Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[NH2:13][C:14]1[C:15]([F:22])=[CH:16][C:17]([Cl:21])=[C:18]([OH:20])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:13][C:14]1[C:15]([F:22])=[CH:16][C:17]([Cl:21])=[C:18]([CH:19]=1)[O:20][C:8]1[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1cc(N)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
To a solution of 3-cyano-4-fluoronitrobenzene (7.0 g, 42.1 mmol) and 5-amino-2-chloro-4-fluorophenol (6.8 g, 42.1 mmol) in N,N-dimethylformamide (200 ml) was added potassium carbonate (8.71 g, 63.1 mmol), and the mixture was stirred at room temperature for 1 hr. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Water (200 mL) was added to the residue, and the mixture was extracted with ethyl acetate (270 mL)/tetrahydrofuran (30 mL). The organic layer was washed with saturated brine (200 mL×2) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was purified by basic silica gel column chromatography (eluate: ethyl acetate). The obtained solution was concentrated under reduced pressure to give the title compound (13.1 g, quantitative) as a yellow powder.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=O)[CH2:3][CH2:2]1.C1(C)C=CC=CC=1.O=P(Cl)(Cl)Cl.Cl.C[Si]([C:29]#[N:30])(C)C>N1C=CC=CC=1>[C:29]([C:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][CH:3]=1)#[N:30]
Reactant: O=C1CCOc2ccccc21
Reactant: C[Si](C)(C)C#N
Agent: Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: N#CC1=CCOc2ccccc21
Reaction time: 12 h

Procedure:
Eleven grams 2H-[1]benzopyran-4-one are dissolved in 33 ml 2.5M trimethylsilyl cyanide (CH2Cl2). After addition of 50 mg Znl2, the mixture is stirred 12 h. Then 30 ml toluene, 115 ml pyridine and 21 ml POCl3 are added and the mixture refluxed for 4 h. On cooling, it is poured into 1000 ml 5% HCl and extracted with four 100 ml portions of ether. The extracts dried over Na2SO4, filtered, concentrated under reduced pressure and vacuum distilled (bulb-to-bulb, oven temperature 150°) to yield 4-cyano-2H[1]benzopyran.
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:21])([F:20])[C-:5]([C:16]([F:19])([F:18])[F:17])[C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9].CN([S+](N(C)C)N(C)C)C>C(#N)C1C=CC=CC=1>[Br:1][C:5]([C:16]([F:17])([F:18])[F:19])([C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[C:4]([F:20])([F:21])[F:3]
Reactant: FC(F)(F)[C-](C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: BrBr
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: N#Cc1ccccc1
Product: FC(F)(F)C(F)(F)C(F)(F)C(Br)(C(F)(F)F)C(F)(F)F
Yield: 75 %

Procedure:
Bromine, 7.99 g (0.05 mol), was added dropwise at 0° to a solution of 0.05 mol of tris(dimethylamino)sulfonium 1,1,1,3,3,4,4,5,5,5-decafluoro-2-(trifluoromethyl)-2-pentanide, prepared as in Example D (except for the amounts), in 40 mL of benzonitrile. The reaction mixture was warmed to 25°, and the volatile portion was distilled out under reduced pressure, and then redistilled at atmospheric pressure to give 12.8 g (75%) of 2-bromo-1,1,1,3,3,4,4,5,5,5-decafluoro-2-(trifluoromethyl)-pentane as a colorless liquid: b.p. 96.5°-97.2°; 19F NMR (CDCl3) δ -65.2 ppm (m, 6F), -81.1 ppm (t, 3F), -105.9 ppm (2F) and -122.6 ppm (2F). Anal. Calcd. for C6BrF13 : C, 18.06; F, 61.91. Found: C, 17.90; F, 61.55.
Reaction SMILES: N1CCCC1.[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]([OH:19])=[O:18])[C:11]([CH3:20])=[C:10]2[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([N:31]2[CH2:36][CH2:35][CH2:34]C[CH2:32]2)(=[O:30])=[O:29])[CH:23]=1>>[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]([OH:19])=[O:18])[C:11]([CH3:20])=[C:10]2[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([N:31]2[CH2:32][CH2:34][CH2:35][CH2:36]2)(=[O:30])=[O:29])[CH:23]=1
Reactant: Cc1c(Cc2cccc(S(=O)(=O)N3CCCCC3)c2)c2cc(F)ccc2n1CC(=O)O
Solvent: C1CCNC1
Product: Cc1c(Cc2cccc(S(=O)(=O)N3CCCC3)c2)c2cc(F)ccc2n1CC(=O)O

Procedure:
Pyrrolidine was used a starting material in Procedure H, otherwise this compound was prepared in a similar manner to Compound 4, using Procedures H, I, J, K & L.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[OH:31][C@@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1>>[N:25]1([C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:10]4[O:9][C:8]([CH2:7][CH2:6][N:34]5[CH2:35][CH2:36][C@@H:32]([OH:31])[CH2:33]5)=[CH:12][C:11]=4[CH:13]=3)=[N:18][CH:19]=2)=[O:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O[C@@H]1CCNC1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CC[C@@H](O)C4)cc3c2)nc1)N1CCOCC1

Procedure:
The product from Example 44E and 3-(R)-hydroxypyrrolidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.82 (s, 1H), 4.55 (m, 1H), 3.3-3.8 (m, 16H), 2.0-2.4 (m, 2H); MS (DCI) m/z 422 (M+H)+;
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][CH:22]1[C:26](=[O:27])[O:25][CH:24]2[CH2:28][CH2:29][CH2:30][CH:23]12.[CH2:31](Br)[CH:32]=[CH2:33]>C1COCC1>[CH2:33]([C@:22]1([CH2:21][C:12]2[CH:13]=[CH:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[C:26](=[O:27])[O:25][C@H:24]2[CH2:28][CH2:29][CH2:30][C@H:23]12)[CH:32]=[CH2:31]
Reactant: O=C1OC2CCCC2C1Cc1ccc2ccccc2c1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@]1(Cc2ccc3ccccc3c2)C(=O)O[C@H]2CCC[C@@H]21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under argon, 1.9 ml of a 1 molar solution of lithium bis-(trimethylsilyl)-amide in THF are added dropwise to a solution, cooled to −78° C., of 0.5 g (1.88 mmol) of the compound from Example 1 in 20 ml of THF such that the temp. of the mixture does not exceed −65° C. After the addition has ended, stirring is continued at −78° C. for 10 min, and 0.26 g (2.25 mmol) of allyl bromide are then added in one portion. Immediately afterwards, the cooling bath is removed and the mixture is allowed to warm to room temp. After 16 h of stirring at room temp., the mixture is taken up in ammonium chloride solution and ethyl acetate and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulphate and then concentrated. The residue was chromatographed over silica gel (mobile phase: dichloromethane). Yield: 255 mg (44%) of a colourless oil. 1H-NMR (200 MHz; CDCl3) δ[ppm]=1.55-2.2 (br m,6H), 2.3 (m, 2H), 2.61 (m,1H), 3.12 (d,1H), 3.3 (d,1H), 4.91 (m,1H), 5.05 (dd,1H), 5.11 (dd, 1H), 5.8 (ddt,1H), 7.35-7.5 (br m,3H), 7.72 (s,1H), 7.80 (m,3H). Diastereomeric purity: >99% de (HPLC).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[N+:12]([O-])=O)[CH3:2]>[Pd].CCOC(C)=O>[NH2:12][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[NH:3][CH2:1][CH3:2])[C:8]#[N:9]
Reactant: CCNc1ccc(C#N)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCNc1ccc(C#N)cc1N
Reaction time: 3 h
Yield: 102.2 %

Procedure:
A 250 mL pressure flask was sparged with a stream of nitrogen and then charged with 4-ethylamino-3-nitrobenzonitrile (1.6 g, 8.5 mmol), EtOAc (35 mL) and 10% w/w Pd/C (1.0 g, 11 mol %). The pressure flask was affixed to a Parr hydrogenation apparatus, evacuated briefly and backfilled with argon (2 cycles), then evacuated briefly and backfilled with hydrogen (3 cycles). The flask was pressurized to 50 psi of hydrogen and shaken vigorously. After 3 h, the flask was vented and sparged with a stream of nitrogen for 5 min. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give the title product (1.4 g, quant.) as a pale brown solid. 1H-NMR (CDCl3): δ 7.14 (1H, dd), 6.91 (1H, d), 6.56 (1H, d), 3.91 (1H, br s), 3.32 (2H, br s), 3.19 (2H, q), 1.31 (3H, t).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1.Br[CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:17]1(=[O:26])[N:16]([CH2:15][CH2:14][CH2:13][O:11][C:5]2[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=2)[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: OCc1cc(O)cc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCOc1cc(CO)cc(CO)c1
Temperature: 25 °C
Yield: 27.9 %

Procedure:
3,5-Bis-hydroxymethylphenol (Felder, D.; Gutierrez Nava, M.; del Pilar Carreon, M.; Eckert, J. F.; Luccisano, M.; Schall, C.; Masson, P.; Gallani, J. L.; Heinrich, B.; Guillon, D.; Nierengarten, J. F. Helv. Chimica Acta 2002, 85, 288) (2.35 g), N-(3-bromo-propyl)-phthalimide (4.49 g) and potassium carbonate (10.53 g) were mixed in acetonitrile (25 mL) and refluxed for 12 h. The reaction mixture was cooled to room temperature and the solvent removed under reduced pressure. The residue was redissolved in dichloromethane and the insoluble residue filtered off. The filtrate was washed with water, dried over magnesium sulfate, and concentrated in vacuo to a residue. The residue was purified by silica gel chromatography (Merck SuperVarioPrep 90 g column, Si60 15-40 μm), eluted with methanol/dichloromethane, 4:96 to give 5-(3-phthalimido-propyloxy)-1,3-bis-(hydroxymethyl)benzene (1.45 g):
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26](F)[CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.N[C@]12CC[C@@H](C(C)C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)[C@@H](C2C=CC(C(OC)=O)=CC=2)CC3)CC1>>[NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([CH:38]([CH3:40])[CH3:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:22])([CH3:23])[C@@H:11]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:31][CH:32]=2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(N)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Product: CC(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoic acid using methyl 4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-amino-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate as the starting material in Step 5. The product was isolated as a white solid (12 mg, 47%). LCMS: m/e 532.43 (M−H)−, 2.37 min (method 10). 1H NMR (500 MHz, METHANOL-d4) δ 7.84 (d, J=8.2 Hz, 2H), 7.19 (d, J=8.2 Hz, 2H), 2.42 (dd, J=13.0, 2.9 Hz, 1H), 2.18 (qd, J=13.3, 3.1 Hz, 1H), 2.07-1.24 (m, 25H), 1.16 (s, 3H), 1.07 (s, 3H), 1.03 (s, 3H), 0.93 (d, J=6.7 Hz, 3H), 0.83 (d, J=6.7 Hz, 3H), 0.79 (s, 3H), 0.74 (s, 3H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.CCN(CC)CC.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:21]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](OC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of (3S)-pyrrolidin-3-ol (0.87 g, 10.0 mmol) in THF (20 mL) was slowly added a solution of di-tert-butyl dicarbonate (2.18 g, 10.0 mmol) in THF (10 mL) at room temperature. After addition was completed, the reaction mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (0-2.5% methanol in dichloromethane) to give intermediate tert-Butyl(3S)-3-hydroxypyrrolidine-1-carboxylate. To a solution of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (900 mg, 4.8 mmol) in CH2Cl2 (6 mL) was added Et3N (699 mg, 6.91 mmol) followed by benzoyl chloride (809 mg, 5.76 mmol) at 0° C. After addition was completed, the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between CH2Cl2 and H2O. The organic layer was successively washed with aqueous NaHCO3 and water, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-1% methanol in dichloromethane) to give the subtitled compound (642 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH2:9]([O:16][C:17]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:17]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([O:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1)=[O:23])=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)c1cccc(C(=O)OCc2ccccc2)c1
Reactant: O=c1cc(O)cc[nH]1
Product: O=C(OCc1ccccc1)c1cccc(C(=O)Oc2cc[nH]c(=O)c2)c1
Yield: 48.7 %

Procedure:
The general procedure of Example 1 was repeated using 2.80 g of 4-hydroxy-2-pyridone and 14.70 g of 3-benzyloxycarbonylbenzoyl chloride, thereby producing 4.29 g of the title compound in a yield of 49%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH3:10].[Br:11]Br>C(O)(=O)C>[CH3:8][C:7]1[C:2]([CH3:1])=[C:3]([S:9][CH3:10])[CH:4]=[CH:5][C:6]=1[Br:11]
Reactant: BrBr
Reactant: CSc1cccc(C)c1C
Solvent: CC(=O)O
Product: CSc1ccc(Br)c(C)c1C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
510 g (3.33 mol) of 2,3-dimethylthioanisole are initially charged in 3 l of glacial acetic acid, and a solution of 592 g (7.4 mol) of bromine in 1 l of glacial acetic acid is added dropwise at room temperature over a period of three hours. The reaction is slightly exothermic. The reaction mixture is stirred at room temperature for another 3.5 hours. The precipitate is then filtered off with suction and the filtrate is admixed with 270 g of sodium acetate and concentrated. The residue is taken up in 2 l of dichloromethane and washed twice with 2 l of sodium bicarbonate solution and twice with sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:29])[CH2:13][NH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[O:16])[CH2:8][CH2:7]1)=[O:5].B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:29])[CH2:13][NH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[O:16])[CH2:8][CH2:7]1)=[O:5]
Reactant: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CNC(=O)c3ccc(-c4ccccc4)cc3)CC2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(O)ccc2Br)CC1)c1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 4 h
Yield: 29.5 %

Procedure:
A solution of Biphenyl-4-carboxylic acid {2-[4-(2-bromo-5-methoxy-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide (prepared by the method as described above) (115 mg, 0.21 mmol) in DCM (5 ml) was cooled to −78° C. To the resulting mixture added BBr3 (357 mg, 1.42 ml, 1.43 mmol) and stirred at same temperature for 4 hrs. The reaction mixture was brought to −30° C. and quenched with cold MeOH dropwise, concentrated the mixture under reduced pressure to get the residue. The obtained residue was purified by preparative HPLC to afford 33 mg (29.5% yield) Biphenyl-4-carboxylic acid {2-[4-(2-bromo-5-hydroxy-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 98.95%. 1H NMR (DMSO-d6): δ 10.1 (s, 1H), 8.7-8.6 (bs, 1H), 8.0-7.9 (d, 2H), 7.8-7.7 (dd, 4H), 7.5-7.4 (m, 4H), 6.8-6.7 (t, 2H), 4.24-4.1 (dd, 2H), 3.74-3.44 (m, 6H), 3.24-3.1 (bd, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C:5](=[O:7])[NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[I:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.O1CCOCC1>[I:15][C:16]1[CH:21]=[CH:20][C:19]([N:4]2[C@@H:3]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]([CH3:14])([CH3:1])[O:6][C:5]2=[O:7])=[CH:18][CH:17]=1
Reactant: CC1(C)OC(=O)N[C@H]1c1ccccc1
Reactant: Ic1ccc(I)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(I)cc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 61.2 %

Procedure:
A resealable tube was charged with (S)-5,5-dimethyl-4-phenyloxazolidin-2-one (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (1.01 g, 5.28 mmol), 1,4-diiodobenzene (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (3.48 g, 10.56 mmol), tribasic potassium phosphate (5.61 g, 26.4 mmol) and dioxane (20.0 mL). The mixture was purged with argon and then copper (I) iodide (1.006 g, 5.28 mmol) and N,N′-dimethylethylenediamine (1.137 mL, 10.56 mmol) were added. The system was purged with argon, the tube was sealed, and the reaction mixture was heated at 100° C. for 12 hours. The reaction mixture was filtered through Celite® brand filter aid and concentrated to afford a purple solid. This material was purified via column chromatography on silica gel (RediSep 80 g column, gradient elution with 0-25% EtOAc-hexane) to afford (S)-3-(4-iodophenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (1.271 g, 3.23 mmol, 61.2% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=7.64-7.59 (m, 2H), 7.39-7.33 (m, 2H), 7.33-7.27 (m, 3H), 7.26-7.20 (m, 2H), 5.43 (s, 1H), 1.61 (s, 3H), 0.89 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([OH:24])[C@H:15]([NH:18][C:19](=[O:23])[CH:20]([Cl:22])[Cl:21])[CH2:16][F:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[Cl:21][CH:20]([Cl:22])[C:19]([NH:18][C@H:15]([CH2:16][F:17])[C@H:14]([OH:24])[C:11]1[CH:10]=[CH:9][C:8]([C:6]2[S:7][C:3]([CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:4][CH:5]=2)=[CH:13][CH:12]=1)=[O:23]
Reactant: NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
To a suspension of N-((1R,2S)-1-(4-(5-(aminomethyl)thiophen-2-yl)phenyl)-3-fluoro-1-hydroxypropan-2-yl)-2,2-dichloroacetamide (150 mg, 0.383 mmol) in dichloromethane is added triethylamine (1604, 1.15 mmol) followed by methanesulfonyl chloride (304, 0.383 mmol). Resulting yellow solution is stirred at room temperature for 30 minutes. The reaction is concentrated then purified using HPLC to give the title compound (99 mg): 1HNMR (400 MHz, DMSO-d6): δ 8.58 (d, 1H), 7.71 (t, 1H), 7.55 (d, 2H), 7.37 (d, 2H), 7.33 (d, 2H), 7.01 (d, 1H), 6.51 (s, 1H), 5.95 (br s, 1H), 4.85 (d, 1H), 4.71-4.52 (m, 1H), 4.44-4.13 (m, 4H), 2.89 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]2[CH:27]=[CH:26][C:12]3[N:13]=[C:14]([C:16]4[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:4][NH:5][C:6](=[O:8])[CH:7]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[CH3:1][C:2]1[C:3]([C:9]2[CH:27]=[CH:26][C:12]3[N:13]=[C:14]([C:16]4[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:4][NH:5][C:6](=[O:8])[CH:7]=1
Reactant: COC(=O)c1ccc(-c2nc3ccc(-c4n[nH]c(=O)cc4C)cc3o2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc(=O)[nH]nc1-c1ccc2nc(-c3ccc(C(=O)O)cc3)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
25 mg (69 μmol) methyl 4-[6-(4-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzoxazol-2-yl]-benzoate is placed in 4 mL DMSO, 350 μL (1 mmol/mL; 346 μmol) sodium hydroxide solution are added and the mixture is stirred overnight at RT. The reaction mixture is adjusted to pH 4 with 10% citric acid and extracted with H2O and DCM. Then the solv. of the organic phase is eliminated i.V. and the residue is separated by HPLC-MS. (xTerra, ACN/H2O+TFA)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:12])[C:7]([S:10][CH3:11])=[N:8][CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+].Cl>C(O)C.O>[Cl:12][C:6]1[C:7]([S:10][CH3:11])=[N:8][CH:9]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=1
Reactant: CSc1ncc(C(C)=O)cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSc1ncc(C(C)O)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.6 %

Procedure:
5-Acetyl-3-chloro-2-methylthiopyridine (24.1 g, 0.12 mol) was slurried in absolute ethanol (200 mL) and sodium borohydride (4.5 g, 0.118 mol) added in portions. The reaction mixture was stirred at room temperature for 48 hours and acidified to pH 2 with 2N hydrochloric acid. This was then diluted with water (200 mL) and the bulk of the ethanol evaporated under reduced pressure, the temperature of the mixture being maintained below 50° C. The reaction mixture was diluted with water (200 mL) and extracted twice with dichloromethane (15 mL). The combined organic extracts were washed with water (200 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulphate, and evaporated to dryness to give the desired product (21.9 g, 90%) as an orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[C:10]([S:12][CH2:13][C:14](=O)[CH3:15])[CH:9]=[CH:8][C:7]=1[C:17]([F:20])([F:19])[F:18])[CH3:2].Cl.[Cl:23][C:24]1[C:25]([F:32])=[C:26]([NH:30]N)[CH:27]=[CH:28][CH:29]=1>>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[C:10]([S:12][C:13]2[C:27]3[C:26](=[C:25]([F:32])[C:24]([Cl:23])=[CH:29][CH:28]=3)[NH:30][C:14]=2[CH3:15])[CH:9]=[CH:8][C:7]=1[C:17]([F:20])([F:19])[F:18])[CH3:2]
Reactant: CCOC(=O)Cc1cc(SCC(C)=O)ccc1C(F)(F)F
Reactant: NNc1cccc(Cl)c1F
Agent: Cl
Product: CCOC(=O)Cc1cc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)ccc1C(F)(F)F

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: [5-(2-Oxo-propylsulfanyl)-2-trifluoromethyl-phenyl]-acetic acid ethyl ester and (3-chloro-2-fluoro-phenyl) hydrazine hydrochloride.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11]([NH2:16])[CH:10]=1)C.[OH-].[Na+].Cl>C1COCC1.O>[NH2:15][C:13]1[N:12]=[C:11]([NH2:16])[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:17])=[O:3])[N:14]=1
Reactant: CCOC(=O)CCCCc1cc(N)nc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(CCCCC(=O)O)nc(N)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The ethyl ester 2-2 (190 mg, 0.8 mmol) in THF (10 mL) and water (10 mL) was treated with 1 N NaOH (1.6 mL, 1.6 mmol). After stirring at room temperature for 16 hours, the solution was neutralized with 1N HCl and then the solvents removed in vacuo. The residue, 2-3 was used as such in the next step.