Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([OH:37])[CH2:21][C:22]([CH3:36])([CH3:35])[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].N1C=CC=CC=1.[C:44](Cl)(=[O:62])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]>C(Cl)Cl>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:37][C:44](=[O:62])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:21][C:22]([CH3:35])([CH3:36])[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: COc1ccc(COC(=O)C(C)(C)CC(O)COC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(C)(C)C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a mixture of 4-methoxybenzyl 5-(N-CBz-L-valyloxy)-4-hydroxy-2,2-dimethylvalerate (20.6 g, 40 mmol), Pyridine (31.6 g, 400 mmol) in CH2Cl2 (500 mL) at 0° C., was added dropwise a solution of stearoyl chloride (18.2 g, 60 mmol) in CH2Cl2 (100 mL). After 1 h at 0° C., the temperature of the reaction mixture was allowed to assume room temperature and then the mixture was stirred for 5 h at room temperature. The mixture was extracted with a 10% aqueous solution of NaHCO2 (300 mL) and the aqueous phase was washed with CH2Cl2 (200 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 1→5% MeOH in CH2Cl2), to give 27.2 g of 4-metoxybenzyl 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvalerate.
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:8][CH2:7][O:6][C:4]1=[O:5].CN1CCOCC1.[C:16]1([C:22](Cl)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[C:16]1([C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:2][CH:3]2[CH2:8][CH2:7][O:6][C:4]2=[O:5])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC1CCOC1=O
Agent: Br
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C1OCCC1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
α-Aminobutyrolactone hydrobromide (10.0 g, 54.9 mmol), N-methylmorpholine (11.2 g, 110.0 mmol) and triphenylmethyl chloride (15.4 g, 55.2 mmol) were dissolved in N,N-dimethylformamide (DMF) (200 ml) (distilled from calcium hydride) and stirred at ambient temperature for 16 hours. The mixture was filtered, and water (200 ml) was added to the DMF-solution. The resulting slurry was stirred for 2 hours, the precipitate was filtered off and washed with a mixutre of DMF and water (1:1, 50 ml). The solid was resuspended in water (100 ml), filtered and dried at 50° C. in vacuo. N-triphenylmethyl-α-amino-butyrolactone was isolated as a white solid. Yield 17.55 g (93.2%), mp 164.5°-165.5° C. (uncorrected).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)([O:3][CH3:4])=[O:2].[OH:30][CH2:31][CH:32]([CH2:34]O)[OH:33].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:34][CH:32]([OH:33])[CH2:31][OH:30])=[O:26])=[CH:28][CH:29]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: OCC(O)CO
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-(15-carbomethoxypentadecylamino)benzoic acid, 1.00 g. of glycerol, and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred under reflux for 4 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2,3-dihydroxypropyl 4-(15-carbomethoxypentadecylamino)benzoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]nc(I)c2c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Clc1cnc2c(c1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 5-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine, 31, (11.6 g, 38.5 mmol), and Na2CO3 (12.2 g, 115 mmol) in N,N-dimethylformamide (200 mL) was added trityl chloride (11.8 g, 42.4 mmol). The mixture was stirred at room temperature overnight. After 16 hr, additional trityl chloride (1.61 g, 5.78 mmol) was added. And the mixture was heated to 60° C. for 45 min. The mixture was cooled, diluted with Et2O, washed with water (2×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 0-40% EtOAc-Hexanes, gradient elution) provided the desired product as a colorless material which was further purified by flash chromatography (SiO2, 100% DCM, isocratic elution): 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J=2.3 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H) and 7.23-7.18 (m, 15H) ppm.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[CH:18]([CH:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][N:33]=3)[CH3:30])[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:28][C:23]1[CH:22]=[C:21]([CH:19]2[CH2:20][N:16]([C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])[CH2:17][CH:18]2[CH:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][N:33]=2)[CH3:30])[CH:26]=[CH:25][C:24]=1[Cl:27]
Reactant: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)CC1c1ccc(Cl)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)C2CCNCC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a stirred solution of 4-[(3RS,4SR)-3-[(SR)-1-(5-cyano-pyridin-2-yloxy)-ethyl]-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl]-piperidine-1-carboxylic acid tert-butyl ester (0.28 g, 0.50 mmol) in 24 mL of CH2Cl2 was added 6 mL of TFA. After one hour at RT, the reaction was quenched by addition of aq. NaOH 1M (until ph=10) and the product was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated under vacuo to yield 0.237 g (99%) of the title compound as a white foam. ES-MS m/e: 473.0 (M+H+).
Reaction SMILES: Cl[C:2]1[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:15])[CH:3]=1.[CH3:16][S:17]([O-:19])=[O:18].[Na+].O.Cl>CN(C)C=O>[CH3:16][S:17]([C:2]1[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:15])[CH:3]=1)(=[O:19])=[O:18]
Reactant: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Reactant: CS(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)O
Temperature: 0 °C
Yield: 53.9 %

Procedure:
6 kg of 4-chloro-2-methyl-5-(methylsulfonyl)benzoic acid are dissolved in 15 l of N,N-dimethylformamide (DMF) at room temperature (25°) and subsequently warmed to 50°. 3.6 kg of sodium methanesulfinate are added to this solution. The internal temperature is then raised to 120° and stirred at this temperature for 2 days, with a further 3 kg of sodium methanesulfinate being added after 24 hours. After cooling to 25°, the reaction mixture is introduced into 40 l of water, and 300 g of activated carbon and 1 kg of kieselguhr are added. 5 l of ice are added to the filtrate, and 3.5 l of concentrated hydrochloric acid are added dropwise (pH=1). Recrystallisation from 2-propanol gives 3.8 kg of 4,5-bismethanesulfonyl-2-methylbenzoic acid; m.p. 234-235°.
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:33]([O:35]C)=[O:34])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.O>[C:1]1([C:7]2[C:16]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]4[C:28]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:21][CH2:22]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:33]([OH:35])=[O:34])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ncccc4C(F)(F)F)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ncccc4C(F)(F)F)CC3)nc2c1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-phenyl-3-(4-(3-(trifluoromethyl)pyridin-2-yl)piperidin-1-yl)quinoxaline-6-carboxylate (236.2 mg, 0.46 mmol, 1.00 equiv, 95%) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (91.2 mg, 5.00 equiv) in water (2 mL), which was added dropwise with stirring. The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrochloric acid. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 105.4 mg (48%) of 2-phenyl-3-(4-(3-(trifluoromethyl)pyridin-2-yl)piperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(Cl)Cl>[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([NH:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:14]
Reactant: CCOC(=O)c1ccc(C)c(N)c1
Reactant: CC1=C(C(=O)O)SCCO1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C)c(NC(=O)C2=C(C)OCCS2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
Thionyl chloride (4.5 g, 0.038 mole) was added to a stirred mixture of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (6.0 g, 0,037 mole) and methylene chloride (100 ml). The mixture was warmed to 30°-35° C. for 3 hours, then evaporated under reduced pressure. The residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (100 ml), and the ice-chilled solution treated dropwise with a solution of ethyl 3-amino-4-methylbenzoate (6.7 g, 0,037 mole) and tziethylamine (4.0 g, 0,040 mole) in methylene chloride (100 ml). The reaction mixture was stirred overnight at room temperature and then worked up by washing in sequence with water, dilute hydrochloric acid, water, 2% sodium hydroxide and water. Evaporation of the solvent gave an oil, which solidified. After recrystallization from ethanol (30 ml), the product (7.1 g, 59% yield) melted at 105°-107° C.
Reaction SMILES: C(O/[CH:4]=[CH:5]/[C:6](=O)[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])C.[CH3:15][S:16][CH:17]([CH3:25])/[CH:18]=[CH:19]/[N:20]1CCCC1.C([O-])(=O)C.[NH4+].O>C(OCC)C>[CH3:15][S:16][CH:17]([C:18]1[CH:4]=[CH:5][C:6]([C:7]([F:12])([F:13])[C:8]([F:9])([F:10])[F:11])=[N:20][CH:19]=1)[CH3:25]
Reactant: CCO/C=C/C(=O)C(F)(F)C(F)(F)F
Reactant: CSC(C)/C=C/N1CCCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CSC(C)c1ccc(C(F)(F)C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 11.8 %

Procedure:
(E)-1-Ethoxy-4,4,5,5,5-pentafluoropent-1-en-3-one (1.09 g, 5 mmol) in anhydrous ethyl ether (5 mL) was treated with 1-((E)-3-methylthiobut-1-enyl)pyrrolidine (0.85 g, 5 mmol) in 2 mL dry ether at −15° C. over a period of 5 min and the reaction was continued for 20 min Then the temperature was allowed to rise to room temperature and the reaction continued for 3 h. The solvent was removed under reduced pressure and the residue re-dissolved in anhydrous DMF (5 mL). Ammonium acetate (0.58 g, 7.5 mmol) was added and the mixture stirred at room temperature over a weekend. Water was added and mixture extracted with ether three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified on silica gel eluted with 8% EtOAc in hexane (v/v) to give 0.16 g of the desired 5-(1-methylthioethyl)-2-pentafluoroethylpyridine (A) as brownish colored oil in 12% yield. GC-MS: mass calcd for C10H11F2N3S [M]+ 271. Found 271.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([CH:20]([CH2:23][CH3:24])[CH2:21][NH2:22])[CH3:19]>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:22][CH2:21][CH:20]([CH2:23][CH3:24])[CH2:18][CH3:19])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CCC(CC)CN
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)CNc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 62.6 %

Procedure:
50.0 g (0.26 mol) of 2,5-dichloro-1-nitrobenzene, 71.9 g (0.52 mol) of potassium carbonate, 45.6 g (0.455 mol) of 2-ethylbutylamine and 0.5 g of 18-crown-6 in 250 ml of dimethylformamide were heated at 80° C. for 4 h. The mixture was then poured into a large quantity of ice-water, and the precipitate was filtered off with suction, dried and recrystallized from methanol to yield 41.8 g (63%) of the product.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)(O)[CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1.[OH-].[Na+]>O>[CH3:6][C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:14]\[CH2:15][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(C(O)(CCN2CCCC2)c2ccccn2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(/C(=C\CN2CCCC2)c2ccccn2)cc1
Temperature: 85 °C
Yield: 152.3 %

Procedure:
60 ml of demineralized water is charged into a round-bottomed flask kept at 25° to 30° C. and then slowly 540 ml of 90% Conc. H2SO4 is added and the temperature is raised to 40° C.-60° C. under stirring. Slowly 200 g of 1-(4-methylphenyl)-1-(2-pyridyl)-3-pyrrolidinopropan-1-ol is charged and the temperature is maintained at 85° C. under stirring. The reaction mass is heated to 100-105° C. and the temperature is maintained for 4 hours under stirring. After completion of the reaction, the reaction mass is cooled to 25°-30° C. and then poured into ice cold water (4 litre) at 5-10° C. under stirring over a period of an hour. 50% NaOH solution (w/w) is added slowly to the reaction mixture by maintaining the temperature at 5° to 20° C. over a period of 2 hours and the contents are stirred for an hour at 25° to 30° C. The reaction mixture is filtered under suction to obtain 286 g of wet triprolidine base comprising >92% E-isomer along with <8% Z-isomer. 2 litres of demineralized water and 286 g of wet triprolidine base are charged into a round-bottom flask at 25° to 30° C. and the contents are stirred for 3 hours by maintaining the same temperature. The contents are filtered and dried under suction for 2 hours. The process is repeated thrice to obtain 1-(4-methylphenyl)-1-(2-pyridyl)-3-pyrrolidino prop-1-ene (150 g, 80%) consisting of >98% E isomer along with <2% Z-isomer.
Reaction SMILES: BrC1N=C(C(C2C3C(Cl)=NC=[N:14][C:13]=3[N:12](C(C)C)C=2)=O)C=CC=1.[NH2:23][C:24]1[C:25]2[C:32]([C:33]([C:35]3C=N[CH:38]=[C:39](N)[CH:40]=3)=[O:34])=[CH:31][N:30]([CH:42]([CH3:44])[CH3:43])[C:26]=2[N:27]=[CH:28][N:29]=1>>[NH2:23][C:24]1[C:25]2[C:32]([C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[C:13]([NH2:14])[N:12]=3)=[O:34])=[CH:31][N:30]([CH:42]([CH3:43])[CH3:44])[C:26]=2[N:27]=[CH:28][N:29]=1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2c(N)ncnc21
Reactant: CC(C)n1cc(C(=O)c2cccc(Br)n2)c2c(Cl)ncnc21
Product: CC(C)n1cc(C(=O)c2cccc(N)n2)c2c(N)ncnc21
Yield: 85 %

Procedure:
The title compound (5.30 g, 85%) was prepared from (6-Bromo-pyridin-2-yl)-(4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (8.0 g, 21.3 mmol) by procedures analogous to those described for the preparation of (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-amino-pyridin-3-yl)-methanone. MS: 297.1 (MH+); HPLC Rf: 370 min. (HPLC method 4); HPLC purity: 100%.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl.[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@@H:31]([NH:33][C:34](=[O:37])[CH2:35][OH:36])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[OH:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@@H:31]([NH:33][C:34](=[O:37])[CH2:35][OH:36])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1
Reactant: ClCc1ccccn1
Reactant: C[C@@H](COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12)NC(=O)CO
Agent: Cl
Product: C[C@@H](COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)NC(=O)CO
Yield: 57 %

Procedure:
The procedure described in Example 3 was repeated using picolyl chloride hydrochloride and N-[(1S)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-2-hydroxyacetamide to give the title compound in 57% yield; NMR spectrum (DMSO-d6) 1.23 (d, 3H), 3.64-3.81 (m, 2H), 4.24-4.36 (m, 2H), 4.45-4.59 (m, 1H), 5.29 (s, 2H), 5.45 (t, 1H), 7.13-7.23 (m, 2H), 7.35 (t, 2H), 7.49-7.53 (m, 1H), 7.56-7.59 (m, 1H), 7.72 (t, 1H), 7.87 (t, 1H), 7.99-8.02 (m, 2H), 8.46 (s, 1H), 8.59 (d, 1H), 9.75 (s, 1H); Mass spectrum MH+ 493.95.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[C:6]([O:8][CH3:9])=[O:7].[N+:18]([O-])([OH:20])=[O:19]>CC(O)=O>[CH3:1][O:2][C:3]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:11][C:10]([N+:18]([O-:20])=[O:19])=[C:5]([CH:4]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: COCCOc1ccc(C(=O)OC)cc1OC
Solvent: CC(=O)O
Product: COCCOc1cc([N+](=O)[O-])c(C(=O)OC)cc1OC
Yield: 79.9 %

Procedure:
Using the procedure described in Example 6A Step 2, methyl 3-methoxy-4-(2-methoxyethoxy)benzoate (8.39 g, 34.9 mmol) was reacted with fuming nitric acid (90%, 3.15 g) in AcOH (60 mL) at 50° C. for 8 hours, to afford methyl 5-methoxy-4-(2-methoxyethoxy)-2-nitrobenzoate as a yellow solid (7.956 g, 80%). 1H NMR (300 MHz, CDCl3) δ 7.51 (s, 1H), 7.07 (s, 1H), 4.25 (t, 2H), 3.96 (s, 3H), 3.91 (s, 3H), 3.82 (t, 2H), 3.46 (s, 3H); LC-MS (ESI) m/z 286 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:4].[F:13][C:14]1[CH:15]=[C:16]([N:33]2[CH2:37][C@H:36]([CH2:38][N:39]3[CH:43]=[CH:42][N:41]=[N:40]3)[O:35][C:34]2=[O:44])[CH:17]=[CH:18][C:19]=1[C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH2:30][C@@H:29]([CH2:31]O)[O:28][N:27]=2)=[CH:24][CH:25]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:31][C@H:29]1[O:28][N:27]=[C:26]([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[CH:18]=[CH:17][C:16]([N:33]4[CH2:37][C@H:36]([CH2:38][N:39]5[CH:43]=[CH:42][N:41]=[N:40]5)[O:35][C:34]4=[O:44])=[CH:15][C:14]=3[F:13])=[CH:21][N:22]=2)[CH2:30]1)=[O:11])=[O:4]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: COC(=O)NCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)NCCCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The methyl carbamate prepared as above (0.25 g, 1.43 mmol), (5R)-3-(3-fluoro-4-{6-[(5S) -5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 0.25 g, 0.57 mmol), 4-dimethylaminopyridine (0.02 g, 0.16 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.25 g, 1.30 mmol) were combined in DMF (4 ml). The suspension was allowed to stir for one hour at room temperature resulting in a clear solution. The mixture was then diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was purified via chromatography (silica gel, 0.5 to 10% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as a white powder (0.33 g), melting point: 90° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.[Br:11]Br>S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Ag+2]>[Br:11][C:8]1[CH:9]=[CH:10][C:5]2[S:4][N:3]=[C:2]([Cl:1])[C:6]=2[CH:7]=1
Reactant: Clc1nsc2ccccc12
Reactant: BrBr
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: Clc1nsc2ccc(Br)cc12
Yield: 25.9 %

Procedure:
3-Chlorobenzo[d]isothiazole (10 g, 59.0 mmol) was added to a solution of bromine (3.2 mL, 62.0 mmol) and silver sulfate (19.6 g, 63.0 mmol) in sulfuric acid (200 mL). The resulting brown mixture was allowed to stir at room temperature for 2h under nitrogen. The color slowly faded to pale yellow as a white precipitate formed. The precipitate was collected by vacuum filtration and triturated with hexanes to yield 5-bromo-3-chlorobenzo[d]isothiazole as a white solid (3.8 g). 1H NMR (300 MHz, CDCl3): 8.18 (s, 1H), 7.8 (d, 1H), 7.64 ppm (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19]>CN(C)C=O>[CH2:16]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:12])=[CH:6][CH:7]=1)[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CC(C)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCCC(C)C)cc1
Reaction time: 12 h
Yield: 76.2 %

Procedure:
Methyl-4-hydroxyphenylacetate (2.00 g, 12.0 mmol) was added in one portion to a stirred suspension of sodium hydride (60% mineral oil suspension; 528 mg, 13.2 mmol) in dimethylformamide (20 mL) at room temperature under nitrogen. After stirring for 30 min 1-bromo-3-methylbutane (1.99 g, 1.58 mL, 13.2 mmol) was added dropwise over 5 min then stirring was continued for 12 h. The volatiles were evaporated then the residue partitioned between dichloromethane (50 mL) and water (50 mL). The phases were separated and the aqueous phase was washed with dichloromethane (2×50 mL). The organics were combined, dried (magnesium sulfate) and the solvent evaporated. The residue was chromatographed on silica gel (20% diethyl ether: cyclohexane) to give the title compound as a colourless oil (2.16 g, 76%). LC/MS: 3.51 min; z/e 254, calcd (M+18) 254. 1H NMR (400 MHz: CDCl3): 7.15 (2H), 6.85 (2H), 4.00 (2H), 3.70 (3H), 3.55 (2H), 1.85 (1H), 1.70 (2H), 0.95 (6H).