluoroacetic anhydride (15 g, 0.071 mol). The stirred solution was subjected to the dropwise addition of 30% aqueous hydrogen peroxide (1.4 g, 0.012 mol) over the course of 15 minutes. A mild exotherm ensued and the mixture was allowed to stir at ambient temperature for 1 hour. The solution was poured onto ice and extracted with 3×50 ml of ethyl acetate; the combined organic layers then were passed through a 1 inch pad of silica gel in a sintered glass funnel under suction. The eluate was evaporated and the residue was chromatographed on silica gel, eluting first with methylene chloride to remove unreacted pyridine and then with ethyl acetate to remove the product N-oxide weighing 1.8 g (90%) as an orange oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[C:12]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([OH:3])=[O:2]>[Pd].C1(C)C(C)=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([OH:3])=[O:2]
Reactant: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCCC3)ccc1O
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3ccccc32)ccc1O
Reaction time: 72 h

Procedure:
A mixture of 3.33 g. (0.01 mole) of 1-(3-carboxy-4-hydroxyphenyl)-2-phenyl-4,5,6,7-tetrahydroindole, 4.0 g. of 10% palladium on carbon, and 250 ml. of xylene was heated under reflux with stirring under nitrogen for 3 days, filtered, and concentrated to a solid. Trituration with cyclohexane afforded 2.4 g. (73%) of solid, m.p. 210°-212°. Recrystallization from acetic acid gave colorless crystals, m.p. 213.5°-214.5°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:30]1[C:35]([C:36]([OH:38])=[O:37])=[CH:34][C:33]2[C:39]([O:41][C:42](=O)[C:32]=2[CH:31]=1)=[O:40]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:39](=[O:40])[C:33]2[C:32](=[CH:31][CH:30]=[C:35]([C:36]([OH:38])=[O:37])[CH:34]=2)[C:42]1=[O:41]
Reactant: CCS(=O)(=O)c1ccc(-c2ccc3oc(-c4ccc(OC)c(N)c4)nc3c2)cc1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: CCS(=O)(=O)c1ccc(-c2ccc3oc(-c4ccc(OC)c(N5C(=O)c6ccc(C(=O)O)cc6C5=O)c4)nc3c2)cc1

Procedure:
Prepared by the method of Example 1b), from 2-(3-amino-4-methoxyphenyl)-5-(4-ethylsulfonylphenyl)benzoxazole (63 mg, 0.15 mmol) and 1,2,4-benzenetricarboxylic anhydride (29 mg, 0.15 mmol) the title compound was obtained (34 mg, 39%). 1H NMR (DMSO) δ 8.57(dd, 1H), 8.57(m, 4H), 8.30(d, 1H) 8.10(m, 4H), 8.03(d, 1H), 7.92(dd, 1H), 7.61(d, 1H), 4.00(s, 3H), 3.45(q, 2H), 1.25(t, 3H). MS 583 m/z (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24](C)[CH:23]=[C:22]4[CH:27]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:29][CH:30]([CH3:35])[CH2:31][C:32]([OH:34])=[O:33].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:27][NH:29][CH:30]([CH3:35])[CH2:31][C:32]([OH:34])=[O:33])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(N)CC(=O)O
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)cn(C)c34)no2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(CC(=O)O)NCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 40 °C
Reaction time: 24 h
Yield: 23.2 %

Procedure:
To a stirred solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole-3-carbaldehyde (D61) (200 mg), 3-aminobutanoic acid (103 mg) and acetic acid (32 mg) in DCM (10 mL) was added NaBH(OAc)3 (223 mg). The reaction was stirred at 40° C. for 24 h. After cooled to room temperature, the mixture was diluted with DCM (10 mL), washed with water (20 mL) and aqueous saturated sodium bicarbonate (20 mL). The organic phase was dried over anhydrous sodium sulphate, evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford 3-({[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}amino)butanoic acid (E51) (55 mg, as TFA salt). δH (DMSO-d6, 400 MHz): 1.36 (9H, m), 2.57 (1H, m), 2.91 (1H, dd), 3.57 (1H, m), 4.46 (2H, s), 4.91 (1H, m), 7.33 (1H, t), 7.47 (1H, d), 7.72 (1H, d), 8.03 (1H, d), 8.05 (1H, d), 8.22 (1H, dd), 8.39 (1H, d), 11.37 (1H, s), 12.81 (1H, br s). MS (ES): C24H26ClN4O4 requires 468; found 366.1 (M—C4H8NO2+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:20][CH3:21])=[O:11])=[CH:7][CH:8]=1
Reactant: CCO
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
2-(4-(Trifluoromethyl)phenyl)acetic acid (5.0 g, 24.49 mmol) was dissolved in ethanol (100 mL). Concentrated sulfuric acid (1 mL) was added, and the mixture was refluxed overnight. After cooling to room temperature, the reaction mixture was concentrated and diluted with diethyl ether. The organic solvent solution was then extracted with water, saturated aqueous sodium bicarbonate solution, and brine. The organic layer was then dried with magnesium sulfate, filtered, and concentrated to obtain the title compound. MS (DCI+) m/z 250 (M+NH4)+.