Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[C:10](Cl)(=[O:12])[CH3:11]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: CC(=O)Cl
Product: CC(=O)Nc1cc(Br)cnc1Cl

Procedure:
Prepared according to the methods described in reagent preparation 26 using 5-bromo-2-chloropyridin-3-amine and acetyl chloride in step 1.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([O:12][CH3:13])=[CH:4][C:3]=1[C:14]([CH3:17])([CH3:16])[CH3:15].S(=O)(=O)(O)O.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([O:1][C:2]1[C:3]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[CH:6][C:7]=1[C:8]([CH3:10])([CH3:11])[CH3:9])(=[O:25])[CH3:24]
Reactant: COc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: COc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
4-Hydroxy-3,5-di-tert-butylanisole (23.6 g) was dissolved in acetic anhydride (150 ml). Following the addition of conc. sulfuric acid (0.5 ml), the mixture was stirred at 70° C. for 2 h. The reaction mixture was concentrated under reduced pressure and a saturated aqueous solution of sodium hydrogen carbonate was added to the concentrate, followed by extraction with ethyl acetate. The extracted layer was dried over anhydrous magnesium acetate and concentrated. The precipitating solid was recrystallized from methanol-water (2:1) to afford 4-acetoxy-3,5-di-tert-butylanisole [24.5 g (yield, 88%)] as a white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[OH-].[Na+]>C(OCC)C>[C:13]1([CH2:12][O:11][C:9]([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][OH:7])=[O:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 101.6 %

Procedure:
To a 0° C. solution of 25 g of (S)-2-pyrrolidinemethanol in 150 ml of diethyl ether is added 54.8 g of benzyl chloroformate. At mid point of addition, 49.4 ml of 5N sodium hydroxide is added, simultaneously, and the reaction stirred at 0° C. for 2 hours. Diethyl ether is added, the layers are separated and the aqueous layer reextracted with diethyl ether. The combined organic layers are dried, filtered and concentrated in vacuo. The residue is purified by chromatography (silica gel, 0-10% methyl alcohol/methylene chloride) to give 59.1 g of (S)-2-hydroxymethyl-1-pyrrolidine carboxylic acid phenylmethyl ester.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[N:7]=[C:6]([C:18]([F:21])([F:20])[F:19])[C:5]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:35])C=1>C(Cl)Cl>[CH2:1]([S:3]([C:4]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:14]([F:15])([F:16])[F:17])[N:7]=[C:6]([C:18]([F:21])([F:19])[F:20])[C:5]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:35])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1SCC
Solvent: ClCCl
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1S(=O)CC
Yield: 90.2 %

Procedure:
To a 0° C. solution of 4.8 g (0.012 mol) of product of Example 33 in 30 ml of CH2Cl2 was added 4.08 g (0.024 mol) of MCPBA. The reaction was monitored by TLC. The reaction mixture was filtered, washed with NaHCO3, dried (MgSO4) and concentrated in vacuo to give 4.56 g of solid which was purified by HPLC using 8% ethyl acetate/cyclohexane to elute the first fraction (1.52 g) followed by 15% ethyl acetate/cyclohexane to elute 1.46 g of the desired product. Recrystallization of the 1.46 g solid in hot hexane afforded 0.88 g (17.4%) of product as a white solid; mp 87°-88.5° C.
Reaction SMILES: N#N.C[Si](C)(C)[O:5][C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]=1.[B-](F)(F)(F)[F:22].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.CC(=O)OCC>C(#N)C>[F:22][CH:11]1[C:6](=[O:5])[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of tert-butyl 4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (5.00 g, 18.40 mmol) in dry acetonitrile (25 mL) was added Selectfluor® (7.55 g, 20.3 mmol) at rt. The reaction mixture was stirred at rt for 2 h then poured into EA and successively washed with aq. 1% NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (hexanes/EA, 4:1) to afford the title compound as a pale yellow solid. LC-MS-conditions 08: tR=0.55 min; [M-CH3+H]+=203.23; TLC: rf (hexanes/EA, 4:1)=0.17.
Reaction SMILES: Cl[O-].[F:3][C:4]([F:16])([F:15])[CH2:5][N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][C:9](=[O:14])[CH2:10]2.[C-:17]#[N:18].[Na+].Cl>C(OCC)C>[C:17]([C:9]1([OH:14])[CH2:8][CH:7]2[N:6]([CH2:5][C:4]([F:3])([F:15])[F:16])[CH:11]([CH2:12][CH2:13]2)[CH2:10]1)#[N:18]
Reactant: [C-]#N
Reactant: O=C1CC2CCC(C1)N2CC(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCOCC
Product: N#CC1(O)CC2CCC(C1)N2CC(F)(F)F

Procedure:
A split-neck jacketed reactor was equipped with a stirrer bar, thermometer, hypochlorite scrubber and pressure equalised dropping funnel. To this was charged 8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-one (3.04 g, 14.5 mmol) and diethyl ether (7 ml). The reaction mixture was agitated and cooled to 0+ C. (recirculating glycol), then around sodium cyanide (1 .07 g, 21.7 mmol) was added via a powder funnel. Hydrochloric acid (5M, 4.0 ml, 20.3 mmol) was added to the reaction mixture via a dropping funnel over 5 minutes and the reaction mixture was then stirred for 24 hours. The pH of the mixture was adjusted from 9 to 5.5 using hydrochloric acid (5M), and the organic layer was separated. The aqueous phase was extracted with diethyl ether (2×30 ml) and the combined organic extracts were washed with dilute hydrochloric acid (30 ml, pH 6). Sulphuric acid (98%, 2 drops) was added to the extracts before drying (MgSO4) and filtering. A further 2 drops of sulphuric acid were added then the ether extracts were concentrated in vacuo to give 3-cyano-3-hydroxy-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane ( 72:28 exo:endo cyano) as a pale yellow solution in diethyl ether. (Reaction conversion 83% by 1H NMR analysis.)
Reaction SMILES: [Cl:1][C:2]1[C:6](C(O)=O)=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1>[Cu-]=O.CN(C)C(=O)C>[Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: O=C(O)c1cn(-c2cccnc2)nc1Cl
Agent: O=[Cu-]
Solvent: CC(=O)N(C)C
Product: Clc1ccn(-c2cccnc2)n1
Temperature: 125 °C

Procedure:
In another embodiment, 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid (4) and copper (I) oxide are mixed with N,N-dimethylacetamide and heated to about 125° C. The 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) can be isolated and purified by standard techniques.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13].[OH-].[NH4+:20].Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:20])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13]
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Agent: Cl
Agent: [OH-]
Product: NS(=O)(=O)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Temperature: -50 °C

Procedure:
The solution from EXAMPLE 14 was charged into a flask fitted with overhead stirrer, nitrogen inlet, temperature probe and cooling bath. The solution was cooled down to −50° C. using an acetone/dry ice bath. Ammonium hydroxide (238 g) solution was slowly added to the reaction mixture through an additional funnel. The internal temperature was kept at about −40° C. HPLC showed the reaction was completed. The solution was cooled down to −60° C. 6 N HCl (600 g) was added to the reaction mixture slowly to keep the temperature under −35° C. The mixture was warmed up to room temperature. The layers were separated, and the organic layer was washed twice with 375 g of 4 N HCl. The organic layer was distilled down under vacuum with bath temperature from 40 to 50° C. Toluene (700 g) was added to the residue, and the mixture was stirred at room temperature for an hour. The mixture was filtered and washed with toluene to obtain the title compound.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:9])=[C:5]([Br:8])[C:6]=1[CH3:7].C[CH2:11][O:12]CC.C([Li])CCC>CN(C)C=O>[Br:8][C:5]1[C:6]([CH3:7])=[C:2]([CH:11]=[O:12])[S:3][C:4]=1[CH3:9]
Reactant: Cc1sc(Br)c(C)c1Br
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: Cc1sc(C=O)c(C)c1Br
Temperature: -35 °C

Procedure:
15.0 G. of 2,4-dibromo-3,5-dimethylthiophene was dissolved in 250 ml. of anhydrous ether and cooled to -70° C. with stirring under argon. 24 Ml. of a 2.4 M solution of n-butyl lithium was slowly added to the solution and the mixture was warmed to -35° C. for 10 minutes, and then cooled again to -70° C. 7.3 G. of dimethylformamide was added slowly to the mixture and the reaction mixture was warmed to room temperature for 14 hours. The resulting solution was poured into ice water, stirred for 20 minutes and extracted with ethyl ether. The ether extracts were combined, washed with an aqueous solution of 5% sodium carbonate, saturated sodium chloride solution, dried with sodium sulfate, filtered and evaporated to yield 4-bromo-3,5-dimethylthiophene-2-carboxaldehyde, m.p. 44°-45° C
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.[C:10]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:12][CH2:13][CH3:14])=[O:11].O1CCOCC1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:15]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1
Reactant: OCc1cnc(Cl)cn1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
To a solution of (5-chloro-2-pyrazinyl)methanol (11.0 g) in dioxane (carbethoxymethylene)triphenylphosphorane (29.2 g). After stirring for 2 hours at room temperature, a resulting precipitate was filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (11.0 g).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:14]=1[CH2:21][C:22](=O)[CH3:23]>CO>[CH3:2][O:3][N:4]=[C:22]([CH3:23])[CH2:21][C:14]1[C:15]([Cl:20])=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=1[Cl:12]
Reactant: CC(=O)Cc1c(Cl)cc(Cl)cc1Cl
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CON=C(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
A solution of O-methyl-hydroxylamine hydrochloride (0.79 g, 9.4 mmol) in methanol (20 ml) was treated with triethylamine (1.32 ml, 9.4 mmol) followed by 1-(2,4,6-trichlorophenyl)-propan-2-one (1.5 g, 6.31 mmole). The resulting mixture was stirred at 60° C. for 3 hours. The reaction mixture was quenched with water and methanol was evaporated off. The resulting aqueous medium was extracted with ethylacetate (3×50 ml). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure (100 mbar; 45° C.). The resulting crude mass was purified by column chromatography using 60-120μ mesh silica gel and product collected at 2% ethyl acetate in hexane as elution system to give 1-(2,4,6-Trichloro-phenyl)-propan-2-one O-methyl-oxime (1.2 g, 76%), which was taken up for further reduction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:25][CH2:26][CH3:27])=[O:22])[CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1C=CC=CC=1.[CH:40](OC1C=C(CC(NC(C2C=CC=CC=2N2CCCCC2)CCC)=O)C=CC=1C(O)=O)(C)C.C(OC1C=C(CC(NC(C2C=C(OC)C=CC=2N2CCCCC2)CCC)=O)C=CC=1C(O)=O)C>>[CH2:1]([O:8][C:9]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH:25]=[C:26]([CH3:40])[CH3:27])=[O:22])[CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2]
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)O)c(OC(C)C)c1)c1ccccc1N1CCCCC1
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCc2ccccc2)c1)c1ccccc1N1CCCCC1
Agent: CCCC(NC(=O)Cc1ccc(C(=O)O)c(OCC)c1)c1cc(OC)ccc1N1CCCCC1
Product: CCOC(=O)c1ccc(CC(=O)NC(C=C(C)C)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
The mixing ratio of 75/25 is obtained from the corresponding ratio of intensities of the particularly characteristics signals in the 400 MHz-1H-NMR spectrum (CDCl3). The position of the signals is: 3-methyl-2-buten-1-yl compound: olefinic H: 5.25 (d), CH3 : 1.64 (s) and 1.77 (s), benzylic >CH-- 6.00 (t), benzylic CH2 --; 3.52 ppm (s) 3-methyl-1-butyl compound: CH3 : 0.90 (d), benzylic >CH-- 5.35 (m), benzylic --CH2 --; 3.54 ppm (s).
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.Cl.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH2:30][NH:29][CH2:28][CH2:27]2>C(O)(C)C>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH2:30][N:29]([CH2:20][CH:2]([OH:1])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]3[C:14]4[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=4[O:12][N:11]=3)[CH2:6][CH2:5]1)[CH2:28][CH2:27]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)CN(CC(O)CN1CCC(c3noc4cc(F)ccc34)CC1)CC2
Reaction time: 8 h
Yield: 11 %

Procedure:
A stirred mixture of 1-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.2 g, 11.6 mmol), K2CO (2 gm, 1.25 eq) and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.3 g, 1.25 eq) in isopropyl alcohol (200 ml) was heated at reflux for 6 hours. The mixture was cooled and filtered. The solvent was removed to about 50 ml and the solution was allowed to stand overnight. Crystals (0.6 g) formed and were collected. The mother liquor was concentrated to a white solid. Recrystallization twice from ethanol yielded the product (1.95 g, m.p. 153°-154° C.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.O=P(Cl)(Cl)[Cl:13].O[C:17]1[C:22]([Cl:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1>>[Cl:13][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(Cl)c1
Solvent: c1ccc2ncccc2c1
Product: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Temperature: 120 °C

Procedure:
Quinoline (0.3 mL, 2.34 mmol) was added to POCl3 (0.5 mL 4.68 mmol) at 0° C. under nitrogen. To this stirred mixture was added 2-hydroxy-3-chloro-5-nitro pyridine (816 mg, 4.68 mmol) obtained in step i above. The reaction mixture was heated at 120° C. for 2 hours, cooled to 0° C. followed by addition of ice-cold water. The precipitate obtained was filtered, washed thoroughly with water and dried to obtain 2,3-dichloro-5-nitro pyridine.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.N1C2C(=CC=CC=2)C=CC=1.[Cl:16][C:17]1[C:18](O)=[N:19][CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1>O>[Cl:3][C:18]1[C:17]([Cl:16])=[CH:22][C:21]([N+:23]([O-:25])=[O:24])=[CH:20][N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(Cl)c1
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Temperature: 120 °C
Yield: 88.9 %

Procedure:
The procedure of Koch and Schnatterer, Synthesis ,1990, 499-501 was followed. To 2-hydroxy-5-nitropyridine (70.0 g, 0.5 mol) in 12 N hydrochloric acid was added dropwise a solution of potassium chlorate (21.4 g, 0.18 mol) in H2O (300 mL) at a rate such that the temperature remained ≤60° C. The mixture was allowed to stir for a further 30 minutes at ca. 50° C., then allowed to cool to ambient temperature, then was further cooled in an ice bath. The yellow solid was collected by filtration, washed with cold H2O, and dried under vacuum at 50° C. to afford 3-chloro-2-hydroxy-5-nitropyridine (72.4 g, 83%) as a yellow powder. To phosphorus oxychloride (37.4 mL, 0.4 mol) at 0° C. was added quinoline (23.6 mL, 0.2 mol), followed by 3-chloro-2-hydroxy-5-nitropyridine (70 g, 0.4 mol) from above. The mixture was heated at 120° C. for 2.5 hours, during which time it became a dark liquid. After cooling to 100° C., H2O (150 mL) was added cautiously, and the mixture was cooled to 0° C. The precipitated solid was collected by filtration, washed with cold H2O, and dried under vacuum at 50° C. to afford 2,3-dichloro-5-nitropyridine (68.6 g, 89%). To 2,3-dichloro-5-nitropyridine (68.5 g, 0.39 mol) in a mixture of H2O (800 mL) and acetic acid (160 mL) were added bits of metallic iron with stirring until the starting material was consumed (TLC analysis). The mixture was filtered, and the filter cake was washed repeatedly with EtOAc. The aqueous filtrate was extracted with EtOAc and the organic fractions were combined and concentrated. The residue was chromatographed (silica gel; MeOH: CHCl3, 0.5:99.5 to 1:99) to afford the title compound (44.5 g, 70%) as a light orange powder: MS (CI/NH3) m/z 163 and 165 (M+H+), 180 and 182 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].CCN(C(C)C)C(C)C>N1C=CC=CC=1>[CH3:21][S:22]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2N)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Yield: 72.1 %

Procedure:
tert-Butyl 4-{2-[(methylsulfonyl)amino]phenyl}-piperazinecarboxylate was prepared following the procedure for Preparation III using, tert-butyl 4-(2-aminophenyl)piperazinecarboxylate (4.4 g, 16 mmol), methanesulfonyl chloride (1.4 mL, 18 mmol) and DIEA (instead of pyridine) (3.1 mL, 18 mmol). The crude material was purified by flash chromatography (SiO2, 4:1 hexane:EtOAc) and concentrated in vacuo to afford the desired compound (4.1 g). MS (ESI, pos. ion) m/z: 356 (M+H), (ESI, neg. ion) m/z: 354 (M−H). Calc'd for C16H25N3O4S: 355.16.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:10](=[O:12])[CH3:11]
Reactant: Nc1ccc(Cl)cc1Br
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(Cl)cc1Br

Procedure:
A solution of 2-bromo-4-chloroaniline (1 g, 4.84 mmol) in acetic anhydride (5 ml, 4.84 mmol) was stirred at RT for 1.5 hrs. The resulting suspension was collected by filtration and dried on a vacuum line to give the title compound as a white solid.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1.O>C(O)(=O)C>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:5](=[O:7])[CH3:6])=[N:10][CH:11]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)cn1
Temperature: 25 °C

Procedure:
Acetic anhydride (27.4 mL) was added to a stirred suspension of 2-amino-5-bromopyridine (10.0 g) in acetic acid (40 mL). The mixture was heated at reflux for 4 hours, then cooled to room temperature and then poured into water (200 mL). The resulting solid was collected, washed three times with water (300 ml) and then dried in vacuo at 70° C., affording the title compound as a white solid (10.9 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[CH3:12][C:13]([O:16][C:17]([NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:18])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C>CO>[C:13]([O:16][C:17](=[O:18])[NH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:8]2[CH:9]=[C:2]([F:1])[C:3]([C:4]#[N:5])=[C:6]([F:11])[CH:7]=2)[CH2:22][CH2:21]1)([CH3:15])([CH3:12])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: N#Cc1c(F)cc(F)cc1F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(F)c(C#N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 57 %

Procedure:
To a solution of 1.0 g (6.4 mmol) of 2,4,6-trifluorobenzonitrile in MeOH (25 mL) was added 1.3 g (6.5 mmol) of 4-N-boc-amino-piperidine along with 1.2 mL (6.7 mmol) of N,N-diisopropylethylamine. The mixture was stirred at room temperature for 3 days then concentrated under reduced pressure to provide a white solid. The solid was washed with large amounts of H2O and dried under vacuum. The solid was recrystallized from hexane/EtOAc to provide 1.23 g (56%) of [1-(4-cyano-3,5-difluoro-phenyl)-piperidin-4-yl]-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [CH:1]([N:4]([CH:10]([CH3:12])[CH3:11])[C:5](=[O:9])[O:6][CH2:7]Cl)([CH3:3])[CH3:2].[OH:13][C@@H:14]([C@H:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([O-:35])=[O:34])=[C:20]([S:23]/[CH:24]=[CH:25]\[C:26]3[S:30][CH:29]=[N:28][C:27]=3[CH2:31][OH:32])[C@H:21]([CH3:22])[C@H:17]12)[CH3:15].[Na+]>>[OH:13][C@@H:14]([C@H:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([O:35][CH2:7][O:6][C:5]([N:4]([CH:10]([CH3:12])[CH3:11])[CH:1]([CH3:3])[CH3:2])=[O:9])=[O:34])=[C:20]([S:23]/[CH:24]=[CH:25]\[C:26]3[S:30][CH:29]=[N:28][C:27]=3[CH2:31][OH:32])[C@H:21]([CH3:22])[C@H:17]12)[CH3:15]
Reactant: CC(C)N(C(=O)OCCl)C(C)C
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CC(C)N(C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12)C(C)C
Yield: 48.7 %

Procedure:
In the same manner as in step b) in Example 125, 150 mg of the title compound was prepared from 133 mg of chloromethyl N,N-diisopropylcarbamate and 231 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].C(N(CC)CC)C.[S:16](Cl)([CH3:19])(=[O:18])=[O:17]>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCc1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
To a solution of 2-pyridylcarbinol (10) (300 mg, 2.70 mmol) and triethyl amine (698 mg, 6.75 mmol) in dry THF (10 mL) at 0° C. was added a solution of mesylchloride (470 mg, 4.1 mmol) in dry THF (10 mL). Reaction mixture was allowed to stir for 2 h at room temperature [reaction was followed by TLC]. Reaction mixture was concentrated to remove THF under reduced pressure and the residue was dissolved in CH2Cl2 (100 mL), washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give compound 11 (300 mg, 59%) as gum and it was taken as such for next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O.[OH-].[Na+]>CC(O)C>[Cl:11][C:12]1[CH:13]=[C:14](/[CH:15]=[C:6](/[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)\[C:7]#[N:8])[CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: N#CCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: N#C/C(=C\c1cccc(Cl)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 850.8 %

Procedure:
Method A To a solution of 4-chlorobenzyl cyanide (5.62 g, 4.00 mmol) and 3-chloro-benzaldehyde (Aldrich) (6.06 g, 4.00 mmol) in iPrOH (250 mL) was added 4 N NaOH (5 mL) dropwise at rt and the reaction mixture was stirred at rt for 10 min to give a white suspension. The solid was filtered and washed with water and iPrOH and then dried overnight in vacuum to give (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (9.33 g, 85.1%) as a white powder which was used in the next step without further purification.