Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCC>[F:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: CCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [K+]
Product: O=[N+]([O-])c1ccccc1F
Temperature: 140 °C
Yield: 78 %

Procedure:
Potassium fluoride (water content 0.2%) (69.6 g; 1.2 mole) and tetradecyltrimethylammonium bromide (18 g; 0.055 mole) were added to molten 2-chloronitrobenzene (157.5 g; 1 mole) with stirring. The mixture was heated to 140° C. for 28 hours. The reaction mixture was then allowed to cool to c. 100° C. and was filtered with the assistance of added toluene. The toluene was distilled and the residue was finally distilled in high vacuum to give 2-fluoronitrobenzene in 78% yield together with 5% recovered 2-chloronitrobenzene.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[NH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:10]=1[C:11]([OH:13])=[O:12].C1C=CC=CC=1>CO>[NH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:10]=1[C:11]([O:13][CH3:1])=[O:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1cccc(Cl)c1C(=O)O
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1c(N)cccc1Cl
Reaction time: 1 h
Yield: 96 %

Procedure:
To prepare this compound, trimethylsilyldiazomethane (2 M in hexanes, 1.5 equiv) was added to a solution of the 2-amino-6-chlorobenzoic acid (1 equiv) in 2:1 benzene:methanol (0.2-0.3 M) at room temperature. After 1 hour, the solvent was removed under reduced pressure to afford methyl 2-amino-6-chlorobenzoate in 96% yield. That product was used without further purification or was purified by flash chromatography (7:3 hexanes:ethyl acetate) in 91% yield.
Reaction SMILES: P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.O=[C:19]1[CH:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])[N:22]2[C:37](=[O:39])[CH2:38][C@H:21]2[CH2:20]1.C(N(C(C)C)CC)(C)C.[N-:49]=[N+:50]=[N-:51].[K+]>CN(C)C1C=CN=CC=1.C(#N)C>[N:49]([C:19]1[CH2:20][C@@H:21]2[CH2:38][C:37](=[O:39])[N:22]2[C:23]=1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:25])=[N+:50]=[N-:51]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1C[C@@H]2CC(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C[C@H]2C1
Reaction time: 0.08 h
Yield: 19.2 %

Procedure:
Diphenyl chlorophosphate (10.9 microliter, 52.6 micromol) was added to a stirred, 0° C. solution of a p-nitrobenzyl 2-oxo-carbapenam-3-carboxylate (15.4 mg, 50.6 micromol), 4-dimethylaminopyridine (1.3 mg, 11 micromol), and diisopropylethylamine (10.4 microliter, 59.7 micromol) in anhydrous acetonitrile (500 microliter). After 5 min., potassium azide (12.6 mg, 155 micromol), and 1, 4, 7, 10, 13, 16-hexaoxacyclooctadecane (13.3 mg, 50.3 micromol) were added. After an additional 5 min. the mixture was washed three times with water, dried over anhydrous magnesium sulfate, filtered, and evaporated under vacuum. The residue was applied to one 20 cm×20 cm 250 micron silica gel preparative thin layer chromatography plate and developed with diethyl ether. Elution with ethyl acetate and evaporation of the eluate under vacuum provided 3.2 mg (19%) p-nitrobenzyl 2-azido-carbapen-2-em-3-carboxylate.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1.Cl([O-])(=O)(=O)=O.C[S+](C)C1C=CC=CC=1>N1C=CC=CC=1>[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: C1=COCC1
Agent: C[S+](C)c1ccccc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Yield: 58.3 %

Procedure:
In 10 ml of pyridine were dissolved 0.39 g of 5-fluorouracil and 0.42 g of 2,3-dihydrofuran. To the solution were added 72 mg of dimethylphenylsulfonium perchlorate and the mixture was reacted for 5 hours at 130° C. After the reaction, pyridine was distilled off under reduced pressure and 20 ml of water were added to the residue. The aqueous solution was treated with caustic soda to have a pH value of 10-11 and then washed with 20 ml of chloroform. The aqueous alkaline solution was treated while cold with diluted hydrochloric acid to adjust the pH value of the solution to 3.5 and then extracted three times with 20 ml of chloroform. The chloroform extract was dried and then the chloroform was distilled off. The residue was recrystallized from ethanol to obtain 0.35 g of 1-(2-tetrahydrofuryl)-5-fluorouracil. The yield was 58.3%.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].Br[CH2:7][CH2:8][O:9][CH2:10][CH2:11]Br.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[O:9]1[CH2:10][CH2:11][C:2]([C:1]#[N:5])([C:3]#[N:4])[CH2:7][CH2:8]1
Reactant: N#CCC#N
Reactant: BrCCOCCBr
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: N#CC1(C#N)CCOCC1
Temperature: 85 °C
Yield: 80.8 %

Procedure:
A mixture of malononitrile (0.991 g, 15 mmol), 1-bromo-2-(2-bromoethoxy)ethane (3.83 g, 16.50 mmol) and DBU (4.97 ml, 33.0 mmol) in DMF (6 ml) was heated at about 85° C. for 3 hours, and then cooled to ambient temperature. The mixture was concentrated in vacuo, the resulting residue was diluted with ethyl acetate, washed three times with water and dried overnight under high vacuum to yield the desired product as a light brown solid (1.65 g). GC-MS: 136 [M]; Retention time=5.76 min. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.14-2.32 (m, 4 H) 3.77-3.96 (m, 4 H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9](O)=[O:10].[BH4-].[Na+].Cl>COCCOCCOC.COC(C)(C)C.O>[F:15][C:14]1[CH:13]=[CH:12][C:8]([CH2:9][OH:10])=[CH:7][C:6]=1[Br:5]
Reactant: O=C(O)c1ccc(F)c(Br)c1
Agent: Cl
Agent: [Al+3]
Agent: [BH4-]
Solvent: COCCOCCOC
Solvent: O
Solvent: COC(C)(C)C
Product: OCc1ccc(F)c(Br)c1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 65.7 %

Procedure:
6.7 g of aluminum chloride were added to a solution of 10.9 g of 95% pure 3-bromo-4-fluorobenzoic acid in 150 ml of diglyme at 20° C. The reaction mixture was subsequently stirred at 20° C. for 10 minutes and 5.7 g of sodium borohydride were then added in portions at 20° to 25° C. After 12 hours, about 100 ml of water (vigorous foaming) and then about 1 ml of 10% strength hydrochloric acid were added dropwise. About 100 ml of tert.-butyl methyl ether were added and the organic phase was separated off. It was washed once with about 30 ml of saturated sodium bicarbonate solution. The ether phase was then concentrated. 6.7 g (76% of theory) of 4-fluoro-3-bromo-benzyl alcohol were obtained.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][NH2:23].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:23][O:22][CH3:21])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.334 g, 1.21 mmol) in DCM (25.0 mL) were added O-methylhydroxylamine 97 (0.193 g, 2.31 mmol), 1-hydroxybenzotriazole (0.25 g, 1.85 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.35 g, 1.82 mmol) and 4-di(methylamino)pyridine (0.34 g, 2.78 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue, which was subjected to chromatography to give (2S,5R)-6-(benzyloxy)-N-methoxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 98 (0.17 g, 46%) as a white foam.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C>[Pd].C1(C)C=CC=CC=1.O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH:11][C:10]([O:14][CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[O:13])=[CH:3][CH:4]=1
Reactant: C=CC(=O)OCC(CC)CCCC
Reactant: COc1ccc(I)cc1
Agent: [Pd]
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCC(CC)COC(=O)C=Cc1ccc(OC)cc1
Reaction time: 1 h
Yield: 92 %

Procedure:
A mixture of 4.68 g (20 mmol) of p-iodoanisole, 4.05 g (22 mmol) of 2-ethylhexyl acrylate, 2.22 g (22 mmol) of triethylamine, 1.32 g (22 mmol) of acetic add and 15 mg of palladium of charcoal (5%) is stirred at 150° C. After one hour it is established by gas chromatography that the reaction has been completed. The mixture is then treated at about 80° C. with water and toluene and the catalyst is filtered off. The organic phase is washed in sequence with 2N hydrochloric acid and water, dried over anhydrous sodium sulphate and concentrated under reduced pressure. After distillation there is obtained pure 2-ethylhexyl p-methoxycinnamate, b.p. about 185° C./0.3 Torr. The yield is 92% of theory. 1H-NMR (CDCl3, 200 MHz): 0.86-0.98 ppm (m, 6H), 1.25-1.72 ppm (m, 9H), 3.84 ppm (s, 3H), 4.11 ppm (d, 6 Hz, 2H), 6.32 ppm (d, 15.5 Hz, 1H), 6.85-6.95 ppm (duplettoid m, 1H), 7.44-7.54 ppm (duplettoid m, 1H), 7.64 ppm (d, 15.5 HZ, 1H).
Reaction SMILES: OS(O)(=O)=O.[C:6]([C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12])([CH3:9])([CH3:8])[CH3:7].[N+:17]([O-])([O-:19])=[O:18].[K+].BrC1N=CC=CC=1C(N)=O>O>[C:6]([C:10]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=1[NH2:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1ccccc1N
Reactant: O=[N+]([O-])[O-]
Agent: NC(=O)c1cccnc1Br
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1N
Temperature: -10 °C

Procedure:
To H2SO4 (98%, 389 mL) in a 500 mL 3-neck flask was added 2-tert-butyl aniline (40.6 mL). The reaction was cooled to −10° C. and KNO3 in 3.89 g aliquots was added every 6 min for a total of 10 aliquots. Tried to maintain temperature at −5° C. to −10° C. After final addition of KNO3, stirred the reaction for five min then it was poured onto ice (50 g). The black mix was diluted with H2O and extracted with EtOAc. The aqueous layer was basified with solid NaOH slowly then extracted with EtOAc (2×). The combined organic layers were washed with 6N NaOH and then with a mix of 6N NaOH and brine, dried over Na2SO4, filtered and concentrated in vacuo to obtain crude 2-tert-butyl-5-nitro-aniline as a dark red-black oil which solidified when standing at RT. The crude material was triturated with about 130 mL hexanes. After decanting the hexanes, the material was dried to obtain a dark-red black solid.
Reaction SMILES: [OH:1][C@H:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C>[O:1]([C@H:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CCOC(=O)C[C@@H](C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred, room temperature solution of ethyl (R)-3-hydroxybutanoate (5.00 g, 37.8 mmol) and tert-butyldimethylsilyl chloride (6.85 g, 45.5 mmol) in DMF (90 mL) was added imidazole (3.87 g, 56.9 mmol). This reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between hexane (300 mL) and water (100 mL). The organic layer was washed with water (2×100 mL) then dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[C:3]=1N.C(O)(C)C.[N+]([O-])(O)=O.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[CH:3]=1
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O=[N+]([O-])O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)cc(Cl)c1
Yield: 90 %

Procedure:
207 parts of 2,6-dichloro-4-nitro-aniline are introduced into 500 parts of isopropanol, and 780 parts of 65 percent strength by weight nitric acid are then added to the mixture. A solution of 125 parts of NaNO2 in 175 parts of water is run in at 50° C., as described in Example 1. The mixture is cooled, 400 parts of water are added and the product is filtered off. 172 parts (90% of theory) of 3,5-dichloro-nitro-benzene, of melting point 55°-57° C., are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[C:3]=1N.COCCO.S(=O)(=O)(O)O.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[CH:3]=1
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: COCCO
Product: O=[N+]([O-])c1cc(Cl)cc(Cl)c1
Yield: 92 %

Procedure:
207 parts of 2,6-dichloro-4-nitro-aniline are introduced into 500 parts of glycol monomethyl ether and 1,000 parts of 50 percent strength by weight sulfuric acid are then added to the mixture. 90 parts of NaNO2 in 150 parts of water are added slowly at 70° C. The mixture is cooled and the product is filtered off. 179 parts (92% of theory) of 3,5-dichloro-nitro-benzene, of melting point 56°-59° C., are obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1>C(Cl)Cl.[O-2].[Mn+2]>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH:8]=[O:9]
Reactant: Cc1c(Br)cccc1CO
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1c(Br)cccc1C=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
(3-bromo-2-methylphenyl)methanol was oxidized as follows: The alcohol (15 mmol) was dissolved in methylene chloride (30 mL). 10 equivalents of activated manganese oxide (IV) was added and the mixture stirred at room temperature for 24 hours. The mixture was filtered through a bed of celite and the solvent removed in-vacuo to leave yellow solid. Product was used crude in next step without further purification. The yield was 93%. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 9.8 (s, 1H) 8.1 (d, 1H) 7.7 (d, 1H), 7.2 (t, 1H), 2.4 (s, 3H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1([O:16][CH2:15][CH2:14][O:13]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH2:15]1[CH2:14][O:13][C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)([CH2:5][CH2:4][CH2:3][OH:2])[O:16]1
Reactant: COC(=O)CCC1(c2ccccc2)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCCCC1(c2ccccc2)OCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a solution of 1.7 g of the ester compound obtained in 20 ml of dry diethyl ether was added 0.7 g of lithium aluminum hydride under ice-cooling, the mixture was stirred for 1 hour at 0° C., and then heated under reflux for 17 hours. After cooling, the reaction mixture was treated successively with an aqueous diethyl ether solution and water, and the precipitate was filtered off. The filtrate was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: benzene/ethyl acetate=10/1 by volume) to obtain 1.3 g of 4,4-ethylenedioxy-4-phenylbutyl alcohol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:9]=1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:9]=1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cn1
Agent: [Ni]
Solvent: CO
Product: CCOC(=O)Cc1ccc(N)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl (5-nitropyridin-2-yl)acetate (2.40 g, 11.4 mmol), Raney-Ni (50 mg) in 100 mL of MeOH was stirred at room temperature overnight. The mixture was filtered and concentrated to give ethyl (5-aminopyridin-2-yl)acetate.
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH2:22])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH:22][C:29]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:30])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: O=C(Cl)C1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CN)cnc32)cc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)C4CCCCC4)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
To a suspension of crude (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (assumed 0.498 mmol) in DCM (10 mL) was added TEA (0.208 mL, 1.49 mmol) followed by cyclohexanecarbonyl chloride (0.101 mL, 0.747 mmol). The mixture was stirred for 30 min at rt and then was diluted with DCM and washed with saturated aqueous NaHCO3 (25 mL) and brine (25 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by silica gel chromatography eluting with a gradient of 40 to 80% EtOAc in DCM to provide N-((5-Tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarboxamide as a tan solid (0.081 g, 39%). LC/MS (Table 2, Method a) Rt=2.40 min; MS m/z: 413 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:9]=[CH:8]1.C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:25][C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:16])([CH3:17])[CH3:1])[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:9]=1
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cn(COCC[Si](C)(C)C)c(Br)n1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
Into a flask containing methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (4.0 g; 15.6 mmol) in CCl4 (100 ml), catalytic AIBN, NBS (3.1 g, 17.1 mmol) were added and stirred at 65° C. for 3 h. The reaction mixture was quenched with aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was concentrated and purified by column chromatography. Yield 3.5 g. 1H-NMR (400 MHz; DMSO-d6): δ 0.04 (s, 9H), 0.84 (t, 2H), 3.53 (t, 2H), 3.75 (s, 3H), 5.30 (s, 2H), 8.25 (s, 1H). LC-MS: [M+1]=335.01.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[C:7](Cl)(=[O:9])[CH3:8]>C1(C)C=CC=CC=1>[C:7]([N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1)(=[O:9])[CH3:8]
Reactant: Cc1c[nH]cn1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(=O)n1cnc(C)c1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A mixture of 50 g (609 mmol) of 4-methylimidazole in 250 ml of toluene was stirred at room temperature under nitrogen and 239 g (304 mmol) of acetyl chloride was added. The mixture was stirred at room temperature for 5 hours, filtered to remove insolubles and the filtrate concentrated giving 19 g (50%) of 1- acetyl-4-methyl-imidazole as a yellow oil which crystallizes on standing. nmr (CDCl3) (δ): 8.06 (s, 1H); 7.17 (s, 1H); 2.57 (s, 3H); 2.23 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-])=O)=[CH:4][CH:3]=1>C(O)(=O)C.CO.[Zn]>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc(Cl)nc1N
Reaction time: 18 h

Procedure:
Add zinc (4.0 g) to a solution of 6-chloro-3-nitropyridin-2-yl-amine (1.0 g, 5.76 mmol) in acetic acid (1.5 mL) and methanol (40 mL). Stir the resulting mixture is at room temperature for 18 hours, and filter through a pad of celite. Evaporate the filtrate to dryness under reduced pressure. Treat the resulting residue with 1N aqueous NaOH and extract with EtOAc. Wash the EtOAc extract with water and saturated aqueous NaCl. Separate the organic layer, dry over Na2SO4, filter and concentrate. Purify by flash column chromatography (50% EtOAc-hexane) to obtain 6-chloro-pyridine-2,3-diamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:19])[C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([Cl:17])[C:10]=1[Cl:18].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[Cl:18][C:10]1[C:11]([Cl:17])=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=1[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:19]
Reactant: COc1ccc(C(=O)c2ccccc2F)c(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(c1ccccc1F)c1ccc(O)c(Cl)c1Cl
Temperature: 0 °C

Procedure:
To a mixture of 38.5 g of 2'-fluoro-4-methoxy-2,3-dichlorobenzophenone and 34.7 g of aluminum chloride in 250 ml of benzene is refluxed for 5 hours, then poured over a mixture of 100 ml of concentrated hydrochloric acid and 100 ml of ice. The two-phase mixture is extracted with ethyl acetate and the combined extracts are dried and concentrated to dryness leaving a solid residue. The residue is triturated with hexane and the resulting solid is recrystallized from an ether-hexane mixture to yield the product 2,3-dichloro-4-hydroxy-2'-fluoro-benzophenone having a melting point of 128° to 131° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[C:4]=1[N:11]1[C:15]2=[N:16][CH:17]=[N:18][C:19]([O:20][C@@H:21]([CH2:32][O:33][C@H:34]([CH3:47])[CH2:35][O:36][Si](C(C)C)(C(C)C)C(C)C)[C:22]([NH:24][C:25]3[CH:30]=[N:29][C:28]([CH3:31])=[CH:27][N:26]=3)=[O:23])=[C:14]2[CH:13]=[N:12]1.C(=O)(O)[O-].[Na+]>CC(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[C:4]=1[N:11]1[C:15]2[N:16]=[CH:17][N:18]=[C:19]([O:20][C@@H:21]([CH2:32][O:33][C@H:34]([CH3:47])[CH2:35][OH:36])[C:22]([NH:24][C:25]3[CH:30]=[N:29][C:28]([CH3:31])=[CH:27][N:26]=3)=[O:23])[C:14]=2[CH:13]=[N:12]1
Reactant: Cc1cnc(NC(=O)[C@H](CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)Oc2ncnc3c2cnn3-c2c(Cl)cccc2C#N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1cnc(NC(=O)[C@H](CO[C@H](C)CO)Oc2ncnc3c2cnn3-c2c(Cl)cccc2C#N)cn1
Reaction time: 6 h
Yield: 84 %

Procedure:
Hydrochloric acid (6M, 4 equivs) was added with stirring to a solution of (2S)-2-(1-(2-chloro-6-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyrazin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate AZ1) (1 equiv) in propan-2-ol (9 rel vols) in an inert atmosphere at ambient temperature. The mixture was stirred for 6 hours then basified carefully with aqueous sodium bicarbonate solution. The volume was reduced to half of the original volume by distillation under reduced pressure and then ethyl acetate and water were added. The mixture was stirred and then the phases were separated. The aqueous phase was extracted with ethyl acetate and the combined organic extract and washings were dried by azeotropic distillation. The product was crystallised from a mixture of ethyl acetate/heptane (5:6 vols). Yield 84%.