Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6]([C:8]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[N:33]=[N:34][N:35]([C:37]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[N:36]=3)=[CH:22][CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=O)C.O>O1CCCC1>[OH:5][CH2:6][C:8]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[N:33]=[N:34][N:35]([C:37]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[N:36]=3)=[CH:24][CH:25]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: CCOC(=O)c1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2ccccc2n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2ccccc2n1
Reaction time: 18 h
Yield: 65.5 %

Procedure:
Lithium borohydride (11 mg) was added to a solution of 2-ethoxycarbonyl-4-([2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methoxy)quinoline (346 mg) in tetrahydrofuran (4 ml) and the mixture stirred for 18 hours. Water (20 ml) was added to the mixture and a white solid precipitated. The solid was collected by filtration, dissolved in ethyl acetate and the solution dried (MgSO4). The solvent was removed by evaporation and the residue crystallised from ethyl acetate/hexane to give 2-hydroxymethy-4-([2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methoxy)quinoline (213 mg), as a white crystalline solid, m.p. 183°-185° C. (dec.); NMR: 4.85(s,2H), 5.18(s,2H), 6.70(s,1H), 6.85-6.98(m,6H), 7.15-7.35(m,13H), 7.35-7.58(m,4H), 7.70(dt,1H), 7.95-8.08(m,2H), 8.15(d,1H); microanalysis, found: C,78.7; H,4.7; N,10.7%; C43H 33 N5O2 requires C,79.2; H,5.1; N,10.7%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[N:7]2)([O-])=O.NN.O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[N:7]2
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2nc1-c1cccs1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccc2[nH]c(=O)c(-c3cccs3)nc2c1

Procedure:
The quinoxalin-2-one of the present example is prepared by reducing 6-nitro-3-thiophen-2-yl-1H-quinoxalin-2-one of Example 39 with H2NNH2.H2O in the presence of Pd/C in refluxing MeOH.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[OH-].[K+]>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(Cl)cc1Oc1ccccc1

Procedure:
Aryl ethers have been formed by reacting aryl halides with phenols under various conditions. Roberts and Turner disclose (J. Chem. Soc., 1925, 127, p. 2004) that 2,4-dichloronitrobenzene reacts with phenol in aqueous KOH, at 100° C., to give a quantitative yield of 4-chloro-2-phenoxynitrobenzene.
Reaction SMILES: C([O:3][C:4]1[C:5]2[N:6]([CH:16]=[C:17]([C:19]([O:21]CC)=[O:20])[N:18]=2)[C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([Cl:14])=[C:9]([Cl:15])[CH:8]=2)C.C(O)C.[OH-].[Na+].Cl>O>[Cl:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[Cl:15])[N:6]1[CH:16]=[C:17]([C:19]([OH:21])=[O:20])[N:18]=[C:5]1[C:4](=[O:3])[NH:13]2
Reactant: CCOC(=O)c1cn2c(n1)c(OCC)nc1cc(Cl)c(Cl)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn2c(n1)c(=O)[nH]c1cc(Cl)c(Cl)cc12
Yield: 101.8 %

Procedure:
A mixture of 0.14 g of the product of Step B, 10 ml of ethanol, 20 ml of water and 3 ml of 1 N sodium hydroxide solution was refluxed overnight and the resulting clear solution was acidified with concentrated hydrochloric acid. The mixture was filtered to obtain 0.12 g of 4,5-dihydro-7,8-dichloro-4-oxoimidazo-[1,2-a]-quinoxaline-2-carboxylic acid in the form of a white crystalline solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[C:12]([NH2:15])=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:29][C:30]1[C:38]2[C:33](=[CH:34][C:35]([C:39](O)=[O:40])=[CH:36][CH:37]=2)[NH:32][CH:31]=1>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[C:12]([NH:15][C:39]([C:35]2[CH:34]=[C:33]3[C:38]([C:30]([Cl:29])=[CH:31][NH:32]3)=[CH:37][CH:36]=2)=[O:40])=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2N)cc1
Product: CC(C)(C)c1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2ccc3c(Cl)c[nH]c3c2)cc1
Yield: 72.2 %

Procedure:
Using the procedure described in Example 9, Part C, 4-t-butyldimethylsilyloxy-N2-(4-t-butylbenzoyl)-1,2-benzenediamine (750 mg, 1.9 mmol) and 3-chloroindole-6-carboxylic acid (372 mg, 1.9 mmol) yielded 790 mg (72%) of the title compound.
Reaction SMILES: [Na+].[CH:2]1([C:5]2[O:9][C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]56[CH2:30][CH2:29][C:26]([CH2:31][C:32]([O-:34])=[O:33])([CH2:27][CH2:28]5)[O:25][CH2:24]6)=[CH:19][CH:18]=4)=[CH:13][CH:12]=3)=[N:7][N:6]=2)[CH2:4][CH2:3]1.Cl>O>[CH:2]1([C:5]2[O:9][C:8]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]56[CH2:30][CH2:29][C:26]([CH2:31][C:32]([OH:34])=[O:33])([CH2:27][CH2:28]5)[O:25][CH2:24]6)=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[N:7][N:6]=2)[CH2:3][CH2:4]1
Reactant: O=C([O-])CC12CCC(c3ccc(-c4ccc(Nc5nnc(C6CC6)o5)cc4)cc3)(CC1)CO2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)CC12CCC(c3ccc(-c4ccc(Nc5nnc(C6CC6)o5)cc4)cc3)(CC1)CO2
Yield: 99 %

Procedure:
To a reaction vial contaminions 2-(4-(4′-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetic acid sodium salt (195 mg, 0.42 mmol) was added water (5 ml). The mixture was stirred and hydrochloric acid was added dropwise until the entire mixture achieved a pH between 3 and 4. The resulting slurry was filtered, washed with water to afford the title compound as white solid after drying (183 mg, 99% yield). HR/MS (M+H)+ found 446.2070. calc. 446.2080. RT: 1.66 (Condition L). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.01 (br. s, 1H) 10.43 (s, 1H) 7.52-7.67 (m, 6H) 7.38 (d, J=8.59 Hz, 2H) 3.89 (s, 2H) 2.32 (s, 2H) 2.08-2.19 (m, 1H) 1.79-2.07 (m, 8H) 1.02-1.12 (m, 2H) 0.91-0.99 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:26]=[C:27]([OH:35])[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:35][C:27]4[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:25]([F:24])[CH:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1cc(F)cc(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4cc(F)cc(C(F)(F)F)c4)ncnc32)CC1

Procedure:
4-[4-(3-Fluoro-5-trifluoromethyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 3-fluoro-5-(trifluoromethyl)phenol (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.94-2.06 (m, 4H), 2.99-3.07 (m, 2H), 4.08-4.11 (m, 2H), 4.99-5.05 (m, 1H), 7.71-7.78 (m, 3H), 8.40 (s, 1H), 8.59 (s, 1H). Mass spectrum MH+=482.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[S:15][CH:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:13][N:12]=1.[C:21]([S:24][CH2:25][CH2:26][C:27](Cl)=[O:28])(=[O:23])[CH3:22]>>[C:21]([S:24][CH2:25][CH2:26][C:27]([N:13]1[N:12]=[C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[S:15][CH:14]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:28])(=[O:23])[CH3:22]
Reactant: CC(=O)SCCC(=O)Cl
Reactant: CCOC(=O)C1NN=C(c2ccc3ccccc3c2)S1
Product: CCOC(=O)C1SC(c2ccc3ccccc3c2)=NN1C(=O)CCSC(C)=O

Procedure:
Prepared from the crude product of step (b) and 3-acetylthiopropanoyl chloride by the process of Example 3, step (b). mp 107°-108°
Reaction SMILES: BrC1C(O)=C(C(CSC2C=CC=CC=2OC)=CC=1)C(OC)=O.[Br:23][C:24]1[C:25]([O:36][CH3:37])=[C:26]([C:31]([CH2:34]Br)=[CH:32][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28].[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[SH:44]>>[Br:23][C:24]1[C:25]([O:36][CH3:37])=[C:26]([C:31]([CH2:34][S:44][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=2)=[CH:32][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Reactant: Sc1ccccn1
Agent: COC(=O)c1c(CSc2ccccc2OC)ccc(Br)c1O
Product: COC(=O)c1c(CSc2ccccn2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 82, starting from methyl 3-bromo-6-bromomethylbenzoate (Intermediate 89) and 2-pyridinethiol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.O[C@@H]([C@@H](C1C=CC(OC)=CC=1)SC1C=CC=CC=1[N+]([O-])=O)C(O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C(OC2CCNCC2)c2ccccn2)cc1
Agent: COc1ccc([C@@H](Sc2ccccc2[N+](=O)[O-])[C@H](O)C(=O)O)cc1
Product: Clc1ccc([C@H](OC2CCNCC2)c2ccccn2)cc1

Procedure:
By treating (±)-4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine and (2R,3R)-2-hydroxy-3-(4-methoxy-phenyl)-3-(2-nitrophenylthio)propionic acid in the same manner as in Example 4-(1), (2) and (3) to afford (S)-4-[(4-chlorophenyl) (2-pyridyl)methoxy]piperidine.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.P(=O)(O)(O)O.[N+]([O-])(O)=O.N([O-])=O.[Na+].[BrH:26]>O>[Br:26][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: Br
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1sc(Br)nc1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
Ethyl 2-amino-4-methylthiazole-5-carboxylate (1.20 g, 6.44 mmoles) was added to a solution of 85% phosphoric acid (18 mL) and 70% nitric acid (9 mL) at 0° C. Aqueous sodium nitrite(1.38 g (20 mmol) in water (9 mL) was immediately added dropwise over 20 minutes. After stirring at 0° C. for 15 minutes, cuprous bromide (930 mg, 6.44 mmoles) in hydrobromic acid (9 mL) was added. After stirring for 10 minutes, water (30 mL) was added. The mixture was filtered and the crude solid purified via silica gel chromatography (10% ethyl acetate/hexane) to afford 1.15 g (4.6 mmoles) of the product as a yellow solid (71%). H1 NMR (CDCl3) δ 4.35 (2H, q, J=7.1 Hz), 2.73 (3H, s), 1.38 (3H, t, J=7.1 Hz).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>COCCOC.CCOC(C)=O.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>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccccc2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 89.0 mg) and phenylboronic acid (48.8 mg) were dissolved in DME (0.8 mL). A solution of 2M NaHCO3 (0.3 mL, 0.6 mmol) was added, the RM was flushed with argon, heated to 90° C., and treated with Pd(PPh3)2Cl2 (14.0 mg, 0.02 mmol). The RM was stirred under argon at 95° C. for 2 h in a capped pressure safe tube. After cooling at RT, the RM was dissolved in EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH) and treated with Si-Thiol (80 mg) in MeOH to afford the title compound as an off-white powder. HPLC (Condition 4) tR=5.09 min, UPLC-MS (Condition 3) tR=1.14 min, m/z=444.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.62-1.73 (m, 1H) 1.74-1.85 (m, 1H) 2.85 (d, J=11.34 Hz, 1H) 3.10-3.26 (m, 2H) 3.32-3.45 (m, 1H) 4.15 (m, J=2.30 Hz, 1H) 4.80 (d, J=3.13 Hz, 1H) 7.25-7.51 (m, 7H) 7.78-7.88 (m, 2H) 7.96 (d, J=2.35 Hz, 1H) 8.72 (d, J=2.30 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH2:8][CH2:7][C:6]=2[O:5][C:4](=[O:13])[CH:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>>[CH:14]([N:17]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:5])[C:11]=2[C:2]([CH3:1])=[CH:3][C:4]1=[O:13])([CH3:16])[CH3:15]
Reactant: Cc1cc(=O)oc2c1C(=O)CCC2
Reactant: CC(C)N
Product: Cc1cc(=O)n(C(C)C)c2c1C(=O)CCC2

Procedure:
Prepared analogously to Example 5(b) from 4-methyl- 5,6,7,8-tetrahydro-cumarin-5-one and isopropylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[CH3:19][S:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])=[O:21]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:26]1[CH2:27][CH2:28][N:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH2:24][CH2:25]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Solvent: CC#N
Product: C[C@@H](N1CCN(S(C)(=O)=O)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 36.4 %

Procedure:
The epoxide IV (300 mg, 1.19 mmol) and LiClO4 (235 mg, 1.43 mmol) were dissolved in 12 mL dry acetonitrile and 1-methanesulfonylpiperazine (190 mg, 1.79 mmol) was added. The mixture was heated to reflux for 4 days, cooled and the solvent evaporated. The residue was dissolved in dichloromethane and then washed with water and brine. The solution was dried over Na2SO4 and the solvent evaporated. The crude reaction products were eluted through a silica gel column using 3% MeOH/97% EtOAc as eluent to give the title compound (180 mg, 36%) as a colorless solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][OH:7])(=[O:3])[CH3:2].CN(C)C=O.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([O:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)NCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)NCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
A solution of N-acetylethanolamine (10.0 g, 6.79 ml, 97 mmol) in a mixture of anhydrous tetrahydrofuran (100 ml) and dimethylformamide (10 ml) was added to a stirred suspension of 80% sodium hydride in oil dispersion (2.90 g, 97 mmol) in dry tetrahydrofuran (140 ml), under nitrogen, at room temperature. After 1 hour, the reaction mixture was heated to 40°-50° C. and then, after a further 0.5 hour, cooled to ice-bath temperature. Next, benzyl bromide (13.8 ml, 116 mmol) was added and the resulting suspension stirred at room temperature for 18 hours, before being cautiously quenched with water (400 ml). The resulting mixture was extracted with ethyl acetate (2×300 ml) and the combined extracts washed with water (200 ml), dried (Na2SO4) and evaporated under reduced pressure. The resulting residue was partitioned between ethyl acetate and water, then the organic phase washed thrice with water, dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with a solvent gradient of methanol:ethyl acetate (0:100 to 10:90), to give the required product (7.8 g) as an oil. Rf 0.21 (SS 17). LRMS: m/z 194.3 (M+1)+.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]([OH:17])([CH3:16])[P:8]([O:13][CH2:14][CH3:15])(=[O:12])[O:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.ClCCl.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:26]([O:17][C:7]([CH3:16])([P:8]([O:9][CH2:10][CH3:11])(=[O:12])[O:13][CH2:14][CH3:15])[CH2:6][S:5][C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CCOP(=O)(OCC)C(C)(O)CSC(C)(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(C)(CSC(C)(C)C)OC(C)=O
Temperature: 20 °C
Reaction time: 8 h

Procedure:
25.2 g (88.6 mmol) of diethyl 2-t-butylthio-1-hydroxy-1-methylethanephosphonate in 130 ml of acetic anhydride are treated with 1 ml of concentrated sulfuric acid, during which process the temperature of the solution rises from 20 to about 30° C. The mixture is subsequently stirred for 8 hours at 20° C., treated with 100 ml of dichloromethane and poured onto 300 ml of ice/water. The organic phase which is separated off is washed in succession with dilute hydrochloric acid, sodium hydrogen carbonate solution and water and dried over sodium sulfate, and the solvent is distilled off in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].B(O)O.[F:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1>>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:12]=[C:13]([O:15][C:33]2[CH:34]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:36]=[C:31]([F:30])[CH:32]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: Fc1cccc(C(F)(F)F)c1
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: OBO
Product: COC(=O)C(CC(C)C)c1cc(Oc2cc(F)cc(C(F)(F)F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 10 %

Procedure:
The title compound was prepared in 10% yield from 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example 15, step (f)) and 3-fluoro,5-trifluoromethylbenzene boronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2([C:36]([F:39])([F:38])[F:37])[O:25][N:24]=[C:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[C:28]([CH3:35])[CH:27]=3)[CH2:22]2)[CH:17]=[C:18]([Cl:20])[CH:19]=1.C(N(CC)CC)C>ClCCl>[C:4]([CH2:3][NH:2][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([C:23]2[CH2:22][C:21]([C:16]3[CH:17]=[C:18]([Cl:20])[CH:19]=[C:14]([Cl:13])[CH:15]=3)([C:36]([F:39])([F:38])[F:37])[O:25][N:24]=2)=[CH:27][C:28]=1[CH3:35])(=[O:5])[NH2:6]
Reactant: NCC(N)=O
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(N)=O
Yield: 87.1 %

Procedure:
In a solution of 0.37 g of glycine amide hydrochloride and 0.71 g of pyridine in 20 ml of dichloromethane, a solution of 1.31 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methylbenzoyl chloride synthesized in Step 3 of Synthetic Example 29 in 10 ml of dichloromethane was added dropwise with stirring under ice cooling, after the completion of the addition, stirred at room temperature for 3 hours, then 3.00 g of triethyl amine was added in the reaction mixture, and continued to stir at the same temperature further for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, 50 ml of ethyl acetate and 50 ml of water were added in the residue, and the organic phase was collected, and the aqueous phase was further extracted with ethyl acetate (50 ml×2). The organic phases together were dehydrated and dried with saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and the solvent was distilled off under reduced pressure, the residual solid was washed with hexane to obtain 1.24 g of the aimed product as white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>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.[Zn].C(COC)OC>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:15]([C:14]2[CH:18]=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=2)=[O:16])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Clc1ccc(CBr)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Zn]
Solvent: COCCOC
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 91 %

Procedure:
To dimethoxyethane (100 mL) was added 4-chlorobenzylbromide (4.1 g), 4-chlorobenzoylchloride (2.56 mL), bis(triphenylphosphine)palladium dichloride (702 mg) and zinc powder (2.6 g) and the mixture was stirred for 2 hours under nitrogen gas atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuo and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=49/1 to 9/1) to obtain (4-chlorobenzyl) (4-chlorophenyl)methanone (4.85 g, yield: 91%) as a powder.