Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:7][C:6]([C:17]([F:20])([F:19])[F:18])=[CH:5][N:4]=1)#[N:2].[I-].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]([CH3:38])[C:30](N2C=C[N+](C)=C2)=[O:31])=[CH:25][CH:24]=1>>[C:1]([C:3]1[C:8]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:30](=[O:31])[N:29]([C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=3)[CH3:38])=[CH:14][CH:15]=2)=[CH:7][C:6]([C:17]([F:20])([F:18])[F:19])=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ncc(C(F)(F)F)cc1Oc1ccc(O)cc1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccc(Cl)cc1
Agent: [I-]
Product: CN(C(=O)Oc1ccc(Oc2cc(C(F)(F)F)cnc2C#N)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared from 4-(2-cyano-5-trifluoromethyl-pyridin-3-yloxy)-phenol and 3-[(4-chlorophenyl)-methyl-carbamoyl]-1-methyl-3H-imidazol-1-ium iodide. The crude product was purified by preparative HPLC (25%). HPLC-MS m/z=448.2 (M+1), Rt: 5.1 min.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].C(N(CC)CC)C.[CH3:15][C:16]1([CH3:30])[C:20]([CH3:22])([CH3:21])[O:19][B:18]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)[O:17]1>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:7])[S:3](=[O:5])(=[O:4])[NH:27][C:26]1[CH:25]=[CH:24][C:23]([B:18]2[O:19][C:20]([CH3:22])([CH3:21])[C:16]([CH3:30])([CH3:15])[O:17]2)=[CH:29][CH:28]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
Dimethylsulfamoyl chloride (492 mg) and triethylamine (0.95 mL) were added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg) in chloroform (5 mL), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0→2:1) to give the title compound as a pale orange powder (427 mg).
Reaction SMILES: Br[C:2]1[C:3]([F:30])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[N:19]([CH2:24][C:25]([F:28])([F:27])[F:26])[N:20]=[C:21]([CH3:23])[N:22]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:29]=1.[CH3:31][C:32]([OH:36])([C:34]#[CH:35])[CH3:33]>C(NC(C)C)(C)C.CN(C=O)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:30][C:3]1[C:2]([C:35]#[C:34][C:32]([OH:36])([CH3:33])[CH3:31])=[CH:29][C:6]2[C:7]3[N:8]([C:12]([C:18]4[N:19]([CH2:24][C:25]([F:27])([F:28])[F:26])[N:20]=[C:21]([CH3:23])[N:22]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: Cc1nc(-c2c(C(N)=O)nc3n2CCOc2cc(F)c(Br)cc2-3)n(CC(F)(F)F)n1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: Cc1nc(-c2c(C(N)=O)nc3n2CCOc2cc(F)c(C#CC(C)(C)O)cc2-3)n(CC(F)(F)F)n1
Temperature: 85 °C

Procedure:
The title compound was prepared similarly according to Procedure E. To a solution of 10-bromo-9-fluoro-3-[5-methyl-2-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (200 mg, 0.41 mmol), PdCl2(PPh3)2 (0.05 equiv., 14.5 mg, 0.02 mmol) and copper (I) iodide (0.05 equiv., 4.0 mg, 0.02 mmol) in diisopropylamine (1.1 mL, 2.6 mL/mmol) and DMF (0.53 mL, 1.3 mL/mmol) was added 2-methyl-3-butyn-2-ol (2.0 equiv., 0.08 mL, 0.82 mmol). The reaction was heated to 85° C. for 30 minutes. The reaction mixture was cooled to room temperature, diluted with methylene chloride and filtered over celite. The crude was purified by reverse-phase HPLC to afford 73 mg (36.3% yield) of a fluffy white solid. 1H NMR (400 MHz, DMSO) δ 8.66 (d, J=8.5 Hz, 1H), 7.99 (br s, 1H), 7.48 (br s, 1H), 7.05 (d, J=10.5 Hz, 1H), 5.53 (s, 1H), 5.12-4.96 (m, 2H), 4.56-4.47 (m, 2H), 4.30-3.98 (m, 2H), 2.37 (s, 3H), 1.50 (s, 6H). M+H=493.2.
Reaction SMILES: C([N:8]1[C:12]2[C:13](=[O:35])[N:14]([CH3:34])[C:15]([CH:24]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:25]([O:27][CH3:28])=[O:26])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)C1C=CC=CC=1.[Li+].CC([N-]C(C)C)C>O1CCCC1>[C:30]([O:29][CH:24]([C:15]1[N:14]([CH3:34])[C:13](=[O:35])[C:12]2[NH:8][CH:9]=[CH:10][C:11]=2[C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)[C:25]([O:27][CH3:28])=[O:26])([CH3:33])([CH3:31])[CH3:32]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c(=O)n1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
A 0° C. solution of methyl 2-(1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-(tert-butoxy)acetate (400 mg, 0.811 mmol) in Tetrahydrofuran (THF) (6 mL) was slowly treated with LDA (2.0 M solution in tetrahydrofuran/heptanes/ethylbenzene) (0.811 mL, 1.623 mmol) and the mixture was allowed to stir at 0° C. for 20 min. The mixture was quenched with HCl (1M) and extracted with Ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-10% Methanol/DCM) to afford methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (205 mg, 0.511 mmol, 63% yield) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 9.46 (s, 1H), 7.50-7.46 (m, 2H), 7.45-7.38 (m, 2H), 7.21-7.19 (m, 1H), 6.10-6.05 (m, 1H), 3.84-3.82 (s, 3H), 3.73-3.71 (s, 3H), 0.96 (s, 9H); LCMS (m/z) ES+=403 (M+1).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:16][S:17]([O-:19])=[O:18].[Na+].[OH-].[K+]>[Cu]I.CS(C)=O>[CH3:16][S:17]([C:2]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:19])=[O:18]
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1Br
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cc(OC(F)(F)F)ccc1C(=O)O
Temperature: 120 °C

Procedure:
To a 16 ml vial was loaded 2-bromo-4-(trifluoromethoxy)benzoic acid (225 mg, 0.79 mmol), sodium methylsulfinate (161 mg, 1.58 mmol), CuI (301 mg, 1.58 mmol), KOH (44 mg, 0.79 mmol, in 0.1 ml water) and 4 ml dimethyl sulfoxide. The reaction mixture was flushed with nitrogen, sealed and heated at 120° C. for 5 hours. After cooling to room temperature, it was diluted with 40 ml ether/ethyl acetate (1:1), 30 ml brine and 10 ml 3N HCl. The mixture was filtered through a pad of celite. The layers were separated, and the organic portion was dried over sodium sulfate, filtered and concentrated. The residue was purified with HPLC on a reverse phase column eluted with water and acetonitrile gradient solvent to give desire product as white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[NH:6]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:7]([C:18](ON1C(=O)CCC1=O)=[O:19])[C@@H:8]([CH3:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[NH:6]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C@H:7]([C:18]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:19])[C@@H:8]([CH3:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCC(=O)O
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Yield: 97.1 %

Procedure:
By using 5.40 g of H-Gly-OH and 22.40 g of Boc-Thr(Bzl)-OSu, and the same procedure as in Reference Example 14 was repeated to obtain 19.60 g (yield: 97.3%) of the above-mentioned objective product.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[N:9]1[C:20](=[O:38])[C@@H:21]([NH:23][C:24](=[O:37])[NH:25][C:26]1[CH:27]=[C:28]([CH2:32][C:33]([O:35]C)=[O:34])[CH:29]=[CH:30][CH:31]=1)[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>O.CO.[OH-].[Na+]>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[N:9]1[C:20](=[O:38])[C@@H:21]([NH:23][C:24](=[O:37])[NH:25][C:26]1[CH:27]=[C:28]([CH2:32][C:33]([OH:35])=[O:34])[CH:29]=[CH:30][CH:31]=1)[CH3:22])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)Cc1cccc(NC(=O)N[C@@H](C)C(=O)N2[C@@H](c3ccccc3F)SC[C@H]2C(=O)OC(C)(C)C)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H](NC(=O)Nc1cccc(CC(=O)O)c1)C(=O)N1[C@@H](c2ccccc2F)SC[C@H]1C(=O)OC(C)(C)C
Yield: 35.1 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 77, but starting from 0.38 g of methyl 3-{3-{(2S)-1-[(2R,4R)-4-tert-butoxycarbonyl-2-(2-fluorophenyl)-3-thiazolidinyl]-1-oxo-2-propyl}ureido}-phenylacetate in 6 cm3 of a water/methanol (30/70 by volume) mixture and 0.05 g of potassium hydroxide. The crude product is dissolved in 3.5 cm3 of 0.1N aqueous sodium hydroxide solution. The solution thus obtained is washed with 2 times 10 cm3 of ethyl acetate, filtered and brought to a pH of 2 by addition of a 1N aqueous sulphuric acid solution. The product precipitated is separated by filtration, washed with 2 times 5 cm3 of water and dried in air. 0.13 g of 3-{3-{(2S)-1-[(2R,4R)-4-tert-butoxycarbonyl-2-(2-fluorophenyl)-3-thiazolidinyl]-1-oxo-2-propyl}ureido}phenylacetic acid, melting at 110° C., is thus obtained ([α]D20 =+103°±4° (C=0.244%; DMF), [proton NMR (200 MHz, DMSO D6, δ in ppm, J in Hz), 2 rotamers at room temperature, peak coalescence at 120° C., characteristic chemical shifts at 120° C.: 1.05 (d, J=7, 3H, --CH3): 1.55 (s, 9H, --C(CH3)3); 3.25 (dd, J=12.5 and 7, 1H, of S--CH2); 3.52 (dd, J=12.5 and 6, 1H, the other H of S--CH2 --); 3.53 (s, 2H, ArCH2COO); 4.4 (m, 1H, N--COCH--N); 4.86 (dd, J=7 and 6, N--CH--COO); 6.3 (d, J=8, 1H, --NHCO--); 6.83 (s,1H, S--CH--N); 6.89 (bd, J=8, 1H, in position 4 on CO--NH--Ph--); 7.10 to 7.5 (m, 6H, aromatic); 8.0 (bt, J=8.5, 1H, in position 6 on S--CH--Ph--); 8.29 (broad, 1H, ArNHCO--)], [infrared spectrum (KBr), characteristic bands in cm-1 : 3380, 2980, 2935, 2700 to 2250 (broad band), 1735, 1640, 1615, 1595, 1560, 1490, 1460, 1370, 1235, 1155, 760, 705].
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:31][Si](C)(C)C>CC(CC)=O>[ClH:31].[CH3:30][N:2]([CH3:1])[C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:4][CH2:5][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccn2)CCC(CC(=O)NCCc2c[nH]c3ccccc23)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
The less polar diastereoisomer of 2-(4-dimethylamino-4-pyridin-2-ylcyclohexyl)-N-[2-(1H-indol-3-yl)ethyl]acetamide (141 mg, 0.348 mmol) was dissolved in ethyl methyl ketone (6 ml), and chlorotrimethylsilane (0.126 ml, 1.0 mmol) was added. After a reaction time of 1 h, the hydrochloride was obtained as a beige-coloured solid in a yield of 84% (130 mg) with an m.p. of 150-153° C. (Example 47).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(O)c2ccccc2n1-c1ccccc1
Solvent: CC(=O)O
Product: O=c1c([N+](=O)[O-])c(O)c2ccccc2n1-c1ccccc1

Procedure:
A solution of 4-hydroxy-1-phenyl carbostyril (2.20g.; 0.0093 mole) in glacial acetic acid (10 ml.) was treated rapidly with concentrated nitric acid (2.5 ml. d 1.42) and the mixture heated on a steam bath for 21/2 mins. The red solution deposited a dark yellow solid on cooling which, after dilution with ethanol, was filtered off and washed well with ethanol, m.p. (AcOH -- EtOH) 167° - 169° C. (Found; C, 64.13; H, 3.70; N, 9.85; C15H10N2O4 requires; C, 63.83; H, 3.57; N, 9.92%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:22]([O-])([OH:24])=[O:23]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[C:10]([N+:22]([O-:24])=[O:23])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCN2C(C)=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)CC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
A 4-neck 22 L round bottom flask equipped with mechanical stirrer and thermowell was charged with 1-acetyl-5-(methyloxy)-2,3-dihydro-1H-indole (300 g, 1.56 mol) made in accordance with Step B, immediately above, and acetic anhydride (12 L). The resulting mixture was cooled to 0° C. then nitric acid (70%,.100 mL, 1.56 mol) was added dropwise. The reaction was stirred at room temperature overnight and then cooled to 0° C. The solid formed was collected by vacuum filtration and washed with water (200 mL) and MTBE (200 mL), then dried in a oven to give 1-acetyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole as a yellow solid (239 g, 65% yield). 1H-NMR (CDCl3, 300 MHz) δ 8.43 (s, 1H), 7.31 (s, 1H), 4.13 (t, 2H), 3.87 (s, 3H), 3.22 (t, 2H), 2.14 (s, 3H).
Reaction SMILES: O1CCCCC1.[C:7]1([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([Li])CCC.[C:25](=[O:27])=[O:26]>C1COCC1>[OH:19][C:16]1[CH:15]=[CH:14][C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:18][C:17]=1[C:25]([OH:27])=[O:26]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOCC1
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-hydroxy-5-phenylbenzoic acid was synthesized as follows. A solution of tetrahydropyran (THP)-protected 4-phenylphenol (474 mg. 2 mmol., prepared from 4-phenylphenol by standard methods described in Green and Wuts at pp. 31-34) in anhydrous THF (5 mL) was cooled to -78° C. and treated with n-Butyllithium (2 mL of 1.6M in hexanes). The reaction mixture was stirred and warmed to ambient temperature during which a tan suspension formed. After 2 hours, the reaction mixture was cooled to -78° C. and treated with excess anhydrous CO2 for several minutes. The reaction mixture was stirred and warmed to ambient temperature. After 2 hours, the reaction mixture was partitioned between ethyl ether and aqueous 1N NaOH. The aqueous layer was cooled to 0° C. with ice and acidified to pH 2 with aqueous 1N HCl. The aqueous solution was partitioned with methylene chloride. The organic layer was dried over magnesium sulfate. Concentration in vacuo yielded crude product as an off-white solid (258 mg, 2-hydroxy-5-phenylbenzoic acid). NMR spectroscopy of the crude material was consistent with the expected structure. 1H NMR (DMSO-d6) δ8.04 (d, J=3 Hz, 1H), 7.76 (dd, J=9, 3 Hz, 1H), 7.62 (d, J=7 Hz, 2H), 7.44 (t, J=7 Hz, 2H), 7.32 (t, J=7 Hz, 1H), 7.00 (d, J=9 Hz, 1H). Mass calculated: 466.5. Mass found 467.2. LC Gradient 25-45% acetonitrile over 13 minutes. LC retention time 3.5 minutes. The material was used without further purification.
Reaction SMILES: [Li+].[B-](CC)(CC)CC.[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[S:18]([C:21]2[CH:22]=[CH:23][C:24]([O:31][CH2:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:25]([CH:30]=2)[C:26](OC)=[O:27])(=[O:20])=[O:19])=[CH:13][CH:12]=1)[CH3:10].[Cl-].[NH4+].Cl>O1CCCC1>[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH2:39][CH:40]([CH3:41])[CH3:42])[S:18]([C:21]2[CH:22]=[CH:23][C:24]([O:31][CH2:32][CH:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[C:25]([CH2:26][OH:27])[CH:30]=2)(=[O:19])=[O:20])=[CH:13][CH:12]=1)[CH3:10]
Reactant: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)c(C(=O)OC)c2)cc1
Agent: CC[B-](CC)CC
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)c(CO)c2)cc1
Reaction time: 1 h
Yield: 79.6 %

Procedure:
A solution of Super-Hydride® (1 M in tetrahydrofuran, 0.449 mL, 0.449 mmol) was added over 5 minutes, to a solution of methyl 5-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)-2-((tetrahydro-2H-pyran-4-yl)methoxy)benzoate (100 mg, 0.204 mmol) in tetrahydrofuran (THF) (2 mL) under nitrogen. The solution was stirred for 1 hour then was added to a 1:1 mixture of ammonium chloride solution and HCl (2 N, 10 mL). The mixture was extracted with tert-butyl methyl ether (TBME) (2×5 mL), then organics dried and evaporated. The residue was purified by silica (Si) chromatography (0-50% ethyl acetate-cyclohexane) to give the title compound as a white foam (75 mg). LCMS [LCMS1] Rt 1.28 min, m/z (ES+) 462 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:20])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH2:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:54][CH2:55][C:56]1[C:57](=[O:64])[NH:58][C:59]([CH3:63])=[CH:60][C:61]=1[CH3:62]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:20])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH2:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:54][CH2:55][C:56]1[C:57](=[O:64])[NH:58][C:59]([CH3:63])=[CH:60][C:61]=1[CH3:62])=[O:9]
Reactant: CCc1c(C(=O)O)cc(Cl)cc1N(C)C1CCOCC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c(C(=O)NCc2c(C)cc(C)[nH]c2=O)cc(Cl)cc1N(C)C1CCOCC1
Yield: 64 %

Procedure:
To a solution of 5-chloro-2-ethyl-3-[methyl(oxan-4-yl)amino]benzoic acid (100 mg, 0.34 mmol) in DMF (2 ml) at room temperature under nitrogen was added HBTU (153 mg, 0.4 mmol) followed by N-ethyl-N-(propan-2-yl)propan-2-amine (88 μl, 0.5 mmol) and 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 63 mg, 0.37 mmol). After stirring for 3 hours at room temperature EtOAc (30 ml) was added to the reaction mixture and this was then washed with deionized water (5 ml) followed by saturated NaHCO3(aq) (3×5 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (5 g silica, Isolute cartridge, gradient of eluents; 100% DCM to 96:4 DCM:MeOH) to give 94 mg (65%) of the title compound as an off-white solid. LC-MS 95%, m/z=432.1/434.1, 1H NMR (500 MHz, Chloroform-d) δ ppm 11.34 (s, 1H), 7.14-7.08 (m, 2H), 7.03 (d, J=2.0 Hz, 1H), 5.95 (s, 1H), 4.52 (d, J=5.8 Hz, 2H), 3.96 (d, J=11.2 Hz, 2H), 3.33 (td, J=11.4, 2.3 Hz, 2H), 2.96-2.85 (m, 1H), 2.79 (q, J=7.4 Hz, 2H), 2.58 (s, 3H), 2.39 (s, 3H), 2.23 (s, 3H), 1.73-1.62 (m, 4H), 1.05 (t, J=7.4 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]#[N:10])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[C:22]([NH2:24])[CH:21]=[C:20]([Cl:25])[C:19]=1[OH:26]>C1(C)C=CC=CC=1>[CH3:8][C:7]1[C:2]([O:26][C:19]2[C:18]([Cl:17])=[CH:23][C:22]([NH2:24])=[CH:21][C:20]=2[Cl:25])=[N:3][CH:4]=[C:5]([C:9]#[N:10])[CH:6]=1
Reactant: Cc1cc(C#N)cnc1Cl
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)cnc1Oc1c(Cl)cc(N)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a 100 mL round bottom flask equipped with a water condenser, thermometer, magnetic stirrer, and under nitrogen atmosphere was added 2-chloro-3-methyl-5-cyanopyridine (7.10 g, 46.6 mmol), potassium carbonate (9.02 g, 65.2 mmol), 2,6-dichloro-4-aminophenol (10.77 g, 60.5 mmol), and dimethylformanide (70 mL). The resulting mixture was stirred at room temperature for 1 hour, 90° for 2 hours, and 110° for 3 hours. It was then cooled, filtered, and concentrated to give a brown mixture. This mixture was dissolved in 500 mL of toluene and washed with four 150 mL portions of 4% sodium hydroxide, water, and brine. It was then dried (Na2SO4) and concentrated to give the desired product as a brown solid (8.00 g, 27.2 mmol). m.p. 211.5°-212.5°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)=[O:11])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Li+].[Cl-].[CH2:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[CH:27]([C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:10]=[CH:8][C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1)=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C=Cc1ccccc1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=C(C(=O)c1ccc(C=Cc2ccccc2)cc1)c1ccc(C=Cc2ccccc2)cc1
Temperature: 100 °C
Yield: 139.4 %

Procedure:
A schlenk tube was charged with 4,4′-dibromobenzil (2.0 g, 5.4 mmol), K2CO3 (3.75 g, 27.2 mmol), Bu4NBr (1.75 g, 5.4 mmol), LiCl (0.23 g, 5.4 mmol), Pd(OAc)2 (0.12 g, 0.54 mmol), styrene (1.6 mL, 13.6 mmol), and 50 mL of dry DMF. The reaction mixture was heated at 100° C. for 14 h. The reaction mixture was allowed to cool down to room temperature and extracted with CH2Cl2. The organic phase was washed with H2O and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, dichloromethane:hexanes=1:2 (v/v), then dichloromethane:hexanes=1:1 (v/v)) to give a light yellow solid (1.56 g, 69.3%). 1H NMR (300 MHz, CDCl3, δ): 7.97 (d, J=8.3 Hz, 4H), 7.62 (d, J=8.8 Hz, 4H), 7.53 (d, J=6.8 Hz, 4H), 7.27-7.40 (m, 6H), 7.26 (d, J=16.6 Hz, 2H), 7.12 (d, J=16.6 Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3, δ): 193.82, 143.82, 136.45, 132.63, 131.83, 130.48, 128.83, 128.60, 127.17, 126.96, 126.84. HRMS-FAB (m/z): [M+H]+ calcd for C30H23O2, 415.1698; found, 415.1699. Anal. Calcd for C30H22O2: C, 86.93; H, 5.35. Found: C, 86.90; H, 5.26.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([OH:12])[CH3:11])=[CH:8][CH:9]=1
Reactant: CC(=O)c1ccc(OC(F)(F)F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-Trifluoromethoxyphenyl)ethanone (1.00 g, 4.90 mmol) in THF (5 mL) at 0° C. was added IM LiAlH4 in THF (5.9 mL, 5.9 mmol), and the solution was allowed to warm to rt. A few drops of water were added to quench. The mixture was concentrated in vacuo, transferred to a separatory funnel, and extracted using DCM and sat. aq. Rochelle salt. The organic layer was concentrated in vacuo to afford the title compound as a clear oil.