Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5](/[CH:9]=[N:10]/[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:6]=[CH:7][CH:8]=1.C(N(CC)C(C)C)(C)C.[N+:29]([CH3:32])([O-:31])=[O:30]>C(OCC)(=O)C>[N+:29]([CH2:32][CH:9]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:18])([F:19])[F:1])[CH:4]=1)([O-:31])=[O:30]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)/N=C/c1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(C[N+](=O)[O-])c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Of the compound from Example 11A, 3.6 g (13.17 mmol) were introduced in 26 ml of nitromethane and admixed with 0.69 ml (3.95 mmol) of N,N-diisopropylethylamine. The mixture was stirred at RT for 2 h. The reaction mixture was diluted with ethyl acetate and washed in succession twice each with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, and then with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated on a rotary evaporator. The residue (about 5 g) was dissolved in 15 ml of isopropanol at reflux. After cooling, the precipitated product was isolated by filtration, washed with a little isopropanol and sucked dry. After further drying in an HV, the title compound was obtained: 2.26 g (51% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]3[C:26]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:25][N:24]=[C:13]3[CH:14]([NH:16]C(=O)OC(C)(C)C)[CH2:15][C:4]=2[CH:3]=1>C(OCC)(=O)C>[ClH:1].[NH2:16][CH:14]1[C:13]2=[N:24][CH:25]=[C:26]([C:27]([OH:30])([CH3:28])[CH3:29])[N:12]2[CH2:11][C:5]2[C:6]3[CH:7]=[N:8][NH:9][C:10]=3[C:2]([Cl:1])=[CH:3][C:4]=2[CH2:15]1
Reactant: CC(C)(C)OC(=O)NC1Cc2cc(Cl)c3[nH]ncc3c2Cn2c(C(C)(C)O)cnc21
Solvent: CCOC(C)=O
Product: CC(C)(O)c1cnc2n1Cc1c(cc(Cl)c3[nH]ncc13)CC2N
Product: Cl
Temperature: 25 °C

Procedure:
A solution of tert-butyl [4-chloro-10-(1-hydroxy-1-methylethyl)-3,6,7,12-tetrahydroimidazo[1′,2′:1,7]azepino[3,4-e]indazol-7-yl]carbamate from Step F in Ethyl acetate (50 mL) was cooled to 0° C. HCl gas was bubbled into the solution until saturated and the reaction allowed to warm slowly to room temperature. The reaction was concentrated at reduced pressure and dried to give a quantitative yield of the title compound. MS: m/z 331 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH:13]([CH3:18])[CH2:12]1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=2)[C:15](=[O:17])[CH2:14][CH:13]([CH3:18])[CH2:12]1
Reactant: COc1cccc(OC)c1C1CC(C)CC(=O)N1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: COc1cccc(OC)c1C1CC(C)CC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)-4-methylpiperidin-2-one with commercially available 1-(bromomethyl)-4-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions D): tR=1.13 min.; [M+H]+: 423.91 g/mol.
Reaction SMILES: [Br:1][C:2]1[CH:3]2O[CH:10]([CH:11]=1)[C:9]1[C:4]2=[CH:5][CH:6]=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[I-].[Na+].C[Si](Cl)(C)C>C(#N)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:8]=2)[CH:3]=1
Reactant: FC(F)(F)c1ccc2c(c1)C1C=C(Br)C2O1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: FC(F)(F)c1ccc2cc(Br)ccc2c1

Procedure:
2-Bromo-6-(trifluoromethyl)-1,4dihydro-1,4-epoxynaphthalene (624 mg, 2.14 mmol) and sodium iodide (980 mg, 6.54 mmol) were dissolved in 13 mL of dry acetonitrile and trimethylsilyl chloride (0.823 mL, 6.54 mmol) added. The resultant mixture was stirred at ambient temperature for 3.5 h, poured into hexanes, and the organic layer washed successively with two portions of water and one portion of brine. The organic layer was dried over magnesium sulfate, concentrated in vacuo, and the residue purified by flash column chromatography (SiO2, 5% ethyl acetate/hexanes) to give 2-bromo-6-(trifluoromethyl)naphthalene as a white solid. 1H NMR (500 MHz, CDCl3) δ: 8.15 (s, 1H); 8.11 (s, 1H); 7.89 (d, J=8.7 Hz, 1H); 7.83 (d, J=8.7 Hz, 1H); 7.70 (dd, J=1.6, 8.7 Hz, 1H); 7.69 (dd, J=1.8, 8.7 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][C@@H:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][CH2:16][C@H:15]2[CH:21]([CH3:23])[CH3:22])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:24]S(C)(=O)=C.[I-].[Na+].[OH-].[Na+]>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:24][C@H:10]2[C:11]([O:13][C@@H:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][CH2:16][C@H:15]2[CH:21]([CH3:23])[CH3:22])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)/C=C/c1ccc(F)c(F)c1
Reactant: C=S(C)(C)=O
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (E)-3-(3,4-difluorophenyl)-2-propenoate (approximately 8.6 kg) in dimethyl sulfoxide (approximately 27.9 kg) was added with stirring over 20 minutes to a mixture of dimethylsulfoxonium methylide (approximately 2.6 kg, prepared as described above), sodium iodide (approximately 4.2 kg), water (approximately 500 g) and sodium hydroxide (approximately 56 g) in dimethylsulfoxide(27.7 kg) at 25° C. The reaction mixture was stirred for a further 2 hours and 50 minutes at 25° C., then used directly for the preparation of (1R,2S,5R)-2-iopropyl-5-methylcyclohexyl trans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylate.
Reaction SMILES: [O:1]=[CH:2][C:3](Cl)(Cl)Cl.S([O-])([O-])(=O)=O.[Na+].[Na+].[Cl:14][C:15]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17].Cl.Cl.[NH2:25][OH:26]>O>[Cl:14][C:15]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][C:2](=[O:1])/[CH:3]=[N:25]/[OH:26]
Reactant: NO
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Nc1cccc(Cl)c1Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(/C=N/O)Nc1cccc(Cl)c1Cl
Temperature: 100 °C
Yield: 90.6 %

Procedure:
To a solution containing chloral (4 g, 27 mmol) and sodium sulfate (35 g, 244 mmol) in 20 mL of water was added a solution containing 2,3-dichloroaniline (4.47 g, 27.6 mmol) and 3.5 mL of concentrated HCl in 5 mL of water. To this mixture was added 6.0 g (87 mmol) of hydroxylamine hydrochloride in 10 mL of water. The reaction mixture was refluxed in a 100° C. oil bath for 10 minutes. The reaction was cooled to room temperature and 5.7 g of N-(2,3-dichloro-phenyl)-2-[(E)-hydroxyimino]-acetamide was isolated by filtration as a yellow solid (90%): MS (m/e): 233.1 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[CH2:17][N:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=1)([S:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)[C:29]#[N:30])[CH2:15]2.[I-].[Na+]>CN(C)C=O.C1(C)C=CC=CC=1.O>[CH3:48][O:47][C:41]1[CH:40]=[C:39]([C:28]([S:31][C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N:16]2[CH2:15][C:14]3[C:18](=[CH:19][C:20]([O:21][CH3:22])=[C:12]([O:11][CH2:10][CH2:9][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH:13]=3)[CH2:17]2)[C:29]#[N:30])[CH:44]=[CH:43][C:42]=1[O:45][CH3:46]
Reactant: c1c[nH]cn1
Reactant: COc1ccc(C(C#N)(CCCCCN2Cc3cc(OC)c(OCCCl)cc3C2)Sc2ccc(C)cc2)cc1OC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C(C#N)(CCCCCN2Cc3cc(OC)c(OCCn4ccnc4)cc3C2)Sc2ccc(C)cc2)cc1OC
Temperature: 75 °C
Reaction time: 0.67 h

Procedure:
To a solution of 0.11 g of imidazole in 6 mL of N,N-dimethylformamide, under argon, is added 0.036 g of 60% of sodium hydride in oil. After stirring for 40 minutes, a solution of 0.3 g of 5-(2-chloroethoxy)-α-(3,4-dimethoxyphenyl)-1,3-dihydro-6-methoxy-α-[(4-methylphenyl)thio]-2H-isoindole-2-heptanenitrile in 8 mL of toluene is added followed by 0.3 g of sodium iodide. The resulting solution is heated at 75° C. for 21 hours. The solution is cooled and and poured into water. The solution is extracted with ethyl acetate and the organic layer washed with brine and dried over sodium sulfate. The solvent is removed at reduce pressure and the residual oil purified via column chromatography using a gradient elution from 4% methyl alcohol in methylene chloride to 9% methyl alcohol in methylene chloride. This affords 0.196 g of the desired product as a beige oil.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:20]([C:30]([F:33])([F:32])[F:31])[CH:19]=3)=[CH:12][CH:11]=2)[CH2:6]1)=[O:4].O[Li].O>CO.O>[F:32][C:30]([F:31])([F:33])[C:20]1[CH:19]=[C:18]([S:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([CH2:9][N:7]3[CH2:8][CH:5]([C:3]([OH:4])=[O:2])[CH2:6]3)=[CH:11][CH:12]=2)[CH:23]=[CH:22][C:21]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C1CN(Cc2ccc(CSc3ccc(-c4ccccc4)c(C(F)(F)F)c3)cc2)C1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)C1CN(Cc2ccc(CSc3ccc(-c4ccccc4)c(C(F)(F)F)c3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-[4-(2-trifluoromethyl-biphenyl-4-ylsulfanylmethyl)-benzyl]-azetidine-3-carboxylic acid methyl ester (129 mg, 0.2736 mmol, 1 eq.) in a mixture of MeOH (5 mL) and H2O (0.5 mL) is added LiOH—H2O (23 mg, 0.5472 mmol, 2 eq.). The mixture is stirred at room temperature for 3 h. After concentration, the crude product is purified by preparative RP LC-MS to give 1-[4-(2-Trifluoromethyl-biphenyl-4-ylsulfanylmethyl)-benzyl]-azetidine-3-carboxylic acid: 1H NMR (CD3OD, 400 MHz) δ7.61 (s, 1H), 7.60 (d, 1H), 7.56 (d, 2H), 7.46–7.39 (m, 6H), 7.29 (d, 2H), 4.42 (s, 2H), 4.35 (s, 2H), 4.31 (d, 4H), 3.73–3.61 (m, 1H); MS (ES+): (458.1, M+1)+.
Reaction SMILES: N([O-])=[O:2].[Na+].[Cl:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH2:15][O:16][CH2:17][CH2:18][OH:19])=[C:8](N)[N:7]=1>C(O)(=O)C>[Cl:5][C:6]1[NH:7][C:8](=[O:2])[C:9]2[N:10]=[CH:11][N:12]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]=2[N:14]=1
Reactant: O=N[O-]
Reactant: Nc1nc(Cl)nc2c1ncn2COCCO
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]c(Cl)nc2c1ncn2COCCO
Reaction time: 2 h
Yield: 49.8 %

Procedure:
Solid sodium nitrite (0.97 g) was added at room temperature with stirring over a period of one hour to a solution of 2-chloro-9-(2-hydroxyethoxymethyl)adenine (0.5 g) in glacial acetic acid (10 ml). The reaction mixture was stirred for an additional 41/2 hours. The white solid was removed by filtration, washed with cold acetic acid and then well triturated with cold water to remove the sodium acetate present. The solid product was retained. The combined acetic acid filtrate and wash was evaporated at reduced pressure and 40° C. bath temperature and the residual oil triturated with cold water. The resulting solid material was combined with the previously isolated solid and the combined solids dried and recrystallized from ethanol to give 2-chloro-9-(2-hydroxyethoxymethyl) hypoxanthine (0.25 g), m.p>310° C. Elemental analysis and NMR spectrum were consistent with this structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)=O)=[O:9])[CH:5]=[CH:6][CH:7]=1>CN(C)C=O.O.C(OCC)(=O)C.[Zn]>[OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:9])[CH2:10][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C(=O)c1cccc(O)c1)c1cccc(O)c1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1cccc(O)c1)c1cccc(O)c1
Yield: 31.1 %

Procedure:
A mixture of 3,3'-dihydroxybenzil (3.0 g.) and powdered zinc (5.0 g.) in N,N-dimethylformamide (25 ml.) and water (10 ml.) was stirred and heated under reflux for 6 hours. The cooled mixture was filtered through Celite and the filtrate was evaporated under oil pump vacuum to give a syrup. The syrup was dissolved in ethyl acetate and the solution was washed consecutively with dilute hydrochloric acid and saturated brine (thrice). The dried (MgSO4) solution was evaporated to smaller volume and benzene was added. A by-product (0.45 g., m.p. 225°-228°) crystallized on standing. The mother liquor was evaporated to a syrup which was crystallized by seeding from ethyl acetate benzene to give the title product (0.88 g., m.p. 151°-154°) which was shown to be identical with material produced from the two stage reduction (1, Sn/HCl; 2, Zn/chromic sulfate).
Reaction SMILES: [CH3:1][CH:2]([S:4]([NH:7][C@@H:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19]C)=[O:18])[CH:14]=2)[CH2:9]1)(=[O:6])=[O:5])[CH3:3].[OH-].[Li+].CCOC(C)=O.Cl>O.CO>[CH3:3][CH:2]([S:4]([NH:7][C@@H:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=2)[CH2:9]1)(=[O:6])=[O:5])[CH3:1]
Reactant: COC(=O)c1ccc2c(c1)C[C@@H](NS(=O)(=O)C(C)C)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(C(=O)O)cc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.2 %

Procedure:
A mixture of (S)-methyl 2-(1-methylethylsulfonamido)-2,3-dihydro-1H-indene-5-carboxylate (2.320 mmol, 690 mg) and lithium hydroxide (5.10 mmol, 122 mg) in H2O (25 mL) and MeOH (25 mL) was stirred at room temp for 2 days. EtOAc was added followed by 2M aq HCl and the reaction mixture extracted with EtOAc (×3). The EtOAc layers were combined and washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo to give desired product as a white solid (514 mg, 78%). MS (ESI): m/z [M−H]− 282.2
Reaction SMILES: Br.[CH3:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[S:8][C:7]1=[NH:15].[CH3:16][C:17]1([CH3:25])[C:19]([CH3:21])([CH3:20])[CH:18]1[C:22](O)=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[S:8][C:7]1=[N:15][C:22]([CH:18]1[C:19]([CH3:21])([CH3:20])[C:17]1([CH3:25])[CH3:16])=[O:23]
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: COCCn1c2c(sc1=N)CCCC2
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCn1c2c(sc1=NC(=O)C1C(C)(C)C1(C)C)CCCC2

Procedure:
A mixture of the product of Example 121A (156 mg, 0.55 mmol), 2,2,3,3-tetramethylcyclopropanecarboxylic acid (94 mg, 0.66 mmol), HATU (479 mg, 0.83 mmol) and triethylamine (0.46 mL, 3.30 mmol) in 10 mL of DMF was processed according to the method of Example 2B to provide the title compound: 1H NMR (500 MHz, DMSO-d6) δ 1.16 (s, 6H) 1.23 (s, 6H) 1.45 (s, 1H) 1.69-1.82 (m, 4H) 2.43-2.48 (m, 2H) 2.54-2.59 (m, 2H) 3.24 (s, 3H) 3.60 (t, J=5.3 Hz, 2H) 4.16 (t, J=5.3 Hz, 2H); MS (DCI/NH3) m/z 337 (M+H)+.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][C:29]1[CH:30]=[CH:31][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:33][CH:34]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:38][S:35]([C:32]3[CH:31]=[CH:30][C:29]([CH3:28])=[CH:34][CH:33]=3)(=[O:37])=[O:36])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and p-toluenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (42%); 1H NMR (CD3 OD) δ 7.87 (d, J=8.2 Hz, 2H), 7.37–7.08 (m, 15H), 6.87 (d, J=8.2 Hz, 2H), 6.32 (d, J=15.7 Hz, 1H), 2.44 (q, J=7.4 Hz, 2H), 2.40 (s, 3H), 0.89 (t, J=7.3 Hz, 3H); APcI m/z: 508 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH2:21][CH2:22][CH3:23]>C(OCC)(=O)C.O>[NH2:1][C:2]1[C:7]([O:8][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCOc1cccnc1N
Temperature: 50 °C
Yield: 41.4 %

Procedure:
A reaction flask was loaded with 2-amino-3-hydroxypyridine (8 g), dimethylformamide (DMF) (50 ml), and anhydrous potassium carbonate (12 g), and the temperature was raised up to 50° C. with stirring, followed by dropwise addition of n-butylbromide (11.9 g) to the flask in 4 hours with stirring. Then, the mixture was stirred at 60° C. for 2 hours. The heating was stopped, and water (200 ml) was added to the mixture. Ethyl acetate was added to the mixture and the mixture was stirred, followed by collecting the ethyl acetate layer with a separating funnel. The layer was condensed by an evaporator to precipitate crystals, and then the crystals were broken up with hexane. The crystals were filtrated for collection and dried to give crystals of 2-amino-3-butoxypyridine (5 g).
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][N:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.F[C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28].C(N(C(C)C)CC)(C)C>O1CCCC1>[O:3]1[CH2:4][CH2:5][N:6]([C@H:9]2[CH2:10][CH2:11][C@H:12]([NH:15][C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][C:18]=3[N+:27]([O-:29])=[O:28])[CH2:13][CH2:14]2)[CH2:7][CH2:8]1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: N[C@H]1CC[C@H](N2CCOCC2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(N[C@H]2CC[C@H](N3CCOCC3)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of EXAMPLE 324J (1.00 g) and 4-fluoro-3-nitrobenzenesulfonamide (0.90 g) in tetrahydrofuran (15 mL) was added diisopropylethylamine (4.75 mL) and the reaction was stirred at room temperature overnight. The reaction was filtered and the solid washed with dichloromethane. The reaction mixture was combined with the washings were concentrated. The resulting solid was triturated with dichloromethane and filtered to give the title compound.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH:24]([CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)[C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CN1CCOCC1.Cl.[NH2:55][CH2:56][C@H:57]([NH:63][C:64]([O:66][CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)=[O:65])[C:58]([O:60][CH2:61][CH3:62])=[O:59]>C(OCC)(=O)C>[C:43]([O:42][C:40]([N:37]1[CH2:36][CH2:35][CH:34]([CH2:33][CH2:32][CH:24]([C:25](=[O:26])[NH:27][CH2:28][C:29](=[O:30])[NH:55][CH2:56][C@@H:57]([C:58]([O:60][CH2:61][CH3:62])=[O:59])[NH:63][C:64](=[O:65])[O:66][CH2:67][C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=2)[CH2:23][CH2:22][CH:19]2[CH2:20][CH2:21][N:16]([C:14]([O:13][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:15])[CH2:17][CH2:18]2)[CH2:39][CH2:38]1)=[O:41])([CH3:44])([CH3:45])[CH3:46]
Reactant: CCOC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(CCC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)NCC(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](CNC(=O)CNC(=O)C(CCC1CCN(C(=O)OC(C)(C)C)CC1)CCC1CCN(C(=O)OC(C)(C)C)CC1)NC(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 90.9 %

Procedure:
Isobutyl chloroformate (13 g, 95.2 mmol) is added, at room temperature, to a solution of 2-[(4-[1-(tert-butoxycarbonyl)-4-piperidyl]-2-{2-[1-(tert-butoxycarbonyl)-4-piperidyl]ethyl}butanoyl)amino]acetic acid (compound 4) (46 g, 85.2 mmol) in 550 ml of ethyl acetate and N-methylmorpholine (19 g, 188 mmol), and a suspension is obtained. After stirring for 20 minutes, ethyl (2S)-3-amino-2-{[(benzyloxy)carbonyl]amino}propanoate hydrochloride (26.3 g, 86.9 mmol) is added. Stirring is continued for 18 hours at room temperature and the reaction medium is then washed with water, with 1N hydrochloric acid and with water and then dried over sodium sulphate and evaporated to give the crude product, which is purified by flash chromatography (20/1 dichloromethane/methanol) to give 61 g of a white solid.
Reaction SMILES: [Br:1][CH2:2][S:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[C:14]=1[CH3:21].[F:22][C:23]([F:36])([F:35])[S:24]([O:27]S(C(F)(F)F)(=O)=O)(=[O:26])=[O:25]>C(OCC)C>[O-:27][S:24]([C:23]([F:36])([F:35])[F:22])(=[O:26])=[O:25].[Br:1][CH2:2][S+:3]([C:18]1[CH:17]=[C:16]([CH3:19])[C:15]([CH3:20])=[C:14]([CH3:21])[C:13]=1[CH3:12])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: Cc1ccc(S(=O)CBr)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(C)c(C)c1C
Solvent: CCOCC
Product: Cc1ccc([S+](CBr)c2cc(C)c(C)c(C)c2C)cc1
Product: O=S(=O)([O-])C(F)(F)F
Reaction time: 4 h

Procedure:
1-((bromomethyl)sulfinyl)-4-methylbenzene (200 mg, 0.86 mmol) of example 35 was dissolved in dry diethyl ether (6 mL) under argon atmosphere. 1,2,3,4-tetramethylbenzene (0.127 g, 1.1 eq) was added to the previous solution and then the mixture was cooled to a temperature below −60° C. After stabilizing the temperature below −60° C., trifluoromethanesulfonic anhydride (0.145 mL, 1 eq) was slowly added maintaining the same temperature. After 4 hours at −60° C., the precipitate triflate salt was isolated by filtration and dried under vacuum. 0.358 g (83%) of the desired product was obtained as a white solid. mp: 136-138° C. 1H NMR (CDCl3, 400 MHz): δ 7.81 (2H, d, J=8.4 Hz), 7.71 (1H, s), 7.46 (2H, d, J=8.2 Hz), 5.69 (2H, ABQ, J=10.0 Hz), 2.50 (3H, s), 2.43 (3H, s), 2.42 (3H, s), 2.27 (3H, s), 2.26 (3H, s). 13C NMR (CDCl3, 100 MHz): δ 146.5, 143.9, 138.9, 138.8, 136.7, 132.2, 130.6, 126.9, 120.4, 118.5, 35.2, 21.6, 20.8, 17.4, 16.88, 16.81. FT-IR (KBr): 3027, 2954, 1492, 1450, 1400, 1288, 1245, 1220, 1162, 1147, 1027 cm−1.
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].O1CCOC[CH2:24]1>O>[F:3][CH:2]([F:4])[CH2:24][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12]
Reactant: Oc1ccccc1O
Reactant: FC(F)Cl
Reactant: C1COCCO1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1ccccc1OCC(F)F

Procedure:
Analogously to L. N. Sedova et al., Zh. Org. Khim. 6, 568 (1970), 275 g of chlorodifluoromethane are passed into a solution of 100 g of o-dihydroxy-benzene, 220 g of sodium hydroxide and 60 g of sodium dithionite in 500 ml of water and 400 ml of dioxane at 50°-55° C. After distillation at 61°-62° C./1.0-1.1 kPa a mixture of 1,2-bis(difluoromethoxy)benzene and 2-difluoroethoxyphenol is obtained, which is separated by chromatography on silica gel with cyclohexane/ethyl acetate (4:1).