Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[OH-].[Na+]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:19]([C:16]3[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1cnc2[nH]ccc2n1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(Br)cnc32)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (78.0 g, 394 mmol, Ark Pharm) in anhydrous DMF (272 mL) was added drop-wise over about 60 min to a stirred suspension of NaH (60% dispersion in mineral oil, 12.8 g, 532 mmol) in anhydrous DMF (543 mL) at about 0-5° C. The brown reaction solution was stirred for about 30 min at about 0-5° C. then a solution of p-toluenesulfonyl chloride (94.0 g, 492 mmol) in anhydrous DMF (272 mL) was added drop-wise over about 60 min at about 0-5° C. The reaction mixture was stirred at about 0-5° C. for about 1 h then allowed to warm to ambient temperature and stirred for about 18 h. The reaction mixture was poured slowly into ice water (6 L), followed by the addition of aqueous NaOH (2.5 M, 50.0 mL, 125 mmol). The precipitate was collected by filtration and stirred with cold water (3×200 mL). The solid was collected by filtration and dried to constant weight in a vacuum oven at about 55° C. to yield 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (134.6 g, 97%) as a pale beige solid: LC/MS (Table 2, Method d) Rt=1.58 min; MS m/z: 352/354 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.[Cl:12][CH:13]([CH3:17])[C:14](Cl)=[O:15]>C1(C)C=CC=CC=1>[Cl:12][CH:13]([CH3:17])[C:14]([N:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]1[CH3:1])=[O:15]
Reactant: CC(Cl)C(=O)Cl
Reactant: CC1NCCc2ccccc21
Solvent: Cc1ccccc1
Product: CC(Cl)C(=O)N1CCc2ccccc2C1C

Procedure:
A reaction vessel was charged with 50 ml toluene and 2.0 g 1-methyl-1,2,3,4-tetrahydroisoquinoline (prepared by procedure of Example 1--Procedure A). Then, 2.0 ml 2-chloropropionyl chloride was added gradually to the mixture. The reaction mixture was stirred and heated until a homogeneous solution appeared. The mixture was filtered, stripped of solvent, and subjected to Kugelrohr distillation (150° C. @ 0.25 mm Hg) to provide 2.8 g of a yellow oil product having the elemental analysis reported in Table I.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>C1COCC1>[CH2:7]([O:6][P:4]([CH:9]([CH2:24][C:23]1[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
Ethyl 2-(diethoxyphosphoryl)acetate (5.0 ml, 25.2 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 1.10 g, 27.6 mmol) in THF (40 ml) at 0°. After 30 min at room temperature, a solution of 4-nitrobenzylbromide (5.42 g, 25.2 mmol) in THF (40 ml) was added over 30 min. The reaction mixture was stirred for 2 h at room temperature, quenched with water and partitioned between Et2O and water. The aqueous phase was extracted with Et2O and the combined organic layers washed with brine, dried (MgSO4) and evaporated in vacuo. Column chromatography (silica; MeOH/DCM, 1:49) gave the title compound as a pale yellow oil (2.01 g): δH (CDCl3) 8.13 (2H, d, J 8.8 Hz), 7.37 (2H, d, J 8.8 Hz), 4.23-4.06 (1H, m), 3.37-3.20 (3H, m), 1.35 (6H, t, J 7.1 Hz), 1.16 (3H, t, J 7.1 Hz): m/z (EI−, 70V) 360.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.Cl>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1
Reactant: c1ccncc1
Reactant: N#Cc1ccc(N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(-c2ccccn2)cc1

Procedure:
A solution of 7.05 g (102 mmol) of sodium nitrite in 16 ml of water is added dropwise at 5° C. in the course of 30 min to a suspension of 11.8 g (0.10 mol) of 4-amino-benzonitrile in 40 ml of water and 36.2 ml of conc. HCl. The turbid yellow reaction solution is then added dropwise at 35-40° C. over a period of 100 min to 121 ml of pyridine. After 45 minutes' stirring at 90° C. the excess pyridine is evaporated off (RV; 60° C.), and the residue is taken up in ethyl acetate and washed with water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; hexane/ethyl acetate 4:1→3:2→1:1→ethyl acetate) yields 4-(pyridin-2-yl)-benzonitrile, followed by 4-(pyrid-3-yl)-benzonitrile [1H-NMR (CDCl3) 8.86 (dd, J=2, 1, 1H), 8.68 (dd, J=5, 2, 1H), 7.89 (m, 1H), 7.79 (d, J=9, 2H), 7.69 (d, J=9, 2H), 7.43 (dd, J=8, 5, 1H)] and finally 4-(pyridin-4-yl)-benzonitrile.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[CH2:19][C:20](Cl)=[O:21]>C1COCC1>[C:4]1([C@H:7]2[NH:10][C:20](=[O:21])[CH2:19][O:9][CH2:8]2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: NC(CO)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1COC[C@@H](c2ccccc2)N1
Reaction time: 1 h

Procedure:
(R)-Phenylglycinol (0.20 g, 1.46 mmol) in dry THF (10 mL) was treated with triethylamine (0.18 g, 1.75 mmol) in one portion at 0°, under an atmosphere of nitrogen. Chloroacetylchloride (0.20 g, 1.75 mmol) was added dropwise over 15 minutes at 0°. The mixture was allowed to reach room temperature over 1 hour then quenched with water (5 mL) and EtOAc (5 mL). The organic layer was washed with brine (10 mL), dried (MgSO4) and evaporated in vacuo to a white solid. NMR shows the precursor to the product (non ring closed). The solid was dissolved in dry THF (5 mL) and 10M NaOH was added slowly at 0°. The suspension was allowed to reach room temperature over 1.5 hours. The suspension was diluted with water (10 mL) and EtOAc (10 mL) and the organic layer was further washed with water (10 mL), then dried (MgSO4) and evaporated in vacuo to a crude yellow solid, which was taken to the next step without any purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][C@H:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[O:21][CH3:22])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1C=CN=C1.CCOC(C)=O.O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:23])[NH:10][C@H:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][Si:28]([C:25]([CH3:27])([CH3:26])[CH3:24])([CH3:30])[CH3:29])=[CH:16][C:15]=1[O:21][CH3:22])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(O)ccc1[C@H](CO)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1cc(O[Si](C)(C)C(C)(C)C)ccc1[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.5 %

Procedure:
A mixture of [(R)-2-hydroxy-1-(4-hydroxy-2-methoxy-phenyl)-ethyl]-carbamic acid benzyl ester (736.3 mg, 2.32 mmol), TBSCl (840.2 mg, 5.57 mmol) and imidazole (757.2 mg, 11.1 mmol) in DCM was stirred at rt for 24 h. The reaction was worked up with EtOAc/H2O. Flash column provided the titled compound (585.7 mg, 59%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:24]=[CH:23][C:12]3[C@:13]4([CH3:22])[C@@H:18]([CH2:19][CH2:20][C:11]=3[CH:10]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]4)=[CH:5][CH:4]=1)#[N:2].[C:25](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:25][N:17]1[C@H:18]2[C@@:13]([CH3:22])([C:12]3[CH:23]=[CH:24][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[CH:10][C:11]=3[CH2:20][CH2:19]2)[CH2:14][CH2:15][C:16]1=[O:21]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccc(C#N)cc3)ccc12
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(C#N)cc4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(4-cyanophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (24 mg, 0.08 mmol), 0.20 mL of t-butanol, and potassium t-butoxide (26 mg, 0.24 mmol). Methyl iodide (0.014 mL, 0.24 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 20 mg (80%) of the title compound as a white solid. mp 148°-150°. FDMS: m/e=330.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[Br:16][C:17]1[C:22]([O:23][CH2:24][C:25](O)=[O:26])=[CH:21][CH:20]=[C:19]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:18]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CCN(CC)CC>C1COCC1>[Br:16][C:17]1[C:22]([O:23][CH2:24][C:25]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[O:26])=[CH:21][CH:20]=[C:19]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:18]=1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: CC(C)(C)c1ccc(OCC(=O)O)c(Br)n1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)c(Br)n1
Yield: 65.5 %

Procedure:
3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (72 mg, 0.25 mmol) was reacted with (2-bromo-6-tert-butyl-pyridin-3-yloxy)-acetic acid (64 mg), DMTMM (1.2 eq, 83 mg) and NEt3 (2.5 eq, 90 μl) in THF to give the title compound (71 mg, 58.2%) after purification by column chromatography (Hex/EtOAc=1/1).
Reaction SMILES: O[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]3[CH2:19][CH2:20][C:21]4[NH:22][C:23](=[O:26])[CH:24]=[CH:25][C:16]([C:17]=43)=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:3][CH:4]([CH3:6])[CH3:5].S(Cl)([Cl:29])=O>>[Cl:29][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]3[CH2:19][CH2:20][C:21]4[NH:22][C:23](=[O:26])[CH:24]=[CH:25][C:16]([C:17]=43)=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)CC(O)c1ccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)cc1
Reactant: O=S(Cl)Cl
Product: CC(C)CC(Cl)c1ccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)cc1

Procedure:
This compound was prepared from intermediate 228 and thionyl chloride according to the procedure used in Example 171. Received 8.36 g (91%)
Reaction SMILES: [CH:1]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:33](Cl)(=[O:37])/[CH:34]=[CH:35]/[CH3:36].CS(C)=O>C1C=CC=CC=1>[C:33]([N:14]([CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:37])/[CH:34]=[CH:35]/[CH3:36]
Reactant: C/C=C/C(=O)Cl
Reactant: CCOC(=O)CCCCNC(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: C/C=C/C(=O)N(CCCCC(=O)OCC)C(c1ccccc1)c1ccccc1
Yield: 99.6 %

Procedure:
Analogously to Example 19, 7 g of ethyl 5-benzhydrylaminovalerate and 3.2 g of ethyldiisopropylamine are dissolved in 100 ml of benzene and reacted with 2.6 g of crotonyl chloride. As reaction product one obtains 8.5 g of ethyl N-crotonoyl-5-benzhydrylaminovalerate as a viscous non-distillable oil. The saponification of this ester yields 6 g (76%) of N-crotonoyl-5-benzhydrylaminovaleric acid (M.P. 88° to 89°).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Br:7][C:8]1[CH:9]=[N:10]C(C(O)=O)=[N:12][CH:13]=1.CN(C)C=O>ClCCl.CN(C)C=O.CO>[Br:7][C:8]1[CH:13]=[N:12][C:1]([C:2]([Cl:4])=[O:3])=[N:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ncc(Br)cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: O=C(Cl)c1ncc(Br)cn1
Yield: 99.4 %

Procedure:
Oxalyl chloride (47.4 g, 369 mmol) was added to a suspension of 5-Bromo-pyrimidine-2-carboxylic acid (50 g, 250 mmol) in dichloromethane (821 ml) at room temperature followed by 1-2 drop of dimethylformamide. The reaction mixture was stirred under nitrogen for 2 hours LCMS in methanol indicated the presence of the methyl ester and some acid. Dimethylformamide (0.2 ml) was added to the reaction mixture. The acid dissolved after 30 minutes. LCMS showed corresponding methyl ester and no starting material peak was observed. The solvent was removed and dried in vacuo to afford the crude 5-Bromo-pyrimidine-2-carbonyl chloride (55 g, 100%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4][O:5][C:6]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])=[O:7])[CH3:2].[CH2:19]([OH:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25]>>[OH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:26][C:12]([CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:15][CH2:16][CH2:17][CH3:18])=[O:14])=[O:13]
Reactant: OCCCCCCO
Reactant: CCCCC(CC)COC(=O)N1C(=O)C=CC1=O
Product: CCCCC(CC)COC(=O)NC(=O)C=CC(=O)OCCCCCCO

Procedure:
According to the same manner as described in Example 1 except for reacting N-(2-ethylhexyloxycarbonyl)maleimide with 1,6-hexanediol under conditions shown in Table 20, 2-Ethylhexyl N-{3-(6-hydroxyhexyloxycarbonyl)propenoyl)carbamate was obtained. Characteristics and identified structure of the resulting compound are shown in Table 18.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH:2]=1.[CH3:16][O:17][C:18](=[O:34])[CH:19]([CH:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=1>>[CH3:16][O:17][C:18](=[O:34])[CH:19]([CH:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:15][CH:14]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=1
Reactant: COC(=O)C(Cc1cccc(C#N)c1)C1CCCN1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Product: COC(=O)C(Cc1cccc(C#N)c1)C1CCCN1C(=O)c1ccc(-c2cccnc2)cc1
Yield: 80 %

Procedure:
4-Pyridin-3-ylbenzoic acid (0.83 g, 3.5 mmol) and 3-(3-cyanophenyl)-2-(pyrrolidin-2-yl)-propionic acid methyl ester (0.91 g, 3.5 mmol) are coupled as described in EXAMPLE 1B to give the title compound (1.22 g, 2.8 mmol). 1H NMR (CDCl3, 300 MHz) □ 8.98(s, 1H), 8.75(d, 1H), 8.58(d, 1H), 8.03(m, 1H), 7.85-7.60(m, 4H), 4.72-4.45(two m, 1H), 3.80-3.71(m, 1H), 3.68, 3.62(two s, 3H), 3.63-3.40(m, 2H), 3.21-3.10(m, 1H), 2.90-2.78(m, 1H), 2.20-2.05(m, 1H), 2.02-1.50(m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]Br.[Na+].[I-:18]>CC(C)=O>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][I:18]
Reactant: COC(=O)[C@H](CCBr)NC(=O)OC(C)(C)C
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)[C@H](CCI)NC(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 91.8 %

Procedure:
A mixture of (S)-4-bromo-2-tert-butoxycarbonylaminobutyric acid methyl ester (1.19 g, 4.0 mmol) (Example 120, Steps A-D) and NaI (6.0 g, 40.0 mmol) in acetone (25 mL) was heated to 70° C. for 2 hours. The mixture was then cooled to room temperature, concentrated under reduced pressure and partitioned between water (10 mL) and ether (40 mL). The layers were separated and the organic layer was washed with water (10 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure to afford 1.26 g of the product (92% yield).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([F:20])[C:17]=1[CH:18]=[O:19])[C:13]#[N:14].Cl([O-])=[O:22].[Na+].C(OCC)(=O)C>O.CS(C)=O>[C:13]([C:12]1[CH:11]=[C:10]([F:9])[C:17]([C:18]([OH:22])=[O:19])=[C:16]([F:20])[CH:15]=1)#[N:14]
Reactant: N#Cc1cc(F)c(C=O)c(F)c1
Reactant: [O-][Cl+][O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc(F)c(C(=O)O)c(F)c1
Reaction time: 1 h

Procedure:
Potassium phosphate, monobasic (1.0 g, 7.5 mmol) in water (10 mL) was added to a solution of 3,5-difluoro-4-formylbenzonitrile (0.50 g, 0.0030 mol, Aldrich) in DMSO (10 mL). Sodium chlorite (0.7 g, 0.006 mol) in water (10 mL) was added and the reaction was stirred for 1 hour. Ethyl acetate and water were added. Layers were separated, and the aqueous was saturated with solid NaCl and extracted with further ethyl acetate. The combined organic extracts were washed with sat. NaCl, dried and rotovapped to give a white solid. 1H NMR (300 MHz, d6-dmso): δ 7.98-7.91 (m, 2H).
Reaction SMILES: C([C@H]1COC(C)(C)N1C(=O)C(C1C=CN(C2C=CC(C3C=CC=CC=3)=CC=2)C=1)O)C1C=CC=CC=1.[CH2:36]([O:38][C:39](=[O:59])[C:40]([C:42]1[O:46][C:45]([C:47]2[CH:52]=[CH:51][C:50]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:49][CH:48]=2)=[CH:44][CH:43]=1)=[O:41])[CH3:37].[BH4-].[Na+]>>[CH2:36]([O:38][C:39](=[O:59])[CH:40]([C:42]1[O:46][C:45]([C:47]2[CH:52]=[CH:51][C:50]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:49][CH:48]=2)=[CH:44][CH:43]=1)[OH:41])[CH3:37]
Reactant: CCOC(=O)C(=O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Agent: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(O)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(=O)C(O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1

Procedure:
According to the procedure described in Example 13 for the preparation of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(biphenyl-4-yl-1H-pyrrol-3-yl)-2-hydroxy-ethanone, 2-(2-biphenyl-4-yl-furan-5-yl)-2-oxoacetic acid ethyl ester was reduced with NaBH4 to give in quantitative yield 2-(2-biphenyl-4-yl-furan-5-yl)-2-hydroxy-acetic acid ethyl ester as a yellow solid, mp 75-80° C. (d), which was used crude without purification. 1H NMR: δ 7.73 (d, 2H, J=8.5 Hz), 7.62 (d, 4H, J=8.1 Hz), 7.45 (t, 2H, J=7.4 Hz), 7.35 (t, 1H, J=7.4 Hz), 6.66 (d, 1H, J=3.3 Hz), 6.48 (d, 1H, J=3.3 Hz), 5.24 (d, 1H, J=5.9 Hz), 4.36-4.28 (m, 2H), 3.42 (d, 1H, J=6.3 Hz), 1.30 (t, 3H, J=7.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.O.[NH2:14][NH2:15]>O1CCOCC1>[NH2:1][C:2]1[C:3]([C:9]([NH:14][NH2:15])=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: NN
Reactant: COC(=O)c1nc(Br)cnc1N
Solvent: O
Solvent: C1COCCO1
Product: NNC(=O)c1nc(Br)cnc1N
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Methyl 3-amino-6-bromopyrazine-2-carboxylate (15 g, 64.6 mmol) was suspended in 150 mL of dioxane at room temperature. Hydrazine hydrate (6.5 g, 130 mmol) was added and the reaction mixture was stirred at 60° C. for 2 hours. Initially the mixture became clear, but after a while a precipitate formed. The mixture was cooled to ambient temperature and crude product filtered off. The solid was washed with TBME and subsequently stirred in water. The material was filtered and washed with acetone to afford 3-Amino-6-bromopyrazine-2-carbohydrazide 4 as slightly yellow solid. The material was dried in vacuo. (10.5 g, 70%).
Reaction SMILES: O.[C:2](O)([C:4]([F:7])([F:6])[F:5])=[O:3].[F:9][CH:10]([F:30])[CH2:11][O:12][CH:13]1[C:18](OC)([O:19]C)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1.C(=O)(O)[O-].[Na+]>C1COCC1>[F:30][CH:10]([F:9])[CH2:11][O:12][CH:13]1[C:18](=[O:19])[CH2:17][CH2:16][N:15]([C:2](=[O:3])[C:4]([F:7])([F:6])[F:5])[CH2:14]1
Reactant: O=C(O)C(F)(F)F
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OCC(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCN(C(=O)C(F)(F)F)CC1OCC(F)F
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Water (5 mL) and TFA (2 mL) were added to a solution of tert-butyl 3-(2,2-difluoroethoxy)-4,4-dimethoxypiperidine-1-carboxylate obtained in Example (121b) (1.5 g, 4.67 mmol) in THF (30 mL), and the mixture was stirred at 70° C. for one hour. Sodium bicarbonate was added to a pH of about 8, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 5/1, 2/1, 1/1) to obtain 1.1 g of the title compound as a light brown oily substance (86%).
Reaction SMILES: [F:1][C:2]([F:29])([C:25]([F:28])([F:27])[F:26])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([O:10]C(=O)C(F)(F)F)(F)F.C(OCCCCCCC)(=O)C.[F:41]F.[F-].[K+].[F:45][C:46]([F:53])([F:52])[C:47]([F:51])=[C:48]([F:50])[F:49]>COCCOCCOC>[F:45][C:46]([F:53])([F:52])[C:47]([F:51])([C:48]([F:41])([F:50])[F:49])[C:7](=[O:10])[C:6]([F:17])([F:18])[C:5]([F:19])([F:20])[C:4]([F:21])([F:22])[C:3]([F:23])([F:24])[C:2]([F:29])([F:1])[C:25]([F:28])([F:27])[F:26]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: FF
Reactant: O=C(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: CCCCCCCOC(C)=O
Agent: [F-]
Agent: [K+]
Solvent: COCCOCCOC
Product: O=C(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(C(F)(F)F)C(F)(F)F
Temperature: 50 °C

Procedure:
A mixture consisting of 2027 g of trifluoroacetic acid pentadecafluoroheptyl ester (made by reacting heptyl acetate with fluorine gas as described in U.S. Pat. No. 5,399,718 (Costello et al.)), 777 g of 3M™ PF-5052 Performance Liquid (a mixture of perfluorinated solvents, available from 3M Company), 3171 g of anhydrous diglyme and 79 g of anhydrous potassium fluoride were added to a 2-gallon (7.6 L) stainless steel stirred pressure vessel. The vessel was heated and 1816 g of hexafluoropropylene was added over a 2-hour period while maintaining a reaction temperature of about 50° C. The vessel was held at 50° C. for an additional 1½ hours after the hexafluoropropylene addition was complete. The reactor was cooled and drained. The resulting liquid was phase split and the lower phase fractionally distilled to give 565 g of 1,1,1,2,4,4,4-heptafluoro-3-trifluoromethyl-butan-2-one having a boiling point of 25° C. and purity of 95% and 1427 g of 1,1,1,2,4,4,5,5,6,6,7,7,8,8,9,9,9-heptadecafluoro-2-trifluoromethyl-nonan-3-one, having a boiling point of 134° C. and a 98.5% purity as determined by gas chromatography and mass spectroscopy.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[CH3:17])(=O)=O.[Cl-:20].[Li+]>CN1CCCC1=O.O>[Cl:20][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[CH3:17]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1OS(=O)(=O)C(F)(F)F
Reactant: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Reaction time: 10 h

Procedure:
4-Nitro-2,6-dimethylphenyl trifluoromethanesulfonate (4.06 kg, 13.6 mol) is dissolved in anhydrous N-methylpyrrolidinone (42 L) and to this solution is added anhydrous lithium chloride (900 g) all at once. The internal temperature is raised to 120° at which time the color changes to a dark golden brown. After 10 hours at this temperature the color of the solution is dark brown. The reaction is then cooled to 5° and diluted with cold water (5°, 21 L) at such a rate as to keep the temperature below 15°. Afte the addition is complete the mixture is stirred for 1 hour at 5°. The product is collected by filtration and washed with water (4×1 L). This dark brown solid is dissolved in t-butyl methyl ether (42 L) and stirred first with charcoal and then anhydrous magnesium sulfate (10 pounds). After filtration the solvents are removed in vacuo (40°, 3 Torr) to obtain tan solid which is dried in vacuo (25°, 3 Torr) for 2 days to obtain 4-chloro-3,5-dimethylnitrobenzene, m.p. 101°-105°.